2003 Canadian

December 2003 Volume 27 Supplement 2
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Canadian Journal of Diabetes

Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada
A Publication of the Professional Sections of the Canadian Diabetes Association
December 2003 Volume 27 Supplement 2

Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada
A Publication of the Professional Sections of the Canadian Diabetes Association
2003 CLINICAL PRACTICE GUIDELINES
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TABLE OF CONTENTS Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada
Notes to Readers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii Clinical Practice Guidelines Committees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S4 Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories . . . . . . . . . S7 Screening and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S10 Organization and Delivery of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S14 Management Targets for Glycemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18 Monitoring Glycemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S21 Physical Activity and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S24 Nutrition Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S27 Insulin Therapy in Type 1 Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32 Pharmacologic Management of Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37 Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S43 Management of Obesity in Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S46 Psychological Aspects of Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50 Influenza and Pneumococcal Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53 Pancreas and Islet Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S55 Complications Macrovascular Complications, Dyslipidemia and Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58 Nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66 Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72 Foot Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S74 Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S76 Erectile Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81 Diabetes in Special Populations Type 1 Diabetes in Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S84 Type 2 Diabetes in Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91 Pre-existing Diabetes and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S94 Gestational Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
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Diabetes in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106 Type 2 Diabetes in Aboriginal Peoples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S110 Perioperative Glycemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113 Peri-acute Coronary Syndrome Glycemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S115 Appendices Appendix 1: Etiologic Classification of Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118 Appendix 2: History and Examination: Initial and Follow-up Visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119 Appendix 3: Sample Diabetes Patient Care Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122 Appendix 4: Self-monitoring of Blood Glucose (SMBG) Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125 Appendix 5: Basic Carbohydrate Counting for Diabetes Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S126 Appendix 6: The Glycemic Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S128 Appendix 7: Zimbabwe Hand Jive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S130 Appendix 8: Just the Basics:Tips for Healthy Eating, Diabetes Management and Prevention. . . . . . . . . . . . . . . . . . S131 Appendix 9: Insulin Initiation Options in People With Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S135 Appendix 10: Level of Urinary Albumin by Various Test Methods and Stage of Diabetic Nephropathy . . . . . . . . . . . . S136 Appendix 11: Approach to Therapeutics in Diabetic Nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S137 Appendix 12: Diabetes and Foot Care:A Patients Checklist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S138 Appendix 13: Comorbid Conditions in Children With Type 1 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S139 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S141 NOTES TO READERS Overview The Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada are intended to guide practice and are not intended to serve as a comprehensive text on diabetes management. Healthcare professionals must consider the needs, values and preferences of individual patients, use clinical judgement, and work with available human and healthcare service resources in their settings.These guidelines were developed using the best available evidence. It is incumbent upon healthcare professionals to stay current in this rapidly changing field. Unless otherwise specified, these guidelines pertain to the care of adults with diabetes.Two pediatric chapters are included to highlight aspects of care that must be tailored to the pediatric population. Suggested Citation Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2003;27(suppl 2):[inclusive page range of relevant chapter, or entire document]. Reproduction of the Guidelines Reproduction of the Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada in whole or in part is prohibited without written consent of the publisher. Extra Copies Copies of this document may be purchased, for a nominal fee, from the Canadian Diabetes Association (1-800-BANTING). Website These guidelines are also available online at http://www.diabetes.ca.
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Clinical Practice Guidelines Committees

The Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada were developed under the auspices of the Clinical & Scientific Section of the Canadian Diabetes Association.
Executive Committee
Stewart B. Harris MD MPH FCFP FACPM (Chair) Associate Professor, Department of Family Medicine, University of Western Ontario, London, Ontario Sarah E. Capes MD MSc FRCPC Assistant Professor, Department of Medicine, McMaster University, Hamilton, Ontario Donna Lillie RN BA CHE Vice President, Research & Professional Education, Canadian Diabetes Association,Toronto, Ontario
Steering Committee
Cynthia N. Lank BSc(Hon) (Executive Editor) Halifax, Nova Scotia Jeffrey Mahon MD MSc FRCPC Associate Professor of Epidemiology and Biostatistics, and Medicine, University of Western Ontario, London, Ontario Joan Erickson RN BSN CDE Coordinator, Diabetes Programs, Central and South Okanagan, Interior Health Authority, Penticton, British Columbia
Keith G. Dawson MD PhD FRCPC Sub-group Chair, Management Professor (Emeritus) of Medicine, Division of Endocrinology, University of British Columbia, Vancouver, British Columbia Hertzel C. Gerstein MD MSc FRCPC Sub-group Chair, Methods Professor, Departments of Medicine and Clinical Epidemiology and Biostatistics Director, Division of Endocrinology and Metabolism Population Health Institute Chair in Diabetes Research (sponsored by Aventis), McMaster University and Hamilton Health Sciences, Hamilton, Ontario Amir Hanna MB BCh FRCPC FACP Professor, Department of Medicine, University of Toronto, Toronto, Ontario Deputy Director, Division of Endocrinology and Metabolism, St. Michaels Hospital,Toronto, Ontario Robyn Houlden MD FRCPC Sub-group Chair, Microvascular Complications Associate Professor, Division of Endocrinology, Queens University, Kingston, Ontario Lawrence A. Leiter MD FRCPC FACP Sub-group Chair, Macrovascular Complications Professor of Medicine and Nutritional Sciences, University of Toronto,Toronto, Ontario Head, Division of Endocrinology and Metabolism, St. Michaels Hospital,Toronto, Ontario
Sora Ludwig MD FRCPC Sub-group Chair, Organization of Care Associate Professor, Section of Endocrinology and Metabolism, Department of Internal Medicine, University of Manitoba,Winnipeg, Manitoba Medical Advisor, Diabetes and Chronic Diseases Unit, Manitoba Health,Winnipeg, Manitoba Sara J. Meltzer MD FRCPC Sub-group Chair, Pregnancy Associate Professor of Medicine and Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec Staff Endocrinologist, Royal Victoria Hospital, Montreal, Quebec David Miller MD FRCPC Sub-group Chair, Dissemination Victoria, British Columbia Richard Rowe MBBS MAEd FRCPC Division of Endocrinology, Dalhousie University, Halifax, Nova Scotia Ehud Ur MB FRCP Sub-group Chair, Definition and Classification Sub-group Chair, Screening and Prevention Head, Division of Endocrinology, Dalhousie University, Halifax, Nova Scotia
Jean-Franois Yale MD CSPQ Professor of Medicine, McGill University, Montreal, Quebec
Bernard Zinman MDCM Director, Leadership Sinai Centre for Diabetes, Mount Sinai Hospital,Toronto, Ontario Professor of Medicine, University of Toronto, Toronto, Ontario
Expert Committee
Iain S. Begg MB FRCS (Edin) FRCSC University of British Columbia,Vancouver, British Columbia Gillian L. Booth MD MSc FRCPC Division of Endocrinology and Metabolism, St. Michaels Hospital,Toronto, Ontario Assistant Professor, Department of Medicine, University of Toronto,Toronto, Ontario Sharon Brez RN BScN MA(Ed) CDE Advanced Practice Nurse, Department of Endocrinology and Metabolism,The Ottawa Hospital, Ottawa, Ontario Vera Bril MD FRCPC Professor of Medicine, University of Toronto, Toronto, Ontario Director of Clinical Neurophysiology, University Health Network,Toronto, Ontario Alice Y.Y. Cheng MD FRCPC Division of Endocrinology and Metabolism, St. Michaels Hospital,Toronto, Ontario University of Toronto,Toronto, Ontario Maureen Clement MD CCFP Medical Director, Diabetes Education,Vernon Jubilee Hospital,Vernon, British Columbia Clinical Assistant Professor, University of British Columbia, Vernon, British Columbia Catherine L. Cook MD MSc CCFP Medical Officer of Health,Winnipeg Regional Health Authority,Winnipeg, Manitoba Denis Daneman MB BCh FRCPC Professor of Pediatrics, University of Toronto, Toronto, Ontario Chief, Division of Endocrinology,Associate Chief of Research, The Hospital for Sick Children,Toronto, Ontario Heather Dean MD FRCPC Professor of Pediatrics, Department of Pediatrics, University of Manitoba,Winnipeg, Manitoba Peggy Dunbar MEd PDt CDE Coordinator, Diabetes Care Program of Nova Scotia, Halifax, Nova Scotia
Denice S. Feig MD MSc FRCPC Assistant Professor, University of Toronto, Toronto, Ontario Staff Endocrinologist, Mount Sinai Hospital, Toronto, Ontario Catherine Field RD PhD Professor, University of Alberta, Edmonton, Alberta Catherine Freeze RD CDE Provincial Diabetes Coordinator, Health Policy Development, Government of Prince Edward Island, Charlottetown, Prince Edward Island Rjeanne Gougeon PhD McGill Nutrition and Food Science Centre, Montreal, Quebec Steven Grover MD MPA FRCPC Montreal General Hospital, Montreal, Quebec McGill University, Montreal, Quebec Dereck Hunt MD MSc FRCPC Assistant Professor, McMaster University, Hamilton, Ontario Helen Jones RN MSN CDE Clinical Nurse Specialist/Manager, Leadership Sinai Centre for Diabetes, Mount Sinai Hospital,Toronto, Ontario University of Toronto,Toronto, Ontario Tina Kader MD FRCPC CDE Assistant Professor, Endocrinology and Internal Medicine, McGill University, Jewish General Hospital, Montreal, Quebec Glen P. Kenny PhD Associate Professor, Faculty of Health Sciences, School of Human Kinetics, University of Ottawa, Ottawa, Ontario Affiliate Investigator, Ottawa Health Research Institute, Ottawa, Ontario Maria Kraw MD FRCPC Toronto, Ontario David C.W. Lau MD PhD FRCPC Departments of Medicine, Biochemistry and Molecular Biology, and Julia McFarlane Diabetes Research Centre, University of Calgary, Calgary, Alberta
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Gary Lewis MD FRCPC Toronto General Hospital,Toronto, Ontario University of Toronto,Toronto, Ontario Sarah Lawrence MD FRCPC Pediatric Endocrinologist, Assistant Professor of Pediatrics, University of Ottawa, Ottawa, Ontario Margaret L. Lawson MD MSc FRCPC Associate Professor of Pediatrics, University of Ottawa, Ottawa, Ontario Chief, Division of Endocrinology and Metabolism, Childrens Hospital of Eastern Ontario, Ottawa, Ontario Ann C. Macaulay MD CCFP FCFP Associate Professor, Family Medicine, McGill University, Montreal, Quebec Philip McFarlane MD FRCPC Medical Director, Home Dialysis, Division of Nephrology, St. Michaels Hospital, University of Toronto, Toronto, Ontario Graydon Meneilly MD FRCPC Professor and Head, Department of Medicine, University of British Columbia,Vancouver, British Columbia Teik Chye Ooi MBBS FRCPC FRACP FACE Professor of Medicine and Head, Division of Endocrinology and Metabolism,The Ottawa Hospital, University of Ottawa, Ottawa, Ontario Danile Pacaud MD FRCPC Assistant Professor, Department of Pediatrics, University of Calgary, Calgary, Alberta Bruce Perkins MD MPH FRCPC Assistant Professor, University of Toronto,Toronto, Ontario Division of Endocrinology, University Health Network, Toronto, Ontario Robert Petrella MD PhD Associate Professor, Family Medicine and Kinesiology, University of Western Ontario, London, Ontario Sidney B. Radomski MD FRCSC Associate Professor of Surgery (Urology), University of Toronto,Toronto, Ontario Toronto Western Hospital (University Health Network), Toronto, Ontario
Edmond A. Ryan MD FRCPC Professor, University of Alberta, Edmonton, Alberta Ronald J. Sigal MD MPH FRCPC Associate Professor of Medicine and Human Kinetics, University of Ottawa, Ottawa, Ontario Scientist, Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Ontario Jennifer Snyder PDt MSc Clinical Dietitian, McGill University Health Centre, Montreal, Quebec George Steiner MD FRCPC Toronto General Hospital, University of Toronto, Toronto, Ontario Daniel Tessier MD MSc Professor and Head of Geriatrics, Faculty of Medicine, Sherbrooke University, Sherbrooke, Quebec David Thompson MD FRCPC Division of Endocrinology,Vancouver Hospital and B.C.Womens Hospital,Vancouver, British Columbia Kansuda Thongthai MD FRCPC McGill Nutrition and Food Science Centre, Montreal, Quebec Sheldon Tobe MD FRCPC Division of Nephrology, Sunnybrook and Womens College Health Sciences Centre, University of Toronto, Toronto, Ontario Ellen L.Toth MD FRCPC Professor, Department of Medicine, University of Alberta, Edmonton, Alberta T. Michael Vallis PhD Psychologist, QEII Health Sciences Centre, Halifax, Nova Scotia Associate Professor, Dalhousie University, Halifax, Nova Scotia Thomas Wolever MD PhD Professor and Acting Chair, Department of Nutritional Sciences, University of Toronto,Toronto, Ontario Vincent Woo MD FRCPC Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba
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Acknowledgements
Financial assistance for the Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada is generously provided by the following sponsors, in the form of unrestricted educational grants. Sponsors were not involved in any aspect of guidelines development, literature interpretation, the decision to publish, or any other aspect of publication of the guidelines.
Primary Sponsors Abbott Laboratories, Ltd. Aventis Pharma Inc. Bayer Diagnostics Inc. Eli Lilly Canada Inc. GlaxoSmithKline Inc. Hoffmann-La Roche Ltd. LifeScan Canada Ltd. Merck Frosst/Schering Pharmaceuticals Novo Nordisk Canada Inc. Secondary Sponsors Merck Frosst Canada Ltd. Novartis Pharmaceuticals Canada Inc.
SPECIAL THANKS Karen Derrah BSc(Hon),Toronto, Ontario, for her outstanding copy editing and proofreading skills. Michael Lillie,Toronto, Ontario, for his assistance in locating literature references. Sandra Micucci PhD, Hamilton, Ontario, for her assistance with referencing and the evidence-based review process. Elizabeth Neilly, Coordinator, Administrative Services, Research & Professional Education, Canadian Diabetes Association,Toronto, Ontario, for her superb organizational skills.
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Official Journal of the Professional Sections of the Canadian Diabetes Association
Editor-in-Chief Heather J. Dean MD FRCPC Associate Editors Patricia Brubaker PhD Robyn Houlden MD Alexandra Jenkins RD David Lau MD PhD Beth Mitchell PhD CPsych Liam J. Murphy MB PhD Ehud Ur MB FRCP Jean-Franois Yale MD CSPQ National Editorial Board Jean-Louis Chiasson MD Denis Daneman MB BCh FRCPC John Dupr MD BM BCH FRCPC FACP George Fantus MD FRCPC
Marcia Frank RN MHSc CDE Hertzel Gerstein MD FRCPC Doreen Hatton RN BSN MSN Debbie Hinnen RN MN ARNP CDE Helen Jones RN MSN CDE Daniel Metzger MD FAAP FRCPC Edmond Ryan MD FRCPI DCH FRCPC Hugh Tildesley MD FRCPC Bernard Zinman MDCM International Editorial Board Stephanie Amiel MD FRCP Barbara J. Anderson PhD Alan Baron MD Stuart J. Brink MD Suad Efendic MD PhD George Eisenbarth MD PhD Martha Funnell RN MS CDE
Diana Guthrie PhD RN CDE Phillipe Halban PhD Len Harrison MD DSc FRACP FRCPA Robert Henry MD Cheri Ann Hernandez RN PhD CDE Margaret Hume RN MScN CDE Ryuzo Kawamori MD PhD Karmeen Kulkarni RD MS CDE Willy Malaisse MD PhD Kathy Mulcahy RN MSN CDE Stephen ORahilly MD FRCOI FRCF Daniel Porte, Jr. MD Paul Robertson MD Alicia Schiffrin MD Meng Tan MD FACP FRCPC Kerstin Ternulf-Nyhlin RN MS CDE Virginia Valentine RN MS CDE Paul Zimmett AM
Managing Editor Fiona Hendry E-mail: fiona.hendry@diabetes.ca Assistant Editor Lisa Durante E-mail: lisa.durante@diabetes.ca
Advertising Sales Keith Health Care Telephone: (905) 278-6700 Design/Production Dorothy Siemens Design
Members of the Professional Sections of the Canadian Diabetes Association receive Canadian Journal of Diabetes as part of membership. Subscriptions: $35.00 per year in Canada; $50.00 for US orders; $75.00 outside North America (all prices include GST). Canadian Journal of Diabetes is published on a quarterly basis in March, June, September and December by the Professional Sections of the Canadian Diabetes Association, 15 Toronto Street, Suite 800,Toronto, Ontario, M5C 2E3. Reproduction of this journal in whole or in part is prohibited without written consent of the publisher. ISSN 1499-2671. Canadian Journal of Diabetes is indexed in CINAHL and EMBASE. Opinions expressed in articles published in Canadian Journal of Diabetes are those of the authors and do not imply policy of Canadian Diabetes Association or the Professional Sections unless so stated. Advertisements should not be construed as endorsement by Canadian Diabetes Association or the Professional Sections. Canadian Diabetes Association is a nonprofit organization. Charitable Number 11883 0744 RR0001. Donations qualify for a charitable tax credit. Telephone: (416) 363-3373 Fax: (416) 363-7465 Website: http://www.diabetes.ca
I N T RO D U C T I O N
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Introduction
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee
RATIONALE FOR REVISION OF THE 1998 CLINICAL PRACTICE GUIDELINES The 1998 Clinical Practice Guidelines for the Management of Diabetes in Canada (1), developed by the Clinical & Scientific Section of the Canadian Diabetes Association, were the first comprehensive, evidence-based, clinical practice guidelines for diabetes care that allowed readers to independently judge the value of the diagnostic, prognostic and therapeutic recommendations (2). Recently published evidence relevant to the prevention and management of diabetes mellitus justified a complete review of the 1998 recommendations. The Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada were drafted over a 2-year period by a volunteer Expert Committee representing key stakeholders across Canada. The process included a broad-based review to ensure that the diabetes community at large had input into the document. Canada is actively evaluating the structure and guiding principles of its healthcare system (3,4). The need to ration and appropriately allocate healthcare resources is now more commonly accepted (3-5). As the practice of medicine in Canada shifts to an evidence-based model, healthcare professionals will be under increasing pressure to update and incorporate new strategies and information into their practices. With healthcare budgets at the top of the Canadian political agenda, governments require justification of healthcare expenditures. Evidence-based guidelines will inevitably be used in funding decisions (6), and as the trend toward improved cost and efficiency in healthcare delivery continues, so will the need for guidelines (2,7). A GROWING HEALTHCARE PROBLEM Diabetes is a common chronic disease, and type 2 diabetes, which accounts for the vast majority of cases, has become a public health issue that is increasing significantly worldwide. The most recent available Canadian data (from the National Diabetes Surveillance Strategy [NDSS]) indicate that in 1998/1999, the physician-diagnosed prevalence of diabetes in adults (people 20 years of age) was 4.8% (approximately 1 054 100 people) (8). However, population-based studies The initial draft of this chapter was prepared by Stewart B. Harris MD MPH FCFP FACPM.
have identified prevalence rates to be 30 to 50% higher (9-11), suggesting that the true prevalence may be >7%. A number of factors predispose individuals to type 2 diabetes, including heredity, age, ethnicity and socioeconomic status. Population-specific prevalence data reveal a higher burden of disease and increasing rates of complications among certain ethnic groups (12-15). The highest rates of diabetes are seen in the lower income quintiles (16). In the 1998/1999 National Population Health Survey (17), 21.4% of people with diabetes reported low income (vs. 12.8% in the general population) and 42.7% reported not finishing secondary school (vs. 22.5% in the general population). People in lower income brackets and with fewer years of formal education also report higher rates of smoking, less physical activity and higher rates of overweight (17,18), with the latter 2 factors being major precursors of, and modifiable risk factors for, diabetes. Demographic trends that will contribute to an increased prevalence of diabetes in Canada include an aging population (19), increasing immigration from high-risk populations (20) and growth in the Aboriginal population (21), all of which will dramatically affect health service requirements in the acute, chronic and home care sectors (8,22). Primary care providers will have to care for increasing numbers of patients with diabetes who will live longer and with more advanced stages of the disease (16). The increasing prevalence of obesity (23) in the Western World will also result in an increase in the burden of diabetes. Some authors have speculated that increases in childhood obesity and low levels of physical activity will constitute the public health crisis of the 21st century (24,25). Diabetes is costly to both the affected individual and to society. Recent data from Ontario, Canada, indicate that diabetes shortens life spans by an average of 13 years (12). People with diabetes also have medical expenditures that are approximately 2.4 times higher than would be incurred if they did not have diabetes (26). Economic analyses of the costs of diabetes to the Canadian healthcare system have produced estimates that vary widely; however, 1 recent study calculated that the economic cost of diabetes in Canada in 1998 was between US $4.76 and $5.23 billion (27). The annual direct medical costs associated with diabetes care for patients just diagnosed with diabetes, before considering any complications, were US $573 million. Of the complications
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of diabetes, cardiovascular disease (CVD) was by far the costliest (US $637 million), highlighting the importance of CVD prevention in patients with diabetes (27). The direct medical and indirect productivity-related costs of diabetes in the United States (US) for 2002 were recently estimated at US $132 billion (26), representing an approximately 35% increase since 1997. Given the increase over a 5-year period in the US, the 1998 Canadian figures quoted above likely underestimate the true financial burden of the disease. While the prevention of and cure for type 1 diabetes remain elusive, encouraging data have emerged since publication of the 1998 Clinical Practice Guidelines for the Management of Diabetes in Canada demonstrating that type 2 diabetes can be prevented (28-31). Canadian research is urgently needed to define effective strategies, tailored to specific populations, to prevent and treat obesity and to encourage physical activity. Health promotion and disease prevention strategies must also include thoughtful and coordinated government policies aimed at addressing poverty and other systemic barriers to health (3,5,18,32). ADVOCACY AND ACCESS TO CARE All people with diabetes should be assessed on a case-by-case basis and should not be subject to blanket discrimination in any life circumstance (e.g. education, employment, drivers licensing, insurance) because of diabetes.The healthcare system should recognize the rights of people with diabetes by striving to include them in healthcare delivery planning, and ensuring that they have timely, affordable and ongoing access to diabetes education, comprehensive treatment services provided by qualified professionals, and appropriate access to pharmaceuticals and medical devices that can improve quality of life. Such access may also prevent future interventions that are more costly and less effective. In addition, governments should commit to a strategy to ensure that the costs of medications and supplies for the management of diabetes and diabetes-related complications are not a burden to the individual or a barrier to managing the disease. DISSEMINATION AND TRANSLATION OF GUIDELINES Practitioners have been inundated with clinical practice guidelines during the last decade. While the effect of guidelines on family practice has been underresearched, studies on this topic have shown that guidelines have often fallen short of their intended objective to improve patient care and health outcomes (7,33,34).Therefore, the publication of guidelines should be seen as the starting point, rather than the end point, of their development and dissemination (6). The challenges of effective dissemination and implementation of guidelines were identified by the Expert Committee, and a dissemination strategy was developed concurrently with the development of the guidelines. The current guidelines have incorporated appendices and clinical and patient tools,
and identified additional resources to help clinicians adopt and implement evidence-based recommendations. In addition, the web-based version of the guidelines will be fully searchable, and will include relevant links, online risk engines and other web-based resources. Technical reviews and summary articles in subspecialty journals are planned to reach key target audiences. Evidence about prevention and management will also be translated into messages targeted to the general public and people with diabetes. CONCLUSION Ongoing provincial and national monitoring of people with diabetes are now possible with the establishment of the NDSS. Data generated by the NDSS will facilitate the determination of epidemiological trends, the effect of the disease on healthcare resource utilization and economic impact. A better understanding of these issues is needed to help direct healthcare policy as it relates to diabetes. In addition, existing diabetes care models need to be formally evaluated to ensure that they effectively address the needs of people with or at risk of diabetes. The care of people with diabetes is complex.These guidelines are not intended to be a textbook on diabetes care, but rather a useful reference to help translate evidence into practice and to help direct policy. Research and new technologies and therapeutics are rapidly expanding our knowledge of and ability to manage diabetes and its related complications.This and the burgeoning worldwide epidemic make it incumbent upon healthcare professionals to remain current in this everchanging field. REFERENCES
1. Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ. 1998;159(suppl 8):S1-S29. 2. Haynes RB, Gerstein HC.What is evidence? In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:1-12. 3. Romanow RJ. Building on Values. The Future of Health Care in CanadaFinal Report. Ottawa, ON: Commission on the Future of Health Care in Canada; 2002. Publication CP32-85/2002EIN. Available at: http://www.hc-sc.gc.ca/english/care/ romanow/hcc0023.html. Accessed November 7, 2003. 4. Standing Senate Committee on Social Affairs, Science and Technology. The Health of CanadiansThe Federal Role.Volume Six: Recommendations for Reform. Ottawa, ON: The Senate; 2002. Available at: http://www.parl.gc.ca/37/2/parlbus/commbus/ senate/Com-e/SOCI-E/rep-e/repoct02vol6-e.htm.Accessed November 7, 2003. 5. Vinicor F. New models of diabetes healthcare delivery. Can J Diabetes Care. 2001;25(suppl 2):24-30. 6. Harris S,Webster-Bogaert S, Lillie D, et al. A model for the dissemination of clinical practice guidelinesthe Canadian Diabetes Association experience. Can J Diabetes Care. 2000;24:64-69.
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S3 7. Harris SB,Webster-Bogaert S. Evidence-based clinical practice guidelines. In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:48-61. 8. Health Canada. Diabetes in Canada. 2nd ed. Ottawa, ON: Centre for Chronic Disease Prevention and Control, Population and Public Health Branch, Health Canada; 2002. Available at: http://www.hc-sc.gc.ca/pphb-dgspsp/publicat/ dic-dac2/english/01cover_e.html.Accessed November 7, 2003. 9. Leiter LA, Barr A, Blanger A, et al. Diabetes Screening in Canada (DIASCAN) Study: prevalence of undiagnosed diabetes and glucose intolerance in family physician offices. Diabetes Care. 2001;24:1038-1043. 10. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 19881994. Diabetes Care. 1998;21:518-524. 11. Dunstan DW, Zimmet PZ,Welborn TA, et al.The rising prevalence of diabetes and impaired glucose tolerance: the Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care. 2002;25:829-834. 12. Manuel DG, Schultz SE. Diabetes health status and risk factors. In: Hux JE, Booth GL, Slaughter PM, et al, eds. Diabetes in Ontario. An ICES Practice Atlas. Toronto, ON: Institute for Clinical Evaluative Sciences; 2003:4.77-4.94. Available at: http://www.ices.on.ca. Accessed November 7, 2003. 13. First Nations and Inuit Regional Health Survey: National Report 1999. St. Regis, QC: First Nations and Inuit Regional Health Survey National Steering Committee; 1999. Available at: http://www.afn.ca/Programs/Health%20Secretariat/PDFs/ title.pdf. Accessed November 7, 2003. 14. Shah BR, Hux JE, Zinman B. Increasing rates of ischemic heart disease in the Native population of Ontario, Canada. Arch Intern Med. 2000;160:1862-1866. 15. Anand SS,Yusuf S, Vuksan V, et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet. 2000;356:279-284. 16. Hux JE, Tang M. Patterns of prevalence and incidence of diabetes. In: Hux JE, Booth GL, Slaughter PM, et al, eds. Diabetes in Ontario. An ICES Practice Atlas. Toronto, ON: Institute for Clinical Evaluative Sciences; 2003:1.1-1.18. Available at: http://www.ices.on.ca. Accessed November 7, 2003. 17. Statistics Canada. National Population Health Survey Household Component Longitudinal, 19981999. Ottawa, ON: Statistics Canada; 2000. Available at: http://www.statcan.ca/ english/sdds/3225.htm#17214_3.Accessed November 7, 2003. 18. Raphael D. Inequality is Bad for Our Hearts. Why Low Income and Social Exclusion are Major Causes of Heart Disease in Canada. Toronto, ON: North York Heart Health Network; 2001. Available at: http://www.turningpointprogram.org/Pages/ heartFullReport.pdf. Accessed November 7, 2003. 19. Statistics Canada. Profile of the Canadian Population by Age and Sex: Canada Ages. Ottawa, ON: Statistics Canada; 2002. Publication 96F0030XIE2001002.Available at: http://www12. statcan.ca/english/census01/Products/Analytic/companion/ age/contents.cfm. Accessed November 7, 2003. Statistics Canada. Canadas Ethnocultural Portrait: The Changing Mosaic. Ottawa, ON: Statistics Canada; 2003. Publication 96F0030XIE2001008. Available at: http://www12.statcan.ca/ english/census01/Products/Analytic/companion/etoimm/ contents.cfm. Accessed November 7, 2003. Statistics Canada. Aboriginal Identity Population (3), Registered Indian Status (3),Age Groups (11B),Sex (3) and Area of Residence (7) for Population, for Canada, Provinces and Territories, 2001 Census 20% Sample Data (Aboriginal Peoples of Canada). Ottawa, ON: Statistics Canada; 2003. Publication 97F0011XCB2001005. Available at: http://www/statcan.ca/english/IPS/Data/ 97F0011XIE2001006.htm. Accessed November 7, 2003. Amos AF, McCarty DJ, Zimmet P.The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med. 1997;14(suppl 5):S1-S85. Mokdad AH, Bowman BA, Ford ES, et al.The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286:1195-1200. Troiano RP, Flegal KM. Overweight children and adolescents: description, epidemiology, and demographics. Pediatrics. 1998;101:497-504. Tremblay MS, Willms JD. Secular trends in the body mass index of Canadian children. CMAJ. 2000;163:1429-1433. American Diabetes Association. Economic costs of diabetes in the U.S. in 2002. Diabetes Care. 2003;26:917-932. Dawson KG, Gomes D, Gerstein H, et al. The economic cost of diabetes in Canada, 1998. Diabetes Care. 2002;25:1303-1307. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345:790-797. Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344:1343-1350. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance.The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537-544. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. Epp J. Achieving Health for All: A Framework for Health Promotion. Ottawa, ON: Health Canada; 1986. Available at: http://www. frcentre.net/library/AchievingHealthForAll.pdf. Accessed November 7, 2003. Harris SB, Stewart M, Brown JB, et al. Type 2 diabetes in family practice. Room for improvement. Can Fam Physician. 2003;49:778-785. Worrall G, Chaulk P, Freake D.The effects of clinical practice guidelines on patient outcomes in primary care: a systematic review. CMAJ. 1997;156:1705-1712.
20.
21.
22.
23.
24.
25. 26. 27. 28.
29.
30.
31.
32.
33.
34.
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Methods
PROCESS Following the process used to develop the 1998 Clinical Practice Guidelines for the Management of Diabetes in Canada, a Steering Committee with broad expertise was assembled. The relevant literature was evaluated and guidelines were developed and reviewed by an Expert Committee of 61 members representing key stakeholders. Several basic principles were followed as these guidelines were developed and revised. These were adopted to ensure that the values and empirical basis underlying each recommendation were explicitly identified, and to facilitate the critical scrutiny and analysis of each recommendation by other organizations and individuals. Each recommendation had to address a clinically important question related to 1 or more of the prevention, detection or management of diabetes mellitus and its sequelae. Whenever possible, each recommendation had to be justified by the strongest clinically relevant, empirical evidence that could be identified; the citation(s) reporting this evidence had to be noted adjacent to the relevant guideline. The strength of this evidence, based on prespecified criteria from the epidemiological literature and other guidelines processes had to be noted (1-6). This evidence had to be incorporated into a recommendation that was assigned a grade based on the available evidence, its strength, and its applicability. Guidelines based on biological or mechanistic reasoning, expert opinion, or consensus had to be explicitly identified and graded as such. IDENTIFYING AND APPRAISING THE EVIDENCE For each recommendation being developed or revised, the expert reviewer was asked to explicitly define: a) a set of objectives; b) the population to which the guideline would apply; c) the test, risk factor or intervention being addressed; and d) the clinically relevant outcomes being targeted. Following a comprehensive search of the relevant published, peer-reviewed literature, key citations were reviewed and The initial draft of this chapter was prepared by Hertzel C. Gerstein MD MSc FRCPC.
assigned a level of evidence relevant to the objective of the recommendation (Table 1).This level was determined by the cited papers objectives, methodological rigor, susceptibility to bias and generalizability. Because they could not be critically appraised, meeting abstracts, narrative review articles, news reports and other sources were not included in this process. GRADING THE RECOMMENDATIONS After identifying and assessing the evidence in support of a recommendation, the recommendation was assigned a grade from A through D (Table 2). The assigned grade reflected 3 inputs that are listed in order from the most to the least influential: 1) the level of evidence in support of the recommendation; 2) the applicability of the evidence to a Canadian population; and 3) the consensus of the Steering and Executive Committees.The highest possible grade that a recommendation could have was based on the level of evidence. Thus, if a recommendation was based on Level 1 evidence, deemed to be very applicable to Canadians and was supported by strong consensus, it was assigned a grade of A. If it was not deemed to be applicable to Canadians, or was judged to require further supporting evidence, it was assigned a lower grade. Finally, if there was no supportive Level 1, 2 or 3 evidence, or the recommendation was based on the consensus of the Steering and Executive Committees, the highest grade that could be assigned was D. It is important to note that the system chosen for grading recommendations differs from the approach used in some other guidelines documents, such as the one pertaining to the periodic health examination in Canada, in which harmful practices were assigned a grade of D (7). In this Canadian Diabetes Association clinical practice guidelines document, recommendation to avoid any harmful practices would be graded according to the scheme described above. People with diabetes are at high risk for several sequelae that are not exclusive to diabetes (e.g. cardiovascular diseases, renal failure and erectile dysfunction). As such, some evidence relating to these problems was identified that either excluded, did not report on, or did not focus on people with diabetes.Whenever such evidence was identified, a level was assigned using the approach described above. Higher levels were assigned if: a) people with diabetes comprised a predefined subgroup; b) the results in the diabetes subgroup were unlikely to have occurred by chance; and c) the evidence was
S5
generated in response to questions that were formulated prior to the analysis of the results. The degree to which this evidence is relevant to diabetes was embedded in the wording and grading of the recommendation. Finally, several treatment recommendations were based on evidence generated from the use of 1 example of a class of therapeutic agents (e.g. 1 of the statins). Whenever evidence relating to agents that clearly belonged to a recognized class of agents was available, the Expert Committee developed a recommendation relevant to the class, and identified within the recommendation the agent(s) specifically tested. REVIEW OF THE GUIDELINES Submissions were reviewed by the Executive and Steering Committees as they were being developed. In October 2002, a set of selected draft recommendations was presented in a public forum at the Canadian Diabetes Association/ Canadian Society of Endocrinology and Metabolism
Professional Conference and Annual Meetings in Vancouver, British Columbia, Canada. Input from this public forum was subsequently incorporated into the document. In March 2003, the full draft document was circulated nationally and internationally for review by stakeholders and experts in relevant fields.This input was then considered by the Executive and Steering Committees and revisions were made accordingly. Three independent methodologists, who were not directly involved with the initial review and assessment of the evidence, then reviewed each recommendation, its assigned grade and supportive citations. Based on this review, the assigned level of evidence and grade of each recommendation were reassessed and modified, if required. INTERPRETING THE ASSIGNED GRADE OF A RECOMMENDATION The grade assigned to each recommendation is closely linked to the methodological rigor and robustness of the relevant
METHODS
Table 1. Criteria for assigning levels of evidence to the published studies Level Criteria
Studies of diagnosis Level 1 i. Independent interpretation of test results (without knowledge of the result of the diagnostic or gold standard) ii. Independent interpretation of the diagnostic standard (without knowledge of the test result) iii. Selection of people suspected (but not known) to have the disorder iv. Reproducible description of both the test and diagnostic standard v. At least 50 patients with and 50 patients without the disorder Meets 4 of the Level 1 criteria Meets 3 of the Level 1 criteria Meets 1 or 2 of the Level 1 criteria Systematic overview or meta-analysis of high-quality randomized, controlled trials Appropriately designed randomized, controlled trial with adequate power to answer the question posed by the investigators Nonrandomized clinical trial or cohort study with indisputable results Randomized, controlled trial or systematic overview that does not meet Level 1 criteria Nonrandomized clinical trial or cohort study Other a) Inception cohort of patients with the condition of interest, but free of the outcome of interest b) Reproducible inclusion/exclusion criteria c) Follow-up of at least 80% of subjects d) Statistical adjustment for extraneous prognostic factors (confounders) e) Reproducible description of outcome measures Meets criterion a) above, plus 3 of the other 4 criteria Meets criterion a) above, plus 2 of the other criteria Meets criterion a) above, plus 1 of the other criteria
Level 2 Level 3 Level 4 Level 1A
Studies of treatment and prevention
Level 1B Level 2 Level 3 Level 4 Studies of prognosis Level 1
Level 2 Level 3 Level 4
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clinical research. Therefore, as noted above, a high grade reflects a high degree of confidence that following the recommendation will lead to the desired outcome. Similarly, the lower the grade, the weaker the evidence upon which the recommendation is based, and the greater the possibility that the recommendation will change when more evidence is generated in the future. Of note, the assigned grade contains no information regarding the importance of the recommendation or how strongly members of the committee felt about it; it only contains information regarding the evidence upon which the recommendation is based.Thus, many Grade D recommendations were deemed to be very important to the contemporary management of diabetes, based on clinical experience, case series, physiological evidence and current concepts of disease pathophysiology; however, the paucity of clinical evidence addressing the areas of therapy, prevention, diagnosis or prognosis precluded the assignment of a higher grade. Clearly, clinicians need to base clinical decisions on the best available relevant evidence that addresses clinical situations. However, they also need to act in the absence of clinical evidence, and there are many situations where good clinical evidence may be impossible, impractical or too expensive to generate (which implies that it would be impossible to develop Grade A recommendations). For example, it took the United Kingdom Prospective Diabetes Study (UKPDS) Group >20 years to collect and publish Level 1 evidence leading to a Grade A recommendation in support of the role of tight glycemic control to reduce microvascular disease in people with type 2 diabetes. Prior to the publication of the UKPDS results, the recommendation for glycemic control to prevent microvascular consequences was a Grade B recommendation (6). Varying grades of recommendations therefore reflect varying degrees of certainty regarding the strength of inference that can be drawn from the evidence in support of the recommendation. Thus, these evidence-based guidelines and their graded recommendations are designed to satisfy 2 important needs: 1) the explicit identification of the best research upon which the recommendation is based and an assessment of its scientific relevance and quality (captured by
Table 2. Criteria for assigning grades of recommendations for clinical practice Grade
Grade A Grade B Grade C Grade D
the assignment of a level of recommendation to each citation); and 2) the explicit assignment of strength of the recommendation based on this evidence (captured by the grade). In this way, they provide a convenient summary of the evidence to facilitate clinicians task of weighting and incorporating ever-increasing evidence into their daily clinical decision making. They also facilitate the ability of clinicians, healthcare planners, healthcare providers and society in general to critically examine any recommendation and arrive at their own conclusions regarding its appropriateness. Thus, these guidelines facilitate their own scrutiny by others according to the same principles that they use to scrutinize the literature. REFERENCES
1. Straus SE, McAlister FA. What is the prognosis? In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:6-12. 2. Users Guides to the Medical Literature: Essentials of Evidence-based Clinical Practice. Chicago, IL: American Medical Association; 2001. 3. Jaeschke R, Guyatt GH. How should diagnostic tests be chosen and used? In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:13-23. 4. Holbrook AM, Clarke J-A, Raymond C, et al. How should a particular problem be managed? Incorporating evidence about therapies into practice. In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:24-47. 5. Harris SB,Webster-Bogaert SM. Evidence-based clinical practice guidelines. In: Gerstein HC, Haynes RB, eds. Evidencebased Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001: 48-61. 6. Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ. 1998;159(suppl 8):S1-S29. 7. Goldbloom R, Battista RN. The periodic health examination: 1. Introduction. CMAJ. 1986;134:721-723.
Criteria
The best evidence was at Level 1 The best evidence was at Level 2 The best evidence was at Level 3 The best evidence was at Level 4 or consensus
S7
Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories

D E F I N I T I O N A N D D I AG N O S I S
DEFINITION OF DIABETES AND DYSGLYCEMIA Diabetes mellitus is a metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion, insulin action or both. The chronic hyperglycemia of diabetes is associated with significant long-term sequelae, particularly damage, dysfunction and failure of various organsespecially the kidneys, eyes, nerves, heart and blood vessels. Dysglycemia is a qualitative term used to describe blood glucose (BG) that is abnormal, without defining a threshold. The adoption of this term reflects uncertainty about optimal BG ranges and the current understanding that cardiovascular (CV) risk and mortality risk exist in people with even slightly elevated BG levels. CLASSIFICATION OF DIABETES The classification of diabetes is summarized in Table 1 and Appendix 1 (1,2).
Table 1. Classification of diabetes (1)
Type 1 diabetes encompasses diabetes that is primarily a result of pancreatic beta cell destruction and that is prone to ketoacidosis.This form includes cases due to an autoimmune process and those for which the etiology of beta cell destruction is unknown. Type 2 diabetes* may range from predominant insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance. Gestational diabetes mellitus refers to glucose intolerance with first onset or recognition during pregnancy. A wide variety of relatively uncommon conditions are listed under other specific types. These consist mainly of specific genetically defined forms of diabetes or diabetes associated with other diseases or drug use (see Appendix 1). *Includes latent autoimmune diabetes in adults (LADA), the term used to describe the small number of people with apparent type 2 diabetes who appear to have immunemediated loss of pancreatic beta cells (2).
DIAGNOSTIC CRITERIA The diagnostic criteria for diabetes and the plasma glucose (PG) thresholds for other diagnostic categories are summarized in Tables 2 and 3 (1).These criteria are based on venous sample methods used in the laboratory.
Table 2. Diagnosis of diabetes
FPG 7.0 mmol/L Fasting = no caloric intake for at least 8 hours or Casual PG 11.1 mmol/L + symptoms of diabetes Casual = any time of the day, without regard to the interval since the last meal Classic symptoms of diabetes = polyuria, polydipsia and unexplained weight loss or 2hPG in a 75-g OGTT 11.1 mmol/L A confirmatory laboratory glucose test (an FPG, casual PG, or a 2hPG in a 75-g OGTT) must be done in all cases on another day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation. 2hPG = 2-hour plasma glucose FPG = fasting plasma glucose OGTT = oral glucose tolerance test PG = plasma glucose
Table 3. PG levels for diagnosis of IFG, IGT and diabetes FPG (mmol/L)
IFG IFG (isolated) IGT (isolated) IFG and IGT Diabetes 6.16.9 6.16.9 <6.1 6.16.9 7.0 and and and or
2hPG in a 75-g OGTT (mmol/L)

NA <7.8 7.811.0 7.811.0 11.1
The initial draft of this chapter was prepared by Ehud Ur MB FRCP.
2hPG = 2-hour plasma glucose FPG = fasting plasma glucose IFG = impaired fasting glucose IGT = impaired glucose tolerance NA = not applicable OGTT = oral glucose tolerance test PG = plasma glucose
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Diabetes A fasting plasma glucose (FPG) level of 7.0 mmol/L correlates most closely with a 2-hour plasma glucose (2hPG) value of 11.1 mmol/L in a 75-g oral glucose tolerance test (OGTT) and best predicts the development of microvascular disease (1).This permits the diagnosis of diabetes to be made on the basis of the commonly available FPG test.Although the frequency distributions of glycosylated hemoglobin (A1C) levels in some studies have characteristics similar to those obtained from FPG and 2hPG tests, the lack of standardization of the A1C test precludes its use in the diagnosis of diabetes. Prediabetes Elevated BG levels below the threshold for diabetes also have clinical consequences.The term prediabetes is a practical and convenient term for impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (Table 3), which place individuals at risk of developing diabetes and its complications. It is important to stress that not all individuals with prediabetes will necessarily progress to diabetes. Indeed, a significant proportion of people who are diagnosed with IGT will revert to normoglycemia. Identifying people with prediabetes, particularly in the context of the metabolic syndrome, indicates those who would benefit from CV risk factor modification. While people with isolated IFG or isolated IGT do not have the diabetes-associated risk for microvascular disease, they have a higher risk for the development of diabetes and cardiovascular disease (CVD) (3). IGT is more strongly associated with CVD outcomes. However, individuals identified as having both IFG and IGT are at higher risk for diabetes as
Table 4. Clinical identification of the metabolic syndrome using NCEP ATP III criteria (9) Risk factor
FPG BP TG HDL-C Men Women Abdominal obesity Men Women
well as CVD. Lifestyle interventions have been shown to be highly effective in delaying or preventing the onset of diabetes in people with IGT (4,5). Evidence has not yet demonstrated reductions in CVD and total mortality. Metabolic syndrome Dysglycemia and type 2 diabetes are often manifestations of a much broader underlying disorder (6,7), including the metabolic syndromea highly prevalent, multifaceted condition characterized by a distinctive constellation of abnormalities that include abdominal obesity, hypertension, dyslipidemia, insulin resistance and dysglycemia. Patients with the metabolic syndrome are at significant risk of developing diabetes and CVD. Evidence now exists to support an aggressive approach to identifying people with the metabolic syndrome and treating not only the hyperglycemia, but also the associated CV risk factors, such as hypertension, dyslipidemia and abdominal obesity, with the hope of significantly reducing CV morbidity and mortality. A lack of consensus exists regarding operational definitions of the metabolic syndrome. In 1998, the World Health Organization (8) proposed a unifying definition that includes identification of the presence of insulin resistance. More recently, the United States (US) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) provided an operational definition based on 3 or more criteria that does not require a measure of insulin resistance (Table 4) (9). Data from the Third National Health and Nutrition Survey (NHANES III), which employed the ATP III criteria, found that the overall prevalence of the metabolic syndrome in the US was approximately 20 to 25% (10). OTHER RELEVANT GUIDELINES Screening and Prevention, p. S10 Macrovascular Complications, Dyslipidemia and Hypertension, p. S58 Type 2 Diabetes in Children and Adolescents, p. S91 RELEVANT APPENDICES Appendix 1: Etiologic Classification of Diabetes Mellitus, p. S118 Appendix 2: History and Examination: Initial and Follow-up Visits, p. S119 REFERENCES
1. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(suppl 1):S5-S20. 2. Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet. 1997;350:1288-1293.
Defining level*
6.1 mmol/L 130/85 mm Hg 1.7 mmol/L <1.0 mmol/L <1.3 mmol/L Waist circumference >102 cm >88 cm
*A diagnosis of metabolic syndrome is made when 3 or more of the risk determinants are present. BP = blood pressure FPG = fasting plasma glucose HDL-C = high-density lipoprotein cholesterol NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III TG = triglyceride
S9 3. Coutinho M, Gerstein HC, Wang Y, et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999; 22:233-240. 4. Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344:1343-1350. 5. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 6. Zimmet PZ. Diabetes epidemiology as a tool to trigger diabetes research and care. Diabetologia. 1999;42:499-518. 7. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607. 8. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15:539-553. 9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. 10. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA. 2002; 287:356-359.
D E F I N I T I O N A N D D I AG N O S I S
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Screening and Prevention

TYPE 1 DIABETES Screening and prevention The most common form of type 1 diabetes mellitus is marked by immune-mediated destruction of pancreatic beta cellsa process probably incited by environmental factors in genetically predisposed persons. The loss of pancreatic beta cells in persons who subsequently develop type 1 diabetes passes through a subclinical prodrome that can be detected reliably in first- and second-degree relatives of persons with type 1 diabetes by the presence of pancreatic islet autoantibodies in their sera (1-3). While randomized trials testing prevention strategies have been completed recently or are now underway (3-6), safe and effective preventive therapies have not been identified.Therefore, any attempts to prevent type 1 diabetes should be undertaken only within the confines of formal research protocols. TYPE 2 DIABETES Screening for type 2 diabetes Up to 2.7% of the general adult population have undiagnosed type 2 diabetes (7).Tests for hyperglycemia can identify these individuals, many of whom will have or will be at risk for preventable diabetes complications (8). Although the relatively low prevalence of diabetes in the general population makes it unlikely that mass screening will be cost effective, testing for diabetes in people with risk factors for type 2 diabetes or with diabetes-associated conditions is likely to result in more benefit than harm and will lead to overall cost savings (9). Routine testing for type 2 diabetes is, therefore, justifiable in some, but not all, settings (10). Screening individuals as early as at age 40 years in family physicians offices has proven to be useful in detecting unrecognized diabetes (11). Several widely available tests for hyperglycemia have been assessed for their utility in screening for diabetes. These include fasting plasma glucose (FPG), casual plasma glucose (PG), 2-hour plasma glucose (2hPG) in a 75-g oral glucose tolerance test (OGTT), glycosylated hemoglobin (A1C) and The initial draft of this chapter was prepared by Ehud Ur MB FRCP; Sarah E. Capes MD MSc FRCPC;Amir Hanna MB BCh FRCPC FACP; Stewart B. Harris MD MPH FCFP FACPM; Jeffrey Mahon MD MSc FRCPC; Richard Rowe MBBS MAEd FRCPC.
glycosuria assessment (8,10). The FPG is the most reproducible of these tests, although each has advantages and disadvantages in terms of convenience, cost, assay standardization and reliable identification of people for whom evaluation and treatment are worthwhile. While the FPG is the recommended screening test, a 2hPG in a 75-g OGTT may be indicated when FPG is 5.7 to 6.9 mmol/L (12) and suspicion of diabetes or impaired glucose tolerance (IGT) is high (e.g. for individuals with risk factors listed in Table 1) (Figure 1). As people with IGT are at increased risk of type 2 diabetes and have an increased risk of macrovascular complications, the diagnosis of IGT, particularly in seemingly healthy people, has important implications for prognosis (16). Classifying patients with impaired fasting glucose (IFG)
Table 1. Risk factors for type 2 diabetes
Age 40 years First-degree relative with diabetes Member of high-risk population (e.g. people of Aboriginal, Hispanic, South Asian, Asian or African descent) History of IGT or IFG* Presence of complications associated with diabetes Vascular disease* History of GDM History of delivery of a macrosomic infant Hypertension* Dyslipidemia* Overweight* Abdominal obesity* Polycystic ovary syndrome* Acanthosis nigricans* Schizophrenia Other (see Appendix 1) *Associated with the metabolic syndrome. The incidence of type 2 diabetes is at least 3 times higher in people with schizophrenia than in the general population (13,14). Using data collected in 1991, the prevalence of diabetes was assessed in >20 000 individuals diagnosed with schizophrenia.The rate of diagnosed diabetes was 9 to 14%, exceeding rates for the general population prior to the widespread use of new antipsychotic drugs (15). GDM = gestational diabetes mellitus IFG = impaired fasting glucose IGT = impaired glucose tolerance
S11 Figure 1. Screening for type 2 diabetes, IFG and IGT

Every 3 years in individuals 40 years of age with no other risk factors (see Table 1) Earlier and/or more frequently in individuals <40 years of age with risk factors (see Table 1) and as clinically indicated in individuals 40 years of age with other risk factors
FPG
<5.7 mmol/L
5.76.9 mmol/L plus risk factor(s) for diabetes/IGT* (see Table 1)
6.16.9 mmol/L and no risk factors for diabetes/IGT (see Table 1)
7.0 mmol/L
SCREENING AND PREVENTION
2hPG in a 75-g OGTT
Classify patient as: Normal IFG (isolated) IGT (isolated) IFG and IGT Diabetes** FPG <6.1 6.16.9 <6.1 6.16.9 7.0 and and and and or 2hPG <7.8 <7.8 7.811.0 7.811.0 11.1
Normal
Isolated IFG Isolated IGT IFG and IGT
IFG
Diabetes**
Rescreen as clinically indicated
Strategies to prevent diabetes and modify CVD risk factors Rescreen for diabetes at appropriate intervals
Treatment
*In the absence of other risk factors, an FPG of 5.7 to 6.0 mmol/L does not require further investigation, except routine screening at appropriate intervals. **A confirmatory laboratory glucose test (either an FPG, casual PG or a 2hPG in a 75-g OGTT) must be done on another day in all cases in the absence of unequivocal metabolic decompensation. 2hPG = 2-hour plasma glucose CVD = cardiovascular disease FPG = fasting plasma glucose IFG = impaired fasting glucose IGT = impaired glucose tolerance OGTT = oral glucose tolerance test PG = plasma glucose
S12
and/or IGT, particularly in the context of the metabolic syndrome, identifies people who would benefit from cardiovascular risk factor reduction. Preventing type 2 diabetes Preventing type 2 diabetes would result in significant public health benefits, including lower rates of cardiovascular disease (CVD), renal failure, blindness and premature mortality within the population. An epidemiological analysis projected that if all diabetes could be avoided in white American males through effective primary prevention, the risk of all-cause and CVD mortality in the entire population could be reduced by up to 6.2 and 9.0%, respectively (17). American data indicate that 19% of total United States (US) healthcare costs attributable to CVD are due to diabetes (18). Primary approaches to preventing diabetes in a population include: 1) programs targeting high-risk individuals in the community (such as those with IGT or obesity); 2) programs targeting high-risk subgroups of the population (such as high-risk ethnic groups); and 3) programs for the general population (such as those designed to promote physical activity and healthy eating in adults or children) (19-21). Community-based approaches to primary prevention of diabetes and associated risk factors in the general population or in high-risk subgroups are currently being evaluated and require further study. Prospective cohort studies have identified historical, physical and biochemical variables that are associated with subsequent development of type 2 diabetes.These variables include older age, certain ethnic backgrounds, obesity (especially abdominal obesity), physical inactivity, history of gestational diabetes mellitus (GDM), overt coronary artery disease, high fasting insulin level and IGT (22-24). Results of large, well-designed studies assessing lifestyle and pharmacologic interventions in adults to prevent the progression from IGT to diabetes have recently been published: Changes in lifestyle were assessed in the Finnish Diabetes Prevention Study (25) and the Diabetes Prevention Program (DPP) (26). Dietary modification that targeted a low-calorie diet with reduced fat intake and moderate-intensity physical activity of at least 150 minutes/week resulted in weight loss of approximately 5% of initial body weight. In both studies, the risk reduction for diabetes was 58% at 4 years.These studies included comprehensive, sustained programs to achieve these outcomes. Metformin was used in a second arm of the DPP (26). A dosage of 850 mg BID for an average of 2.8 years significantly decreased progression to diabetes by 31%. In younger, more obese subjects, the effects of metformin were more marked compared to lifestyle interventions. To determine whether the observed benefit was a transient pharmacologic effect or more sustained, a repeat OGTT was undertaken after a short washout period.
The results of this study suggested that 26% of the diabetes prevention effect could be accounted for by the pharmacologic action of metformin that did not persist when the drug was stopped.After the washout, the incidence of diabetes was still reduced by 25% (27). The Study to Prevent Non Insulin Dependent Diabetes Mellitus (STOP-NIDDM) used acarbose (Prandase) at a dosage of 100 mg TID in a 5-year study with a mean follow-up of 3.3 years (28). Overall, there was a reduction of 30% in the risk of progression to diabetes.
RECOMMENDATIONS
1. All individuals should be evaluated annually for type 2 diabetes risk on the basis of demographic and clinical criteria [Grade D, Consensus]. 2. Screening for diabetes using an FPG should be performed every 3 years in individuals 40 years of age [Grade D, Consensus]. More frequent and/or earlier testing with either an FPG or 2hPG in a 75-g OGTT should be considered in people with additional risk factors for diabetes [Grade D, Consensus].These risk factors include: First-degree relative with diabetes Member of high-risk population (e.g. people of Aboriginal, Hispanic, Asian, South Asian or African descent) History of IGT or IFG Presence of complications associated with diabetes Vascular disease History of GDM History of delivery of a macrosomic infant Hypertension Dyslipidemia Overweight Abdominal obesity Polycystic ovary syndrome Acanthosis nigricans Schizophrenia Other risk factors (see Appendix 1) 3.Testing with a 2hPG in a 75-g OGTT should be considered in individuals with an FPG of 5.7 to 6.9 mmol/L in order to identify individuals with IGT or diabetes [Grade D, Consensus]. 4. In individuals with IGT, a structured program of lifestyle modification that includes moderate weight loss and regular physical activity should be implemented to reduce the risk of type 2 diabetes [Grade A, Level 1A (25,26)]. 5. In individuals with IGT, pharmacologic therapy with metformin (biguanide) [Grade A, Level 1A (26)] or acarbose (alpha-glucosidase inhibitor) [Grade A, Level 1A (28)] should be considered to reduce the risk of type 2 diabetes.
S13
OTHER RELEVANT GUIDELINES Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories, p. S7 Type 2 Diabetes in Children and Adolescents, p. S91 RELEVANT APPENDIX Appendix 1: Etiologic Classification of Diabetes Mellitus, p. S118 REFERENCES
1. Bingley PJ. Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+ relatives: the ICARUS data set. Diabetes. 1996;45:1720-1728. 2. Verge CF, Gianani R, Kawasaki E, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996;45:926-933. 3. Diabetes Prevention TrialType 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002;346:1685-1691. 4. Lampeter EF, Klinghammer A, Scherbaum WA, et al. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. Diabetes. 1998;47:980-984. 5. Gale EAM. Prevention studies in type 1 diabetes. Exp Clin Endocrinol Diabetes. 1999;107(suppl 3):S101. 6. Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Available at: http://www.trigr.org. Accessed November 7, 2003. 7. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 19881994. Diabetes Care. 1998;21:518-524. 8. Harris MI, Modan M. Screening for NIDDM.Why is there no national program? Diabetes Care. 1994;17:440-444. 9. Eastman RC, Javitt JJ, Herman WH, et al. Prevention strategies for type 2 diabetes mellitus: a health and an economic perspective. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, PA: Lippincott-Raven; 2000:746-756. 10. Knowler WC. Screening for NIDDM. Opportunities for detection, treatment, and prevention. Diabetes Care. 1994; 17:445-450. 11. Leiter LA, Barr A, Blanger A, et al. Diabetes Screening in Canada (DIASCAN) Study: prevalence of undiagnosed diabetes and glucose intolerance in family physician offices. Diabetes Care. 2001;24:1038-1043. 12. Saydah SH, Byrd-Holt D, Harris MI. Projected impact of implementing the results of the Diabetes Prevention Program in the U.S. population. Diabetes Care. 2002;25:1940-1945. 13. McKee HA, DArcy PF,Wilson PJK. Diabetes and schizophreniaa preliminary study. J Clin Hosp Pharm. 1986;11:297-299. 14. Mukherjee S, Decina P, Bocola V, et al. Diabetes mellitus in schizophrenic patients. Compr Psychiatry. 1996;37:68-73.
15. Dixon L,Weiden P, Delahanty J, et al. Prevalence and correlates of diabetes in national schizophrenia samples. Schizophr Bull. 2000;26:903-912. 16. Zimmet P, Alberti KGMM, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782-787. 17. Narayan KM,Thompson TJ, Boyle JP, et al.The use of population attributable risk to estimate the impact of prevention and early detection of type 2 diabetes on population-wide mortality risk in US males. Health Care Manag Sci. 1999;2:223-227. 18. American Diabetes Association. Economic costs of diabetes in the U.S. in 2002. Diabetes Care. 2003;26:917-932. 19. Micucci S, Thomas H, Vohra J. The effectiveness of schoolbased strategies for the primary prevention of obesity and for promoting physical activity and/or nutrition, the major modifiable risk factors for type 2 diabetes: a review of reviews. Hamilton, ON: Public Health Research, Education and Development Program, Ministry of Health and Long-term Care; 2002. 20. Daniel M, Green LW, Marion SA, et al. Effectiveness of community-directed diabetes prevention and control in a rural Aboriginal population in British Columbia, Canada. Soc Sci Med. 1999;48:815-832. 21. Simmons D, Voyle J, Swinburn B, et al. Community-based approaches for the primary prevention of non-insulin-dependent diabetes mellitus. Diabet Med. 1997;14:519-526. 22. Charles MA, Fontbonne A, Thibult N, et al. Risk factors for NIDDM in white population. Paris prospective study. Diabetes. 1991;40:796-799. 23. Eastman RC, Cowie CC, Harris MI. Undiagnosed diabetes or impaired glucose tolerance and cardiovascular risk. Diabetes Care. 1997;20:127-128. 24. Tuomilehto J, Knowler WC, Zimmet P. Primary prevention of non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1992;8:339-353. 25. Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344:1343-1350. 26. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 27. The Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the Diabetes Prevention Program. Diabetes Care. 2003; 26:977-980. 28. Chiasson J-L, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077.
SCREENING AND PREVENTION
S14
Organization and Delivery of Care

INTRODUCTION Successful diabetes care depends on the daily commitment of the person with diabetes mellitus to self-management through the balance of lifestyle and medication. Diabetes care should be organized around a multi- and interdisciplinary diabetes healthcare (DHC) team that can establish and sustain a communication network between the person with diabetes and the necessary healthcare and community systems (1-3). Both the organization and delivery of diabetes care should be comprehensive, according to evidence-based clinical practice guidelines, equitable in access and continuous throughout a persons lifetime.Where possible, diabetes programs and services should be culturally appropriate, community based and respectful of age, gender and socioeconomic conditions. THE DHC TEAM Central to the DHC team is the person with diabetes and his/her family. The core DHC team includes the physician (family physician and/or specialist) and the diabetes educators (nurse and dietitian). As needed, various individual and community healthcare professionals may contribute to the team. Included in, but not exclusive to, this wider team are other medical specialists (e.g. ophthalmologists, cardiologists, neurologists, nephrologists, vascular surgeons, infectious disease specialists, gastroenterologists and obstetricians), other health professionals (e.g. nurses, dietitians, optometrists, pharmacists, podiatrists/chiropodists, social workers, psychologists and other mental health professionals) and community, public health and other health organizations (3-6). The DHC team provides comprehensive, shared care (7). Shared care assumes ongoing communication among and participation of all members of the team. This approach has been shown to increase the commitment and participation of the person with diabetes while also serving to recognize and enhance the roles and practices of the physician and other team members (7-10). While clinical practice guidelines highlight the importance of the DHC team approach to the management of The initial draft of this chapter was prepared by Sora Ludwig MD FRCPC; Peggy Dunbar MEd PDt CDE; Maureen Clement MD CCFP; Robert Petrella MD PhD.
diabetes (11,12), the literature describing the role of specialist care is inconsistent.There is evidence that patients with type 1 diabetes who have a higher proportion of care provided by specialists (endocrinologists, diabetes specialists or diabetes clinics) have reduced incidence of diabetes complications (13). However, in one study, patients (with either type 1 or type 2 diabetes) whose general practitioner either professed a special interest in diabetes or organized diabetes-specific clinics (e.g. diabetes miniclinics) achieved improved glycemic control (14). As access to specialist care varies widely across Canada, research is needed to determine which care models are most appropriate. The family physician has an important role as the first and, at times, principal medical contact for the person with diabetes. Family physicians offer continuity of care for the person with diabetes, as they see the person in the context of his/her family. This unique relationship between the family physician, the patient and the family provides an invaluable resource to meet the varied needs of the person with diabetes. It also provides opportunities to assist and influence families and/or individuals at risk of developing type 2 diabetes.These aspects of practice may provide benefit in terms of long-term adherence to and compliance with care plans. ORGANIZATIONAL INTERVENTIONS There are a number of interventions that have been shown to improve the efficiencies of the DHC setting (3). One of the main interventions is the establishment of a centralized, computerized database system that improves transfer of information among all members of the DHC team, including the person with diabetes. Such systems facilitate evidencebased decision making as well as timely access and continuity of care (3,15-17). The DHC team should work within a structure that provides reminders and recall for diabetes metabolic control and complication risk assessment (3,15,16,18). This structure should include organized diabetes clinics that provide patient and DHC team reminders, including specific clinical tools such as clinical flow charts (see Appendix 3). The DHC team has the obligation to incorporate evidence-based standards of practice. These organizational interventions and, in particular, a system that incorporates regular review and audit can play key roles in delivering and maintaining accepted standards of care and have been
S15
shown to improve diabetes management health outcomes (3,15,16,18-23). Enhancement of the role of all diabetes educator members of the DHC team to act as case managers or care coordinators has been shown to not only improve the efficiencies of the system, but may also improve clinical outcomes (3,24-26). Evidence has demonstrated the benefit of a more direct role enhancement of the diabetes nurse educator to provide adjustment of diabetes medication in a timely manner through a physician-supervised transfer of function (3). MODELS OF CARE Within a model of chronic disease, diabetes care should be patient centred and focussed on self-management (27,28). It is most effective when delivered in a manner that provides ongoing education and comprehensive care together as essential components. It can be enhanced through the use of a variety of educational and behavioural approaches as well as community supports (27).The timeliness of referral for selfmanagement education should be based on the severity of presenting symptoms, the degree of metabolic control and the persons understanding of immediate survival and safety skills and long-term management practices. Diabetes education is effective in enhancing knowledge, skills and behavioural change. It has been shown to improve self-care and clinical outcomes (1,2). It should be interactive, solution focussed and based on the experiences of the learner, as well as staged and tailored to meet individual needs and abilities. Group education and sustained, longterm follow-up have both been shown to enhance knowledge and produce positive outcomes (16,29,30). One of the characteristics of the DHC team is flexibility in its organization, which allows for the flow of information and communication between the core and the expanded team, as required. Thus, the DHC team concept should be adapted to all regional settingsurban, rural and remote (7). Models of regional DHC teams, supported by provincial government policy and structures, currently exist in Manitoba, Nova Scotia, Northern Ontario and Quebec. The physician, as well as other members of the DHC team, also has a role to play in the prevention of diabetes in those at identified risk and in the population as a whole. Interventions to modify diabetes risk factors (healthy eating, physical activity, smoking cessation/avoidance) should become part of daily practice (31). OTHER RELEVANT GUIDELINES Type 1 Diabetes in Children and Adolescents, p. S84 Type 2 Diabetes in Children and Adolescents, p. S91 Pre-existing Diabetes and Pregnancy, p. S94 Gestational Diabetes Mellitus, p. S99 Diabetes in the Elderly, p. S106
RECOMMENDATIONS
1. Diabetes care should be organized around the person with diabetes using a multi- and interdisciplinary DHC team approach [Grade B, Level 2 (3,7)]. 2. Diabetes care should be systematic and incorporate organizational interventions that have been shown to improve healthcare efficiencies, such as databases to provide patient and physician reminders and transfer of information, organized diabetes clinics, and tools, including clinical flow charts [Grade B, Level 2 (3,7,18)]. 3. As an essential member of the DHC team, the family physician and/or specialist and the other members of the DHC team have the responsibility to: Ensure that systematic, structured and standardized diabetes care is available [Grade A, Level 1A (18)]; Incorporate current standards of diabetes care into daily practice [Grade D, Consensus]; Facilitate transfer of information among all members of the team to ensure continuity of care [Grade A, Level 1A (18,32)]; and Endeavour to identify and prevent diabetes in those identified to be at risk [Grade D, Consensus]. 4. People with diabetes should be offered initial and ongoing needs-based diabetes education in a timely manner to enhance self-care practices and behaviours [Grade B, Level 2 (33)]. 5.The role of diabetes nurse educators [Grade B, Level 2 (3)] and other DHC team members [Grade D, Consensus] should be enhanced in cooperation with the physician to improve coordination of care and to effect timely diabetes management changes.
O R G A N I Z AT I O N A N D D E L I V E RY O F C A R E
RELEVANT APPENDIX Appendix 3: Sample Diabetes Patient Care Plan, p. S122 REFERENCES
1. Brown SA. Effects of educational interventions in diabetes care: a meta-analysis of findings. Nurs Res. 1988;37:223-230. 2. Brown SA. Meta-analysis of diabetes patient education research: variations in intervention effects across studies. Res Nurs Health. 1992;15:409-419. 3. Renders CM, Valk GD, Griffin SJ, et al. Interventions to improve the management of diabetes in primary care, outpatient, and community settings: a systematic review. Diabetes Care. 2001;24:1821-1833. 4. Funnell MM. Integrated approaches to the management of NIDDM patients. Diabetes Spectrum. 1996;9:55-59. 5. Dunn SM, Hoskins PL, Constantino M, et al. Diabetic management: the role of the diabetes center. Diabetes Rev. 1994;2:389-402. 6. Clement S. Diabetes self-management education. Diabetes Care. 1995;18:1204-1214. 7. Greenhalgh PM. Shared care for diabetes.A systematic review. Occas Pap R Coll Gen Pract. 1994;(67):i-viii, 1-35.
S16 8. Hoskins PL, Fowler PM, Constantino M, et al. Sharing the care of diabetic patients between hospital and general practitioners: does it work? Diabet Med. 1993;10:81-86. 9. Hurwitz B, Goodman C,Yudkin J. Prompting the clinical care of non-insulin dependent (type II) diabetic patients in an inner city area: one model of community care. BMJ. 1993;306:624-630. 10. Griffin S. Diabetes care in general practice: meta-analysis of randomised control trials. BMJ. 1998;317:390-396. 11. Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ. 1998;159(suppl 8):S1-S29. 12. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003;26(suppl 1): S33-S50. 13. Zgibor JC, Songer TJ, Kelsey SF, et al. Influence of health care providers on the development of diabetes complications: longterm follow-up from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2002;25:1584-1590. 14. Pringle M, Stewart-Evans C, Coupland C, et al. Influences on control in diabetes mellitus: patient, doctor, practice, or delivery of care? BMJ. 1993;306:630-634. 15. Brown JB, Nichols GA, Glauber HS. Case-control study of 10 years of comprehensive diabetes care. West J Med. 2000; 172:85-90. 16. Wagner EH, Grothaus LC, Sandhu N, et al. Chronic care clinics for diabetes in primary care: a system-wide randomized trial. Diabetes Care. 2001;24:695-700. 17. McGill M, Molyneaux LM, Yue DK, et al. A single visit diabetes complication assessment service: a complement to diabetes management at the primary care level. Diabet Med. 1993;10:366-370. 18. Griffin S, Kinmonth AL. Diabetes care: the effectiveness of systems for routine surveillance for people with diabetes. Cochrane Database Syst Rev. 2000(2):CD000541. 19. Hiss RG. Barriers to care in non-insulin-dependent diabetes mellitus. The Michigan experience. Ann Intern Med. 1996; 124:146-148. 20. Benett IJ, Lambert C, Hinds G, et al. Emerging standards for diabetes care from a city-wide primary care audit. Diabet Med. 1994;11:489-492. 21. Kiefe CI, Allison JJ, Williams OD, et al. Improving quality improvement using achievable benchmarks for physician feedback: a randomized controlled trial. JAMA. 2001;285:2871-2879. 22. Thomson OBrien MA, Oxman AD, Davis DA, et al.Audit and feedback versus alternative strategies: effects on professional practice and health care outcomes. Cochrane Database Syst Rev. 2000(2):CD000260. 23. McCullough DK, Price MJ, Hindmarsh M, et al. A populationbased approach to diabetes management in a primary care setting: early results and lessons learned. Eff Clin Pract. 1998;1:12-22. 24. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med. 1993;329:977-986. 25. The DCCT Research Group. Expanded role of the dietitian in the Diabetes Control and Complications Trial: implications for clinical practice. J Am Diet Assoc. 1993;93:758-764, 767. 26. Daly A, Kulkarni K, Boucher J. The new credential: advanced diabetes management. J Am Diet Assoc. 2001;101:940-943. 27. Von Korff M, Gruman J, Schaefer J, et al. Collaborative management of chronic illness. Ann Intern Med. 1997;127:1097-1102. 28. Etzwiler DD. Chronic care: a need in search of a system. Diabetes Educ. 1997;23:569-573. 29. Norris SL, Engelgau MM, Narayan KMV. Effectiveness of selfmanagement training in type 2 diabetes: a systematic review of randomized controlled trials. Diabetes Care. 2001;24:561-587. 30. Rickheim PL, Weaver TW, Flader JL, et al. Assessment of group versus individual diabetes education: a randomized study. Diabetes Care. 2002;25:269-274. 31. Glasgow RE, Strycker LA. Preventive care practices for diabetes management in two primary care samples. Am J Prev Med. 2000;19:9-14. 32. Diabetes Integrated Care Evaluation Team. Integrated care for diabetes: clinical, psychosocial, and economic evaluation. BMJ. 1994;308:1208-1212. 33. Brown SA. Studies of educational interventions and outcomes in diabetic adults: a meta-analysis revisited. Patient Educ Couns. 1990;16:189-215.
M A N AG E M E N T
CANADIAN DIABETES ASSOCIATION
2003 CLINICAL PRACTICE GUIDELINES FOR THE PREVENTION AND MANAGEMENT OF DIABETES IN CANADA
Management
S18
Targets for Glycemic Control

RELATIONSHIP BETWEEN GLUCOSE LEVELS AND COMPLICATIONS OF DIABETES Randomized, controlled trials have provided compelling evidence that long-term complications of diabetes mellitus can be reduced by tight glycemic control. When compared to conventional treatment regimens, intensive treatment regimens aimed at lowering glycosylated hemoglobin (A1C) levels toward the normal range have been associated with a reduction in microvascular complications in people with type 1 diabetes (1) and type 2 diabetes (2,3). A1C levels >7.0% are associated with a significantly increased risk of both microvascular and macrovascular complications, regardless of underlying treatment (3-6). Secondary analyses from the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated a continuous relationship between A1C and diabetes complications, with no apparent threshold of benefit (4,5). In the DCCT, a 10% reduction in A1C (e.g. from 8.0 to 7.2%) was associated with a 40 to 50% lower risk of retinopathy progression, although the absolute reduction in risk was substantially less at lower A1C levels (4). In the UKPDS, this relationship was directly linear, with each 1.0% (absolute) reduction in mean A1C associated with a 37% decline in the risk of microvascular complications, a 14% lower rate of myocardial infarction (MI) and fewer deaths from diabetes or any cause (5). Further analyses from the DCCT indicate that average capillary blood glucose (BG) levels based on both pre- and postprandial measurements are also directly correlated to the risk of complications (7). Intensively treated patients in the DCCT adjusted their insulin doses in order to achieve target fasting blood glucose (FBG) and preprandial capillary BG levels of 3.9 to 6.7 mmol/L, and were able to achieve an average of 7.7 mmol/L (1). In the Kumamoto study, FBG levels >6.7 mmol/L predicted an increased risk of microvascular complications in patients with type 2 diabetes (2). Fasting plasma glucose (FPG) has also been shown to be directly related to cardiovascular (CV) events, with the increase in risk apparent even at levels that are within the normal range for people without diabetes (8). The initial draft of this chapter was prepared by Gillian L. Booth MD MSc FRCPC.
While there are no direct data relating postprandial glucose levels to complications in persons with type 1 diabetes, 90-minute postprandial glucose levels obtained periodically throughout the DCCT (mean 9.4 mmol/L in the intensive therapy group vs. 14.4 mmol/L in the conventional therapy group) appeared to be as good as or an even better predictor of A1C than preprandial glucose levels (1,9). In the Kumamoto study, the risk of microvascular complications increased with 2-hour postprandial BG levels >10.0 mmol/L (2). Moreover, postprandial plasma glucose (PG) levels appear to be a powerful risk factor for mortality. The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study found that PG levels taken 2 hours after an oral glucose tolerance test ranging from 7.8 to 11.0 mmol/L were associated with a 1.5-fold higher mortality rate, while levels 11.1 mmol/L (whole blood concentration 10.0 mmol/L) were associated with a 2-fold greater mortality compared to those <7.8 mmol/L (10). Postchallenge PG remained an independent predictor of CV mortality after adjusting for other risk factors, including FPG (11). In contrast, FPG was no longer a significant predictor after controlling for postprandial PG elevations (11). Additionally, the Diabetes Intervention Study found that a 1-hour postprandial BG level 8.0 mmol/L conferred the lowest risk of MI or death among patients with type 2 diabetes, while levels >10.0 mmol/L were associated with the highest risk (12). RISK OF HYPOGLYCEMIA While these data suggest that the lowest risk of complications will occur in those who achieve normoglycemia, the absolute benefit of lowering A1C levels from 7.0 to 6.0% is expected to be small and must be weighed against the risk of hypoglycemia. In the DCCT, few individuals were able to maintain normal A1C levels throughout the study (1). Furthermore, the risk of severe hypoglycemia was 3 times higher among participants receiving intensive therapy.While rates of severe hypoglycemia among individuals with type 2 diabetes treated in the UKPDS were lower than those observed in the DCCT, intensive therapy increased this risk by 2- to 3-fold, particularly among those using insulin (3). Based on these findings, normoglycemia may not be an appropriate goal in individuals with either type 1 diabetes or type 2 diabetes who are at risk for severe hypoglycemia.
M A N AG E M E N T
S19 Table 1. Recommended targets for glycemic control* A1C** FPG/preprandial PG (%) (mmol/L)
Target for most patients Normal range (consider for patients in whom it can be achieved safely) 7.0 6.0 4.07.0 4.06.0
2-hour postprandial PG (mmol/L)

5.010.0 5.08.0
*Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors. Glycemic targets for children 12 years of age and pregnant women differ from these targets. Please refer to Other Relevant Guidelines for further details. **An A1C of 7.0% corresponds to a laboratory value of 0.070. Where possible, Canadian laboratories should standardize their A1C values to DCCT levels (reference range: 0.040 to 0.060). However, as many laboratories continue to use a different reference range, the target A1C value should be adjusted based on the specific reference range used by the laboratory that performed the test. As a useful guide: an A1C target of 7.0% refers to a threshold that is approximately 15% above the upper limit of normal. A1C = glycosylated hemoglobin DCCT = Diabetes Control and Complications Trial FPG = fasting plasma glucose PG = plasma glucose
GLYCEMIC TARGETS The glycemic targets recommended for most patients with type 1 and type 2 diabetes are listed in Table 1. However, clinical judgement is required to determine which people can reasonably and safely achieve these targets. Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors (e.g. the patients age, prognosis, the presence of diabetes complications or comorbidities, and their risk for and ability to perceive hypoglycemia). To make the guidelines easier to incorporate into clinical practice, a single A1C target is provided and PG targets have been rounded to whole numbers.
RECOMMENDATIONS
1. Glycemic targets must be individualized; however, therapy in most patients with type 1 or type 2 diabetes should be targeted to achieve an A1C 7.0% in order to reduce the risk of microvascular [Grade A, Level 1A (1,3)] and macrovascular complications [Grade C, Level 3 (5)]. 2.To achieve an A1C 7.0%, patients with type 1 or type 2 diabetes should aim for FPG or preprandial PG targets of 4.0 to 7.0 mmol/L and 2-hour postprandial PG targets of 5.0 to 10.0 mmol/L [Grade B, Level 2 (1-3)]. 3. If it can be safely achieved, lowering PG targets toward the normal range should be considered [Grade C, Level 3 (4,5,8,10)]: A1C 6.0% [Grade D, Consensus]; FPG/preprandial PG: 4.0 to 6.0 mmol/L [Grade D, Consensus]; and 2-hour postprandial PG: 5.0 to 8.0 mmol/L [Grade D, Consensus].
OTHER RELEVANT GUIDELINES Hypoglycemia, p. S43 Type 1 Diabetes in Children and Adolescents, p. S84 Pre-existing Diabetes and Pregnancy, p. S94 Gestational Diabetes Mellitus, p. S99 Diabetes in the Elderly, p. S106 REFERENCES
1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986. 2. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103-117. 3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-853. 4. The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995; 44:968-983. 5. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.
S20 6. Standl E, Balletshofer B, Dahl B, et al. Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich General Practitioner Project. Diabetologia. 1996;39:1540-1545. 7. Service FJ, OBrien PC. The relation of glycaemia to the risk of development and progression of retinopathy in the Diabetic [sic] Control and Complications Trial. Diabetologia. 2001; 44:1215-1220. 8. Coutinho M, Gerstein HC, Wang Y, et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999; 22:233-240. 9. Rohlfing CL, Wiedmeyer H-M, Little RR, et al. Defining the relationship between plasma glucose and HbA1c: analysis of glucose profiles and HbA1c in the Diabetes Control and Complications Trial. Diabetes Care. 2002;25:275-278. 10. The DECODE Study Group on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and American Diabetic [sic] Association diagnostic criteria. Lancet. 1999;354:617-621. 11. The DECODE Study Group, on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;161:397-405. 12. Hanefeld M, Fischer S, Julius U, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia. 1996;39:1577-1583.
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Monitoring Glycemic Control

GLYCOSYLATED HEMOGLOBIN TESTING The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) clearly demonstrated that glycemic control (as measured by glycosylated hemoglobin [A1C]) and the development of long-term complications are correlated in both type 1 and type 2 diabetes. Since A1C reflects glycemia over the usual 120-day life span of erythrocytes, measurement of this indicator of treatment effectiveness should be undertaken approximately every 3 months to ensure that glycemic goals are being met or maintained (1). Additional information regarding dietary choices, physical activity and blood glucose (BG) levels before and after meals may be required to guide treatment decisions. A1C is the preferred standard for assessing glycosylated hemoglobin, and laboratories are encouraged to use assay methods for this test that are standardized against the DCCT reference (1,2). SELF-MONITORING OF BLOOD GLUCOSE Most people with diabetes benefit from self-monitoring of blood glucose (SMBG) (3).These benefits, including improved A1C, avoidance of hypoglycemia and increased lifestyle flexibility, are enhanced when individuals are prepared to adjust their dietary choices, physical activity and medication(s) in response to BG values (4,5). Patients should be taught to interpret SMBG results and make appropriate changes. Frequency of SMBG The frequency of SMBG should be determined individually, based on the treatment prescribed, the type of diabetes, the need for information about BG levels and the individuals capacity to use the information from testing to modify behaviours or adjust medications. Strategies that employ patient empowerment and behaviour change theory may be most effective in supporting the incorporation of SMBG into the diabetes management routine (4,6). In type 1 diabetes, performance of 3 self-tests per day has been associated with a statistically and clinically significant 1.0% reduction in A1C levels (3).The results of multiple The initial draft of this chapter was prepared by Sharon Brez RN BScN MA(Ed) CDE.
tests each day provide information that is better correlated to A1C than fasting blood glucose (FBG) results alone. BG measurements taken after lunch, after dinner and at bedtime have the highest correlation to A1C (7). For people with type 2 diabetes who are treated with lifestyle modifications alone or in combination with oral antihyperglycemic agents, the optimal frequency of SMBG remains unclear (3,8-10). However, recent evidence indicates benefits of testing on glycemic control, especially when this information is used to make appropriate, timely treatment adjustments (3,6). In people with type 2 diabetes treated with medications, testing at least once daily is associated with a 0.6% lower A1C than less frequent monitoring (3). In those managed by lifestyle alone, any frequency of testing is associated with a lower A1C (3). In people with type 2 diabetes, postprandial plasma glucose (PG) results are generally better correlated to A1C than tests taken at other times of the day (11,12). In people with very poor glycemic control, however, fasting plasma glucose (FPG) may more strongly impact overall glycemia (12). Individuals who use intensive management (multiple daily insulin injections or continuous subcutaneous insulin infusion), with the goal of near normalization of BG levels, can use information obtained from preprandial and bedtime testing, as well as intermittent postprandial and night-time tests, to adjust insulin dosages. Since night-time hypoglycemia may be more frequent in intensively managed individuals, periodic overnight testing at a time corresponding to peak insulin action should be undertaken (13-17). For people using insulin or oral antihyperglycemic agents, SMBG before, during and, especially, for many hours after exercise is important for establishing response to exercise. This information should be used to make appropriate adjustments to exercise, medication or carbohydrate intake to avoid significant dysglycemia. Verification of accuracy of SMBG performance and results Variability exists between BG results obtained using selfmonitoring devices and laboratory testing of PG. A difference of <20% between capillary BG and simultaneous venous FPG levels (at BG levels >4.2 mmol/L) is considered acceptable (2). Less variation is recommended for BG readings 4.2 mmol/L (2). In order to assure accuracy of BG
S22
meter readings, meter results should be compared with laboratory measurement of PG at least annually and when indicators of glycemic control do not match meter readings. In addition, as errors in testing techniques are commonly observed, periodic re-education on correct monitoring technique may improve the accuracy of SMBG results (4,18). In rare situations, therapeutic interventions may interfere with the accuracy of some BG meter results (e.g. icodextrincontaining peritoneal dialysis may cause false high readings in meters utilizing glucose dehydrogenase methods). Alternate site testing BG meters are now available that allow SMBG using blood samples from sites other than the fingertip (usually the forearm). Limited evidence precludes definitive recommendations regarding alternate site testing, and accuracy of results over a wide range of BG levels has not yet been established. During periods of rapid change in BG levels (e.g. after meals or exercise), fingertip testing has been shown to more accurately reflect glycemic status than forearm testing (19,20).As a result, fingertip testing may be preferred after meals, when medication action is peaking, or when hypoglycemia is suspected. KETONE TESTING Ketone testing is recommended for all people with type 1 diabetes during periods of acute illness, when preprandial BG levels are elevated (>14.0 mmol/L) and when symptoms of diabetic ketoacidosis (DKA), such as nausea, vomiting or abdominal pain, are present (1). If all of these conditions are present, ketone testing should also be considered in those with type 2 diabetes, as DKA can occur in these individuals. Testing methods that measure beta-hydroxybutyric acid (i.e. meter blood tests) may be preferred over those that measure acetoacetate or acetone (i.e. urine tests). During DKA, the equilibrium that is usually present between these ketone bodies shifts toward formation of beta-hydroxybutyric acid.Assays that do not measure beta-hydroxybutyric acid may underestimate total ketone levels. Blood tests that quantify beta-hydroxybutyric acid may be useful in monitoring the treatment of DKA, since acetoacetate or acetone may actually increase as beta-hydroxybutyric acid decreases with effective treatment (1,2). Urine ketone test strips remain the most commonly used method for ketone testing; however, this method is prone to false positive and false negative results in certain circumstances and may provide a less accurate indication of ketoacidosis status (1,2). CONTINUOUS GLUCOSE MONITORING Continuous monitoring of interstitial glucose concentrations using continuous or intermittent devices is now available.While this new technology may provide useful clinical information that will inform the treatment decisions of people with diabetes and their healthcare teams, there are currently no analytical
standards for this method of glucose analysis and insufficient evidence exists to support its widespread use (2,21).
RECOMMENDATIONS
1. A1C should be measured approximately every 3 months to ensure that glycemic goals are being met or maintained [Grade D, Consensus]. 2. All people with diabetes, who are able, should be taught how to self-manage their diabetes, including SMBG [Grade A, Level 1A (4)]. 3. SMBG should be recommended as an essential part of daily diabetes management for all people using insulin or oral antihyperglycemic agents. People with type 1 diabetes should measure their BG at least 3 times per day. The frequency of SMBG in those with type 2 diabetes should be individualized depending on glycemic control and type of therapy. For most people with type 2 diabetes treated with insulin or oral antihyperglycemic agents, BG measurement at least once daily is recommended [Grade C, Level 3 (3)]. In many situations, more frequent testing may be required to provide the information needed to make behavioural or treatment adjustments required to achieve desired BG levels [Grade D, Consensus]. 4. SMBG should include both preprandial and 2-hour postprandial testing [Grade D, Consensus]. 5. Individuals who are conducting SMBG should receive initial instruction and periodic re-education regarding home glucose monitoring [Grade A, Level 1A (4)]. 6. In order to ensure accuracy of BG meter readings, meter results should be compared with laboratory measurement of simultaneous venous FPG at least annually, and when indicators of glycemic control do not match meter readings [Grade D, Consensus]. 7. During periods of acute illness, people with type 1 diabetes should be instructed to perform ketone testing when preprandial BG levels are >14.0 mmol/L and in the presence of symptoms of DKA [Grade D, Consensus]. If all of the conditions noted above are present in someone with type 2 diabetes, ketone testing should be considered [Grade D, Consensus].
OTHER RELEVANT GUIDELINES Targets for Glycemic Control, p. S18 Physical Activity and Diabetes, p. S24 Insulin Therapy in Type 1 Diabetes, p. S32 Hypoglycemia, p. S43 Type 1 Diabetes in Children and Adolescents, p. S84 Pre-existing Diabetes and Pregnancy, p. S94 Gestational Diabetes Mellitus, p. S99 RELEVANT APPENDIX Appendix 4: Self-monitoring of Blood Glucose (SMBG) Records, p. S125
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REFERENCES
1. American Diabetes Association. Tests of glycemia in diabetes. Diabetes Care. 2002;25:S97-S99. 2. Sacks DB, Bruns DE, Goldstein DE, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2002;48:436-472. 3. Karter AJ, Ackerson LM, Darbinian JA, et al. Self-monitoring of blood glucose levels and glycemic control: the Northern California Kaiser Permanente Diabetes Registry. Am J Med. 2001;111:1-9. 4. Norris SL, Engelgau MM, Narayan KMV. Effectiveness of selfmanagement training in type 2 diabetes: a systematic review of randomized controlled trials. Diabetes Care. 2001;24:561-587. 5. Franciosi M, Pellegrini F, De Berardis G, et al. The impact of blood glucose self-monitoring on metabolic control and quality of life in type 2 diabetic patients: an urgent need for better educational strategies. Diabetes Care. 2001;24:1870-1877. 6. Jones H, Edwards L,Vallis TM, et al. Changes in diabetes selfcare behaviors make a difference in glycemic control: the Diabetes Stages of Change (DiSC) study. Diabetes Care. 2003;26:732-737. 7. Rohlfing CL, Wiedmeyer H-M, Little RR, et al. Defining the relationship between plasma glucose and HbA1c: analysis of glucose profiles and HbA1c in the Diabetes Control and Complications Trial. Diabetes Care. 2002;25:275-278. 8. Harris MI. Frequency of blood glucose monitoring in relation to glycemic control in patients with type 2 diabetes. Diabetes Care. 2001;24:979-982. 9. Faas A, Schellevis FG, van Eijk JTM.The efficacy of self-monitoring of blood glucose in NIDDM subjects. A criteria-based literature review. Diabetes Care. 1997;20:1482-1486. 10. Coster S, Gulliford MC, Seed PT, et al. Self-monitoring in type 2 diabetes mellitus: a meta-analysis. Diabet Med. 2000; 17:755-761. 11. Avignon A, Radauceanu A, Monnier L. Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. Diabetes Care. 1997;20:1822-1826. 12. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26:881-885. 13. The DCCT Research Group. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med. 1991;90:450-459. 14. Gale EAM, Tattersall RB. Unrecognised nocturnal hypoglycaemia in insulin-treated diabetics. Lancet. 1979;1:1049-1052. 15. Beregszszi M, Tubiana-Rufi N, Benali K, et al. Nocturnal hypoglycemia in children and adolescents with insulindependent diabetes mellitus: prevalence and risk factors. J Pediatr. 1997;131:27-33. 16. Vervoort G, Goldschmidt HM, van Doorn LG. Nocturnal blood glucose profiles in patients with type 1 diabetes mellitus on multiple (> or = 4) daily insulin injection regimens. Diabet Med. 1996;13:794-799.
17. Jones TW, Porter P, Sherwin RS, et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med. 1998;338:1657-1662. 18. Bergenstal R, Pearson J, Cembrowski GS, et al. Identifying variables associated with inaccurate self-monitoring of blood glucose: proposed guidelines to improve accuracy. Diabetes Educ. 2000;26:981-989. 19. Jungheim K, Koschinsky T. Glucose monitoring at the arm: risky delays of hypoglycemia and hyperglycemia detection. Diabetes Care. 2002;25:956-960. 20. Ellison JM, Stegmann JM, Colner SL, et al. Rapid changes in postprandial blood glucose produce concentration differences at finger, forearm, and thigh sampling sites. Diabetes Care. 2002;25:961-964. 21. Monsod TP, Flanagan DE, Rife F, et al. Do sensor glucose levels accurately predict plasma glucose concentrations during hypoglycemia and hyperinsulinemia? Diabetes Care. 2002; 25:889-893.
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Physical Activity and Diabetes

BENEFITS OF PHYSICAL ACTIVITY Physical activity can help people with diabetes mellitus achieve a variety of goals, including increased cardiorespiratory fitness, increased vigour, improved glycemic control, decreased insulin resistance, improved lipid profile, and maintenance of weight loss (1,2). (The terms physical activity and exercise are used interchangeably in this section.) A systematic review and meta-analysis found that supervised programs involving aerobic or resistance exercise improved glycemic control in adults with type 2 diabetes (3). In contrast, clinical trials evaluating exercise interventions in people with type 1 diabetes have not demonstrated an effect of exercise on glycemic control (4,5). Moderate to high levels of physical activity and cardiorespiratory fitness are associated with substantial reductions in morbidity and mortality in both men and women and in both type 1 and type 2 diabetes. Large cohort studies have demonstrated that in people with type 2 diabetes, regular physical activity (6,7) and/or moderate to high cardiorespiratory fitness (6) were associated with reductions in cardiovascular and overall mortality of 45 to 70% over 12 to 14 years. In type 1 diabetes, a cohort study found that 7-year mortality was 50% lower in those reporting 2000 kcal of weekly exercise (equivalent to 7 hours/week of brisk walking) compared to those reporting <1000 kcal of physical activity per week (8). EXERCISE CONSIDERATIONS IN PEOPLE WITH DIABETES Patients with diabetes should be informed that regular exercise is a key part of their treatment plan. Before beginning a program of physical activity more vigorous than walking, people with diabetes should be assessed for conditions that might contraindicate certain types of exercise, predispose to injury (e.g. severe autonomic neuropathy, severe peripheral neuropathy, preproliferative or proliferative retinopathy, which requires treatment prior to beginning vigorous exercise) or be associated with increased likelihood of cardiovascular disease (CVD). An exercise electrocardiogram (ECG) stress test should be considered for previously sedentary The initial draft of this chapter was prepared by Ronald J. Sigal MD MPH FRCPC; Glen P. Kenny PhD.
individuals with diabetes at high risk for CVD who wish to undertake exercise more vigorous than brisk walking (see Macrovascular Complications, Dyslipidemia and Hypertension, p. S58). Previously sedentary individuals may have to gradually build up their amount of exercise, starting with as little as 5 to 10 minutes/day. Multiple, shorter exercise sessions lasting at least 10 minutes each in the course of a day should be considered, as this regimen is probably as useful as a single longer session of equivalent length and intensity (9,10). Studies have demonstrated a role for both aerobic and resistance exercise in suitable people with diabetes (Table 1 and Table 2). Brisk walking is the most popular and most
Table 1. Aerobic exercise Definition Intensity
Rhythmic, repeated and continuous movements of the same large muscle groups for at least 10 minutes at a time Moderate effort: 5070% of persons maximum heart rate
Examples
Brisk walking Biking Continuous swimming Dancing Water aerobics Raking leaves Brisk walking up an incline Jogging Aerobics Hockey Basketball Fast swimming Fast dancing
Vigorous effort: >70% of persons maximum heart rate
Table 2. Resistance exercise Definition Examples

Activities that use muscular strength to move a weight or work against a resistant load* Weight lifting Exercise with weight machines Start with 1 set of 1015 repetitions, progress to 2 sets of 1015 repetitions, then progress to 3 sets of 8 repetitions, 3 times/week
*Initial instruction and periodic supervision recommended
M A N AG E M E N T
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feasible type of aerobic exercise in most overweight middleaged and elderly people with diabetes. For most middle-aged individuals, moderately brisk walking would be an example of moderate aerobic exercise, while brisk walking up an incline or jogging would be vigorous aerobic exercise. Resistance exercise performed 2 or 3 times/week may provide benefits that complement those of aerobic training (e.g. increased strength and vigour, and increased resting metabolic rate). The studies reporting the greatest impact of resistance exercise on glycosylated hemoglobin (A1C) have had subjects progress to 3 sets of approximately 8 resistance-type exercises at moderately high intensity (8 repetitions at the maximum weight that can be lifted 8 times), 3 times/week (11,12). Individuals wishing to begin resistance exercise should receive initial instruction and periodic supervision by a qualified exercise specialist. During and after all but the most intense exercise, blood glucose (BG) tends to decline due to increased glucose disposal and insulin sensitivity. However, during and especially after brief, very intense exercise (e.g. competitive track and field, hockey, basketball, intense resistance training), BG will rise as a result of increases in glucose production that exceed increases in glucose disposal (13). Despite a strong body of evidence supporting the health benefits of lifestyle modification in people with type 2 diabetes, application in primary care remains a challenge (14). Family physicians can heighten awareness of the importance of physical activity by promoting regular exercise as a key component of therapy and by identifying resources in the community (15,16).
RECOMMENDATIONS
1. An exercise ECG stress test should be considered for previously sedentary individuals with diabetes at high risk for CVD who wish to undertake exercise more vigorous than brisk walking [Grade D, Consensus]. 2. People with type 2 diabetes should accumulate at least 150 minutes of moderate-intensity aerobic exercise each week, spread over at least 3 nonconsecutive days of the week [Grade B, Level 2 (3)] or, if willing, should be encouraged to accumulate 4 hours of exercise per week [Grade C, Level 3 (7)]. 3. People with diabetes (including elderly people) should also be encouraged to perform resistance exercise 3 times per week [Grade B, Level 2 (11,17)].
Foot Care, p. S74 Type 2 Diabetes in Children and Adolescents, p. S91 Pre-existing Diabetes and Pregnancy, p. S94 Gestational Diabetes Mellitus, p. S99 Type 2 Diabetes in Aboriginal Peoples, p. S110 RELATED WEBSITES Beginners Weight Training Program. Available at: http:// www.netfit.co.uk/beginners-weight-web.htm. Accessed November 7, 2003. Diabetes Exercise and Sports Association. Available at: http://www.diabetes-exercise.org. Accessed November 7, 2003. Fitness, Nutrition, Exercise, Forums, Quizzes and Article Experts. Available at: http://www.myfit.ca. Accessed November 7, 2003. Health Canada, Canadian Society for Exercise Physiology. Canadas Physical Activity Guide web site. Available at: http://www.hc-sc.gc.ca/hppb/paguide/. Accessed November 7, 2003. REFERENCES
1. Ivy JL, Zderic TW, Fogt DL. Prevention and treatment of non-insulin-dependent diabetes mellitus. Exerc Sport Sci Rev. 1999;27:1-35. 2. Wing RR. Weight loss in the management of type 2 diabetes. In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:252-276. 3. Boul NG, Haddad E, Kenny GP, et al. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA. 2001; 286:1218-1227. 4. Wallberg-Henriksson H, Gunnarsson R, Rssner S, et al. Long-term physical training in female type 1 (insulindependent) diabetic patients: absence of significant effect on glycaemic control and lipoprotein levels. Diabetologia. 1986;29:53-57. 5. Zinman B, Zuniga-Guajardo S, Kelly D. Comparison of the acute and long-term effects of exercise on glucose control in type I diabetes. Diabetes Care. 1984;7:515-519. 6. Wei M, Gibbons LW, Kampert JB, et al. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med. 2000;132:605-611. 7. Hu FB, Stampfer MJ, Solomon C, et al. Physical activity and risk for cardiovascular events in diabetic women. Ann Intern Med. 2001;134:96-105. 8. Moy CS, Songer TJ, LaPorte RE, et al. Insulin-dependent diabetes mellitus, physical activity, and death. Am J Epidemiol. 1993;137:74-81. 9. Murphy MH, Hardman AE. Training effects of short and long bouts of brisk walking in sedentary women. Med Sci Sports Exerc. 1998;30:152-157. 10. Jakicic JM, Winters C, Lang W, et al. Effects of intermittent exercise and use of home exercise equipment on adherence,
OTHER RELEVANT GUIDELINES Screening and Prevention, p. S10 Monitoring Glycemic Control, p. S21 Insulin Therapy in Type 1 Diabetes, p. S32 Hypoglycemia, p. S43 Macrovascular Complications, Dyslipidemia and Hypertension, p. S58
S26 weight loss, and fitness in overweight women: a randomized trial. JAMA. 1999;282:1554-1560. Dunstan DW, Daly RM, Owen N, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care. 2002;25:1729-1736. Castaneda C, Layne JE, Munoz-Orians L, et al. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes. Diabetes Care. 2002;25:2335-2341. Sigal RJ, Purdon C, Fisher SJ, et al. Hyperinsulinemia prevents prolonged hyperglycemia after intense exercise in insulindependent diabetic subjects. J Clin Endocrinol Metab. 1994; 79:1049-1057. Harris SB, Petrella RJ, Leadbetter W. Use of lifestyle interventions for type 2 diabetes: relevance for family physicians. Can Fam Physician. 2003. In press. Eden KB, Orleans CT, Mulrow CD, et al. Does counseling by clinicians improve physical activity? A summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137:208-215. Petrella RJ, Lattanzio CN. Does counseling help patients get active? Systematic review of the literature. Can Fam Physician. 2002;48:72-80. Durak EP, Jovanovic-Peterson L, Peterson CM. Randomized crossover study of effect of resistance training on glycemic control, muscular strength, and cholesterol in type I diabetic men. Diabetes Care. 1990;13:1039-1043.
11.
12.
13.
14.
15.
16.
17.
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Nutrition Therapy
INTRODUCTION Nutrition therapy is an integral part of the treatment of diabetes mellitus and patient self-management. The goals of nutrition therapy are to improve or maintain quality of life, nutritional status and physiological health, and to prevent and treat the acute and long-term complications of diabetes and the associated comorbid conditions. It is well documented that nutrition therapy can improve glycemic control (1). Nutrition therapy can result in a reduction in glycosylated hemoglobin (A1C) of 1.0 to 2.0% (2-4) and, when used in combination with other components of diabetes care, can further improve clinical and metabolic outcomes (2-4). Individuals with or at risk of diabetes benefit from nutrition and lifestyle counselling provided by a registered dietitian with expertise in diabetes management when delivered in a small group or one-on-one setting (5-7).To achieve sustained metabolic control and improved lifestyle/behavioural outcomes, nutrition therapy should be based on individual needs and should be regularly evaluated and reinforced (8,9). As evidence is limited for the rigid adherence to one dietary prescription over another (10), nutrition therapy and meal planning should be individualized to accommodate the persons preferences, age, needs, culture, lifestyle and readiness to change. In general, people with diabetes should follow a healthy diet recommended for the general population in Canadas Guidelines for Healthy Eating (11). This includes consuming a variety of foods from the 4 food groups (grain products, vegetables and fruits, milk products, meat and alternatives), attaining and maintaining a healthy body weight, decreasing total fat intake to <30% of calories and ensuring an adequate intake of carbohydrate, protein, essential fatty acids, vitamins and minerals. Consistency in meal patterns may help control blood glucose (BG) (12) and weight. Inclusion of snacks as part of a persons meal plan should be individualized based on metabolic control and treatment regimen, and be balanced against the potential risk of weight gain (13).While small, frequent meals may reduce glycemic excursions, frequent food intake The initial draft of this chapter was prepared by Thomas Wolever MD PhD; Rjeanne Gougeon PhD; Catherine Freeze RD CDE; Catherine Field RD PhD; Kansuda Thongthai MD FRCPC.
may also lead to excess energy intake (14). People with diabetes should be counselled to consume snacks only if required due to the demands of antihyperglycemic therapy. CARBOHYDRATE Individuals using insulin therapy should adjust their insulin based on the carbohydrate (starch and sugar) content of their meals. For people with diabetes using intensive insulin treatment regimens, education on matching insulin to carbohydrate content (e.g. carbohydrate counting) is recommended (15) (see Appendix 5). Both the amount (16) and source (17) of carbohydrate in a meal influence the postprandial glycemic response (18). Isocaloric replacement of carbohydrate with monounsaturated fats for periods of 2 to 6 weeks has been shown to reduce acute postprandial glycemic responses (16) and lower fasting plasma triglycerides (TGs) and very low-density lipoprotein cholesterol concentrations without inducing weight gain, although no long-term studies have been conducted (16,19). Consuming a diet containing 40% of energy from carbohydrate, 40% from total fat (29% of energy from monounsaturated fat) for 15 days has been shown to improve insulin sensitivity in subjects with type 2 diabetes compared with a diet containing 60% of energy from carbohydrate and 20% from total fat (13% monounsaturated fat) (20). Replacing high-glycemic-index foods with low-glycemicindex foods in mixed meals reduces acute BG responses in people with type 1 or type 2 diabetes (21,22). Dietary advice aimed at increasing the use of low-glycemic-index foods helps to optimize glycemic control in children and adults with type 1 diabetes by reducing A1C and the number of hypoglycemic episodes (23,24). Choosing low-glycemicindex foods within the same category of food more often may help to optimize glycemic control in patients with type 2 diabetes (25,26).The decision to teach individuals to use the glycemic index should be based on the individual patients interest and ability (see Appendix 6). In general, if a highcarbohydrate diet includes high-glycemic-index foods, refined carbohydrates and low fibre, it may be deleterious, but if it is based on low-glycemic-index foods, it may be beneficial. Sucrose Sucrose intake of up to 10% of total daily energy (e.g. 50 g/day in a 2000 kcal/day diet) is acceptable, as there is no evidence
S28
that sucrose intake up to this level has any deleterious effect on glycemic control or lipids in people with type 1 or type 2 diabetes (27-29). Intake of sucrose >10% of total daily energy may increase BG and TG levels in some individuals (30,31). Fructose Consumption of up to 60 g of added fructose (e.g. fructosesweetened beverages or foods) per day in place of an equal amount of sucrose is unlikely to have any harmful effect for most people with diabetes (32). However, fructose has no definite advantage over sucrose in long-term use. Consumption of >60 g of added fructose per day by people with diabetes is not recommended. Sugar alcohols Sugar alcohols (maltitol, mannitol, sorbitol, isomalt and xylitol) vary in the degree to which they are absorbed. Consumption of >10 g/day may produce adverse gastrointestinal symptoms in some individuals (33). Although there are no long-term studies of consumption of sugar alcohols by people with diabetes, consumption of up to 10 g/day by people with diabetes does not appear to result in adverse effects. Sweeteners Saccharin, aspartame, acesulfame potassium, cyclamates and sucralose have been approved by Health Canada for consumption, and all have been shown to be safe when used by people with
Table 1. Acceptable daily intake* of sweeteners (34) Sweetener
Acesulfame potassium Aspartame Cyclamate Saccharin Sucralose
diabetes (Table 1) (34).While the safety of sweeteners in pregnancy has not been rigorously studied, acesulfame potassium, aspartame and sucralose are acceptable in moderation based on their history of use and lack of reported adverse effects during pregnancy and lactation (35). Saccharin and cyclamates are not recommended during pregnancy and lactation (34,35).
Table 3. Summary of nutritional considerations for people with diabetes
People with diabetes should follow Canadas Guidelines for Healthy Eating Eat a variety of foods Emphasize cereals, breads and other whole grain products, fruits and vegetables Choose lower fat dairy products, leaner meats and foods prepared with little or no fat Achieve and maintain a healthy body weight through regular physical activity and healthy eating Limit sodium, alcohol and caffeine Carbohydrate (5055% of energy) Include whole grains, fruits, vegetables and milk Within the same food category, consume low-glycemicindex foods in place of high-glycemic-index foods Sucrose intake of up to 10% of daily energy is acceptable The use of saccharin, aspartame, acesulfame potassium, cyclamates and sucralose is acceptable Intake of 10 g/day of sugar alcohols (maltitol, mannitol, sorbitol, isomalt and xylitol) can be safe in those for whom it is deemed appropriate Up to 60 g of added fructose (e.g. fructose-sweetened beverages and foods) is acceptable Protein (1520% of energy) There is no evidence to suggest that usual protein intake (1520% of energy) should be modified Fat (<30% of energy) Restrict combined saturated fats and trans fatty acids to <10% of energy intake Limit polyunsaturated fat to <10% of energy intake Consume monounsaturated fats instead of saturated fats more often Include foods rich in polyunsaturated omega-3 fatty acids and plants oils Vitamin and mineral supplements Routine supplementation is not necessary In the case of identified deficiency, limited dietary intake or special need, supplementation may be recommended Alcohol People using insulin or insulin secretagogues should be aware of delayed hypoglycemia that can occur up to 14 hours after alcohol consumption Limit intake to 12 drinks/day (<14 standard drinks/week for men and <9 drinks/week for women)
Acceptable daily intake (mg/kg body weight)

15 40 11 5 9
*Defined as the amount of sweetener that can be safely consumed on a daily basis over a persons lifetime without any adverse effects
Table 2. Examples of standard alcoholic drinks Drink

Beer Table wine Spirits Fortified wine (e.g. sherry, port)
Ethanol content (%)

5 12 40 18
Quantity (mL)
341 (12 oz) 142 (5 oz) 43 (1.5 oz) 85 (3 oz)
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PROTEIN There is no evidence to suggest that the usual protein intake (15 to 20% of energy) needs to be modified in people with diabetes. FAT Current recommendations for the general population of fat intake of <30% of energy apply equally to people with diabetes. Saturated fats and trans fatty acids combined should be restricted to <10% of energy, and polyunsaturated fats should also be limited to <10% of energy. Meal plans should favour monounsaturated fats, when possible, and include foods rich in polyunsaturated omega-3 fatty acids (e.g. fatty fish) and plant oils (e.g. canola, walnut, linseed). Flexibility regarding total fat intake may be appropriate. For example, if an individuals fat intake is primarily composed of mono- and polyunsaturated fats and is low in trans fatty acids, a higher fat intake (i.e. 30% of total daily energy) may be justified (36-38). VITAMIN AND MINERAL SUPPLEMENTS People with diabetes should be encouraged to meet their nutritional needs by consuming a well-balanced diet. Routine vitamin and mineral supplementation is generally not recommended. Supplementation may be recommended in the case of identified deficiency, limited dietary intake (39) or other special need. Antioxidant supplements (vitamin E, vitamin C or beta-carotene) have not demonstrated benefits in cardiovascular disease outcomes or glycemic control (40-42). As there is evidence that long-term beta-carotene supplementation may be harmful when consumed by smokers, antioxidant supplementation should be discussed with patients who smoke (41,43). ALCOHOL The same precautions regarding alcohol consumption in the general population apply to people with diabetes.When consumed with food, moderate amounts of alcohol (1 to 2 standard drinks) (Table 2) do not cause hyperglycemia or hypoglycemia, or require modification of the usual meal plan. Alcohol consumption should be limited to 2 standard drinks/day and <14 standard drinks/week for men and <9 for women (44,45). For people with type 1 diabetes, moderate consumption of alcohol 2 or 3 hours after the evening meal may result in delayed hypoglycemia the next morning after breakfast (46). Alcohol ingestion may mask the symptoms of hypoglycemia (47), reduce hepatic production of glucose, and impair an individuals judgement. Healthcare professionals should discuss alcohol use with their patients (48) to inform them of the potential risks and prevention of hypoglycemia. SUMMARY OF NUTRITIONAL CONSIDERATIONS A summary of nutritional considerations for people with diabetes is shown in Table 3.
RECOMMENDATIONS
1. Nutrition counselling by a registered dietitian is recommended for people with type 2 diabetes [Grade C, Level 3 (3)] and people with type 1 diabetes [Grade D, Consensus] to lower A1C levels. Counselling is equally effective when given in a small group or one-on-one setting [Grade B, Level 2 (5)]. 2.To meet their nutritional needs, individuals with diabetes should be encouraged to follow Canadas Guidelines for Healthy Eating [Grade D, Consensus]. 3. People with diabetes should choose low-glycemic-index foods in place of high-glycemic-index foods within the same category of foods more often to help optimize glycemic control [Grade B, Level 2 (23-26)]. 4. Sucrose and sucrose-containing foods can be substituted for other carbohydrates as part of mixed meals up to a maximum of 10% of energy, provided adequate control of BG and lipids is maintained [Grade B, Level 2 (27,28)]. 5. All people with diabetes should consider restricting combined saturated fats and trans fatty acids to <10% of energy. Meal plans should favour monounsaturated fats, when possible, and include foods rich in polyunsaturated omega-3 fatty acids and plant oils [Grade D, Consensus]. 6. For people with diabetes on intensive insulin treatment regimens, education on matching insulin to carbohydrate content (e.g. carbohydrate counting) is recommended [Grade D, Consensus]. 7. The diabetes healthcare team should discuss alcohol use with people with diabetes [Grade D, Consensus]. People with type 1 diabetes should be informed of the risk of morning hypoglycemia resulting from alcohol consumed 2 to 3 hours after the previous evenings meal [Grade C, Level 3 (46)].
OTHER RELEVANT GUIDELINES Screening and Prevention, p. S10 Physical Activity and Diabetes, p. S24 Management of Obesity in Diabetes, p. S46 Macrovascular Complications, Dyslipidemia and Hypertension, p. S58 Pre-existing Diabetes and Pregnancy, p. S94 Gestational Diabetes Mellitus, p. S99 RELEVANT APPENDICES Appendix 5: Basic Carbohydrate Counting for Diabetes Management, p. S126 Appendix 6:The Glycemic Index, p. S128 Appendix 7: Zimbabwe Hand Jive, p. S130 Appendix 8: Just the Basics:Tips for Healthy Eating, Diabetes Management and Prevention, p. S131
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RELATED WEBSITES Canadian Diabetes Association, Dietitians of Canada. Nutrition Labelling Education Centre. Available at http:// www.healthyeatingisinstore.ca. Accessed November 7, 2003. Health Canada. Canadas Food Guide to Healthy Eating. Available at: http://www.hc-sc.gc.ca/hpfb-dgpsa/onppbppn/food_guide_rainbow_e.html.Accessed November 7, 2003. REFERENCES
1. Pastors JG, Warshaw H, Daly A, et al. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care. 2002;25:608-613. 2. Pi-Sunyer FX, Maggio CA, McCarron DA, et al. Multicenter randomized trial of a comprehensive prepared meal program in type 2 diabetes. Diabetes Care. 1999;22:191-197. 3. Franz MJ, Monk A, Barry B, et al. Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin-dependent diabetes mellitus: a randomized, controlled clinical trial. J Am Diet Assoc. 1995;95:1009-1017. 4. Kulkarni K, Castle G, Gregory R, et al. Nutrition Practice Guidelines for Type 1 Diabetes Mellitus positively affect dietitian practices and patient outcomes. J Am Diet Assoc. 1998;98:62-72. 5. Rickheim PL, Weaver TW, Flader JL, et al. Assessment of group versus individual diabetes education: a randomized study. Diabetes Care. 2002;25:269-274. 6. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 7. Tuomilehto J, Knowler WC, Zimmet P. Primary prevention of non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1992;8:339-353. 8. Clement S. Diabetes self-management education. Diabetes Care. 1995;18:1204-1214. 9. Norris SL, Engelgau MM, Narayan KMV. Effectiveness of selfmanagement training in type 2 diabetes: a systematic review of randomized controlled trials. Diabetes Care. 2001;24:561-587. 10. Christensen NK,Terry RD,Wyatt S, et al. Quantitative assessment of dietary adherence in patients with insulin-dependent diabetes mellitus. Diabetes Care. 1983;6:245-250. 11. Health Canada. Action Towards Healthy Eating Canadas Guidelines for Healthy Eating and Recommended Strategies for Implementation. Ottawa, ON: Health Canada, Health Products and Food Branch, Office of Nutrition Policy and Promotion; 1990. Publication H39-166/1990E. 12. Wolever TMS, Hamad S, Chiasson J-L, et al. Day-to-day consistency in amount and source of carbohydrate intake associated with improved blood glucose control in type 1 diabetes. J Am Coll Nutr. 1999;18:242-247. 13. Kalergis M, Schiffrin A, Gougeon R, et al. Impact of bedtime snack composition on prevention of nocturnal hypoglycemia in adults with type 1 diabetes undergoing intensive insulin
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management using lispro insulin before meals: a randomized, placebo-controlled, crossover trial. Diabetes Care. 2003;26:9-15. Arnold L, Mann JI, Ball MJ. Metabolic effects of alterations in meal frequency in type 2 diabetes. Diabetes Care. 1997; 20:1651-1654. Gillespie SJ, Kulkarni KD, Daly AE. Using carbohydrate counting in diabetes clinical practice. J Am Diet Assoc. 1998;98:897-905. Garg A, Bantle JP, Henry RR, et al. Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus. JAMA. 1994;271:1421-1428. Jenkins DJA,Wolever TMS, Collier GR, et al. Metabolic effects of a low-glycemic-index diet. Am J Clin Nutr. 1987;46:968-975. Wolever TMS, Jenkins DJA, Vuksan V, et al. Variation in meal fat content does not affect the relative glycaemic response of spaghetti in subjects with type II diabetes. Diab Nutr Metab. 1992;5:191-197. Luscombe ND, Noakes M, Clifton PM. Diets high and low in glycemic index versus high monounsaturated fat diets: effects on glucose and lipid metabolism in NIDDM. Eur J Clin Nutr. 1999;53:473-478. Parillo M, Rivellese AA, Ciardullo AV, et al. A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. Metabolism. 1992;41:1373-1378. Hermansen K, Rasmussen O,Arnfred J, et al. Glycemic effects of spaghetti and potato consumed as part of mixed meal on IDDM patients. Diabetes Care. 1987;10:401-406. Collier GR, Wolever TMS, Wong GS, et al. Prediction of glycemic response to mixed meals in noninsulin-dependent diabetic subjects. Am J Clin Nutr. 1986;44:349-352. Giacco R, Parillo M, Rivellese AA, et al. Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients. Diabetes Care. 2000;23:1461-1466. Gilbertson HR, Brand-Miller JC, Thorburn AW, et al. The effect of flexible low glycemic index dietary advice versus measured carbohydrate exchange diets on glycemic control in children with type 1 diabetes. Diabetes Care. 2001;24:1137-1143. Brand JC, Colagiuri S, Crossman S, et al. Low-glycemic index foods improve long-term glycemic control in NIDDM. Diabetes Care. 1991;14:95-101. Frost G,Wilding J, Beecham J. Dietary advice based on the glycaemic index improves dietary profile and metabolic control in type 2 diabetic patients. Diabet Med. 1994;11:397-401. Colagiuri S, Miller JJ, Edwards RA. Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus. Am J Clin Nutr. 1989; 50:474-478. Chantelau EA, Gsseringer G, Sonnenberg GE, et al. Moderate intake of sucrose does not impair metabolic control in pump-treated diabetic out-patients. Diabetologia. 1985; 28:204-207. Cooper PL, Wahlqvist ML, Simpson RW. Sucrose versus
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S31 saccharin as an added sweetener in non-insulin-dependent diabetes: short- and medium-term metabolic effects. Diabet Med. 1988;5:676-680. Coulston AM, Hollenbeck CB, Donner CC, et al. Metabolic effects of added dietary sucrose in individuals with noninsulindependent diabetes mellitus (NIDDM). Metabolism. 1985; 34:962-966. Jellish WS, Emanuele MA, Abraira C. Graded sucrose/carbohydrate diets in overtly hypertriglyceridemic diabetic patients. Am J Med. 1984;77:1015-1022. Nutrition Subcommittee of the British Diabetic Associations Professional Advisory Committee. Sucrose and fructose in the diabetic diet. Diabet Med. 1990;7:764-769. Wolever TMS, Piekarz A, Hollands M, et al. Sugar alcohols and diabetes: a review. Can J Diabetes. 2002;26:356-362. Wolever T, Barbeau M-C, Charron S, et al. Guidelines for the nutritional management of diabetes mellitus in the new millennium: a position statement by the Canadian Diabetes Association. Can J Diabetes Care. 1999;23(3):56-69. Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2002;25:148-198. Howard BV. Dietary fat and diabetes: a consensus view. Am J Med. 2002;113(suppl 9B):38S-40S. Grundy SM, Abate N, Chandalia M. Diet composition and the metabolic syndrome: what is the optimal fat intake? Am J Med. 2002;113(suppl 9B):25S-29S. Jenkins DJA, Kendall CWC, Augustin LSA, et al. High-complex carbohydrate or lente carbohydrate foods? Am J Med. 2002;113(suppl 9B):30S-37S. Barringer TA, Kirk JK, Santaniello AC, et al. Effect of a multivitamin and mineral supplement on infection and quality of life.A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:365-371. The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med. 2000;342:154-160. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of -tocopherol and -carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349:1715-1720. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:23-33 Omenn GS, Goodman GE,Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst. 1996;88:1550-1559. Bondy SJ, Rehm J, Ashley MJ, et al. Low-risk drinking guidelines: the scientific evidence. Can J Public Health. 1999;90:264-270. Ashley MJ, Ferrence R, Room R, et al. Moderate drinking and health. Implications of recent evidence. Can Fam Physician. 1997;43:687-694. 46. Turner BC, Jenkins E, Kerr D, et al.The effect of evening alcohol consumption on next-morning glucose control in type 1 diabetes. Diabetes Care. 2001;24:1888-1893. 47. Kerr D, Macdonald IA, Heller SR, et al. Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes. Diabetologia. 1990;33:216-221. 48. Gallagher A, Connolly V, Kelly WF. Alcohol consumption in patients with diabetes mellitus [letter]. Diabet Med. 2001; 18:72-73.
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Insulin Therapy in Type 1 Diabetes

INTRODUCTION Insulin therapy remains the mainstay of treatment for type 1 diabetes mellitus. Insulin is primarily produced by recombinant DNA technology and is formulated either as chemically identical to human insulin or as a modification of human insulin (insulin analogues) designed to improve pharmacokinetics.Animal insulins are becoming less commercially available. Insulin preparations can be classified according to their duration of action, and further differentiated by their onset of action and peak action time (Table 1). Premixed insulin preparations are available, but are not suitable for patients with type 1 diabetes who usually need to frequently change the individual components of their insulin regimens. INSULIN DELIVERY SYSTEMS Insulin can be administered by syringe, pen (or pen-like device) or pump (continuous subcutaneous insulin infusion [CSII]). Insulin pen devices facilitate the use of multiple injections of insulin and their use should be encouraged. CSII therapy is a safe and effective way to deliver intensive insulin therapy for selected patients and may provide some advantages over other methods of intensive therapy (1-3). INITIATION OF INSULIN THERAPY Patients must receive initial and ongoing education that includes comprehensive information on how to care for and use insulin, recognition and treatment of hypoglycemia, management of sick days, adjustments for food intake and physical activity, and self-monitoring of blood glucose (SMBG). INSULIN REGIMENS A variety of insulin regimens have been used and studied. Insulin regimens should be adapted to an individuals treatment goals, lifestyle, diet, age, general health, motivation, capacity for hypoglycemia awareness and self-management, and social and financial circumstances. After an initial honeymoon period, during which insulin requirements may decrease, insulin requirements will increase with time due to progressive beta cell destruction in both children and adults with type 1 diabetes. The initial draft of this chapter was prepared by Ellen L.Toth MD FRCPC; Jean-FranoisYale MD CSPQ; Keith G. Dawson MD PhD FRCPC.
While fixed-dose regimens (conventional therapy) were previously the most commonly used regimens, and are occasionally still used, they are not preferred. The Diabetes Control and Complications Trial (DCCT) conclusively demonstrated that intensive treatment of type 1 diabetes significantly delays the onset and slows the progression of microvascular complications (4).The most successful protocols for type 1 diabetes rely on basal-bolus regimens with intermediate- or long-acting insulin, or extended long-acting insulin analogue once or twice daily as the basal insulin, and fast-acting insulin or rapid-acting insulin analogue as the bolus insulin for food intake at each meal (intensive therapy). Such protocols attempt to imitate normal pancreatic secretion, which consists of basal insulin secretion and a bolus
Table 1. Types of insulin Insulin type/action Trade names
Rapid-acting analogue (clear) Onset: 1015 min Peak: 6090 min Duration: 45 h Fast-acting (clear) Onset: 0.51 h Peak: 24 h Duration: 58 h Intermediate-acting (cloudy) Onset: 13 h Peak: 58 h Duration: up to 18 h Long-acting (cloudy) Onset: 34 h Peak: 815 h Duration: 2226 h Humalog (insulin lispro) NovoRapid (insulin aspart)
Humulin-R Novolinge Toronto
Humulin-L Humulin-N Novolinge NPH Humulin-U
Extended long-acting analogue Lantus* (insulin glargine) Onset: 90 min Duration: 24 h Premixed (cloudy) A single vial or cartridge contains a fixed ratio of insulin (% rapid- or fastacting to % intermediateacting insulin) Humalog Mix25 Humulin (20/80, 30/70) Novolinge (10/90, 20/80, 30/70, 40/60, 50/50)
*Approved, but not yet available, in Canada
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component (postprandial insulin secretion). Insulin lispro (Humalog) and insulin aspart (NovoRapid) should be administered 0 to 15 minutes before meals; however, since their onset of action is very fast, they can also be administered up to 15 minutes after a meal. Regular insulin should ideally be administered 30 to 45 minutes prior to a meal. Insulin lispro or insulin aspart, in combination with adequate basal insulin, is preferred to regular insulin to achieve postprandial glycemic targets and improve glycosylated hemoglobin (A1C) while minimizing the occurrence of hypoglycemia (5-11). Insulin glargine (Lantus) is an extended long-acting insulin analogue, approved, but not yet available, in Canada, but approved and in use in the United States and Europe.When used as a basal insulin in well-controlled patients (with regular insulin for meals), insulin glargine results in lower fasting plasma glucose (FPG) levels and less nocturnal hypoglycemia compared to once- or twice-daily NPH. No difference in A1C was observed between the 2 regimens after 6 months of treatment (12). Due to its acidic pH, insulin glargine must not be mixed with other insulins in the same syringe.
RECOMMENDATIONS
1.To achieve glycemic targets in people with type 1 diabetes, multiple daily insulin injections (3 or 4 per day) or the use of CSII as part of an intensive diabetes management regimen should be considered [Grade A, Level 1A (4)]. 2. Insulin aspart or insulin lispro, in combination with adequate basal insulin, is preferred to regular insulin to achieve postprandial glycemic targets and improve A1C while minimizing the occurrence of hypoglycemia [Grade B, Level 2 (5-11)]. 3. Insulin lispro or insulin aspart should be used when CSII is used in patients with type 1 diabetes [Grade B, Level 2 (13,14)]. Buffered regular insulin is equally effective in experienced insulin pump users [Grade B, Level 2 (14)]. (Buffered regular insulin is available only by special request through the manufacturer or Health Canada.) 4. Insulin glargine should be considered for use as the basal insulin in well-controlled patients who have problems controlling their FPG levels or to reduce overnight hypoglycemia [Grade B, Level 2 (12)].
include an estimate of cause, frequency, symptoms, recognition, severity and treatment. Severe hypoglycemic reactions and hypoglycemia unawareness Asymptomatic hypoglycemia is the presence of a biochemically low blood glucose (BG) level without any symptoms. Hypoglycemia unawareness occurs when the threshold for the development of autonomic warning symptoms is close to or lower than the threshold for the neuroglycopenic symptoms, such that the first signs of hypoglycemia will often be confusion or loss of consciousness. Severe hypoglycemic reactions are the primary barrier to achieving optimal glycemic control in people with type 1 diabetes (15). Severe hypoglycemic episodes occur frequently during sleep or in the absence of hypoglycemia awareness that alerts patients to take actions to correct their BG levels (16,17). Asymptomatic nocturnal hypoglycemia is common and often lasts >4 hours (16,18-21). Hypoglycemia is more likely to cause seizures during the night than during the day.To reduce the risk of asymptomatic nocturnal hypoglycemia, individuals using intensive insulin therapy should periodically monitor overnight BG levels at a time that corresponds with the peak action time of their overnight insulin. In people with type 1 diabetes, hypoglycemia occurs at an average rate of approximately 2 episodes per week. Increasing frequency of hypoglycemia can lead to a decrease in the hormonal responses to hypoglycemia (22), which, in turn, can lead to decreased awareness of hypoglycemia and defective glucose counterregulation. Hypoglycemia unawareness and defective glucose counterregulation are potentially reversible. Strict avoidance of hypoglycemia for a period of 2 days to 3 months has been associated with improvement in the recognition of severe hypoglycemia, in the counterregulatory hormone responses, or both (23-29). The major risk factors for severe hypoglycemia include a prior episode of severe hypoglycemia (30-32), a current low A1C (<6.0%) (16,31,33,34), hypoglycemia unawareness (35), long duration of diabetes (33,36), autonomic neuropathy (37), adolescence (38) and preschool-age children unable to detect and/or treat mild hypoglycemia on their own (Table 2).
Table 2. Risk factors for severe hypoglycemia
Prior episode of severe hypoglycemia Current low A1C (<6.0%) Hypoglycemia unawareness Long duration of diabetes Autonomic neuropathy Adolescence Preschool-age children unable to detect and/or treat mild hypoglycemia on their own A1C = glycosylated hemoglobin
HYPOGLYCEMIA Drug-induced hypoglycemia is a major obstacle for individuals with type 1 diabetes who are trying to achieve glycemic targets. Hypoglycemia can be severe and result in confusion, coma or seizure, requiring the assistance of other individuals. Significant risk of hypoglycemia often necessitates less stringent glycemic goals. The negative social and emotional impact of hypoglycemia may make patients reluctant to intensify therapy. The diabetes healthcare team should review the patients experience with hypoglycemia at each visit. This should
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Patients at high risk for severe hypoglycemia should be informed of their risk and counselled, along with their significant others, on preventing and treating hypoglycemia (including use of glucagon), preventing driving and industrial accidents through SMBG and taking appropriate precautions prior to the activity, and documenting BG readings taken during sleeping hours. Individuals may need to have their insulin regimen adjusted appropriately to lower their risk. Animal vs. human insulin There is no significant clinical difference between animal and human insulin in terms of the symptomatic response to (39,40) or the frequency of hypoglycemia (41,42). Furthermore, there is no proof that animal insulins afford advantages regarding hypoglycemia awareness (40). Intensive vs. conventional insulin therapy Hypoglycemia is the most common adverse effect of intensive insulin therapy in patients with type 1 diabetes. In the DCCT, 35% of patients in the conventional treatment group and 65% in the intensive group experienced at least 1 episode of severe hypoglycemia (31). In a meta-analysis of 14 trials, the median incidence of severe hypoglycemia was 4.6 and 7.9 episodes per 100 patient-years in the conventionally treated and intensively treated patients, respectively (34). Studies have suggested that with adequate self-management education, appropriate glycemic targets, SMBG and professional support, intensive therapy may result in less hypoglycemia than reported in the DCCT (43-47). Rapid-acting insulin analogues vs. regular insulin Studies have found no differences in the onset, magnitude and temporal pattern of the physiologic, symptomatic and counterregulatory hormonal responses to acute hypoglycemia induced by regular human insulin compared with the rapidacting insulin analogue lispro (48,49). Lifestyle factors Deviations from recommended or appropriate self-management behaviours, such as eating less food, taking more insulin and engaging in more activity, account for 85% of hypoglycemic episodes (50,51). For patients managed with fixed-dose insulin regimens, care should be taken to develop an individualized meal and activity plan that the person can and will follow (52).Adding bedtime snacks may be required to avoid nocturnal hypoglycemia (53,54). Knowledge of the acute effects of exercise is mandatory. Low- to moderate-intensity exercise lowers BG levels both during and after the activity, increasing the risk of a hypoglycemic episode.These effects on BG levels can be modified by altering diet, insulin and the type and timing of exercise. In contrast, high-intensity exercise raises BG levels during and immediately after the event. SMBG before, during and, especially, for many hours after exercise is important for
establishing the patients response to exercise and guiding the appropriate management of exercise. If preprandial BG level is >14.0 mmol/L and urine ketone level is >8.0 mmol/L or blood ketone level is >3.0 mmol/L, exercise should not be performed, as metabolic deterioration will occur (55).
RECOMMENDATIONS
5. Risk factors for severe hypoglycemia should be identified in people with type 1 diabetes so that appropriate strategies can be used to minimize hypoglycemia [Grade D, Consensus]. 6.The following strategies should be implemented to reduce the risk of hypoglycemia and to increase physiologic counterregulatory responses to hypoglycemia in individuals with hypoglycemia unawareness: increased frequency of SMBG, including episodic assessment during sleeping hours; less stringent glycemic targets; and multiple insulin injections [Grade D, Level 4 (27,28)]. 7.All individuals currently using insulin or starting intensive insulin therapy should be counselled about the risk and prevention of insulin-induced hypoglycemia [Grade D, Consensus]. 8. In an attempt to reduce the development of hypoglycemia unawareness in people with type 1 diabetes, the frequency of mild hypoglycemic episodes should be minimized (<3 episodes per week), particularly in those at high risk [Grade D, Level 4 (22)]. 9.To reduce the risk of asymptomatic nocturnal hypoglycemia, individuals should periodically monitor overnight BG levels at a time that corresponds with the peak action time of their overnight insulin and consume a bedtime snack with at least 15 g of carbohydrate and 15 g of protein if their bedtime BG level is <7.0 mmol/L [Grade B, Level 2 (54)].
OTHER RELEVANT GUIDELINES Organization and Delivery of Care, p. S14 Targets for Glycemic Control, p. S18 Monitoring Glycemic Control, p. S21 Physical Activity and Diabetes, p. S24 Nutrition Therapy, p. S27 Pharmacologic Management of Type 2 Diabetes, p. S37 Hypoglycemia, p. S43 Type 1 Diabetes in Children and Adolescents, p. S84 Type 2 Diabetes in Children and Adolescents, p. S91 Pre-existing Diabetes and Pregnancy, p. S94 Gestational Diabetes Mellitus, p. S99 Diabetes in the Elderly, p. S106 Perioperative Glycemic Control, p. S113 Peri-acute Coronary Syndrome Glycemic Control, p. S115 REFERENCES
1. Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive
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S35 insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ. 2002;324:705-708. Tsui E, Barnie A, Ross S, et al. Intensive insulin therapy with insulin lispro: a randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection. Diabetes Care. 2001;24:1722-1727. DeVries JH, Snoek FJ, Kostense PJ, et al. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care. 2002;25:2074-2080. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986. Ciofetta M, Lalli C, Del Sindaco P, et al. Contribution of postprandial versus interprandial blood glucose to HbA1c in type 1 diabetes on physiologic intensive therapy with lispro insulin at mealtime. Diabetes Care. 1999;22:795-800. Raskin P, Guthrie RA, Leiter L, et al. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care. 2000;23:583-588. Home PD, Lindholm A, Riis A. Insulin aspart vs. human insulin in the management of long-term blood glucose control in type 1 diabetes mellitus: a randomized controlled trial. Diabet Med. 2000;17:762-770. Anderson JH Jr, Brunelle RL, Koivisto VA, et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Diabetes. 1997;46:265-270. Holleman F, Schmitt H, Rottiers R, et al. Reduced frequency of severe hypoglycemia and coma in well-controlled IDDM patients treated with insulin lispro. Diabetes Care. 1997; 20:1827-1832. Brunelle BL, Llewelyn J, Anderson JH Jr, et al. Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care. 1998;21:1726-1731. Annuzzi G, Del Prato S, Arcari R, et al. Preprandial combination of lispro and NPH insulin improves overall blood glucose control in type 1 diabetic patients: a multicenter randomized crossover trial. Nutr Metab Cardiovasc Dis. 2001;11:168-175. Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care. 2000;23:639-643. Zinman B, Tildesley H, Chiasson J-L, et al. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes. 1997;46:440-443. Bode B, Weinstein R, Bell D, et al. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care. 2002;25:439-444. Cryer PE. Banting lecture. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes. 1994;43:1378-1389. 16. The DCCT Research Group. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med. 1991;90:450-459. 17. Daneman D, Frank M, Perlman K, et al. Severe hypoglycemia in children with insulin-dependent diabetes mellitus: frequency and predisposing factors. J Pediatr. 1989;115:681-685. 18. Porter PA, Byrne G, Stick S, et al. Nocturnal hypoglycaemia and sleep disturbances in young teenagers with insulin dependent diabetes mellitus. Arch Dis Child. 1996;75:120-123. 19. Gale EAM, Tattersall RB. Unrecognised nocturnal hypoglycaemia in insulin-treated diabetics. Lancet. 1979;1:1049-1052. 20. Beregszszi M, Tubiana-Rufi N, Benali K, et al. Nocturnal hypoglycemia in children and adolescents with insulin-dependent diabetes mellitus: prevalence and risk factors. J Pediatr. 1997;131:27-33. 21. Vervoort G, Goldschmidt HM, van Doorn LG. Nocturnal blood glucose profiles in patients with type 1 diabetes mellitus on multiple (> or = 4) daily insulin injection regimens. Diabet Med. 1996;13:794-799. 22. Ovalle F, Fanelli CG, Paramore DS, et al. Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus. Diabetes. 1998; 47:1472-1479. 23. Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes. 1994;43:1426-1434. 24. Fanelli C, Pampanelli S, Epifano L, et al. Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM. Diabetologia. 1994;37:1265-1276. 25. Dagogo-Jack S, Fanelli CG, Cryer PE. Durable reversal of hypoglycemia unawareness in type 1 diabetes [letter]. Diabetes Care. 1999;22:866-867. 26. Davis M, Mellman M, Friedman S, et al. Recovery of epinephrine response but not hypoglycemic symptom threshold after intensive therapy in type 1 diabetes. Am J Med. 1994;97:535-542. 27. Liu D, McManus RM, Ryan EA. Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months of less strict glycemic control. Clin Invest Med. 1996;19:71-82. 28. Lingenfelser T, Buettner U, Martin J, et al. Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoidance of hypoglycemia in IDDM. Diabetes Care. 1995;18:321-325. 29. Fanelli CG, Epifano L, Rambotti AM, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes. 1993;42:1683-1689. 30. The Diabetes Control and Complications Trial Research Group. 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S37
Pharmacologic Management of Type 2 Diabetes

ORAL ANTIHYPERGLYCEMIC AGENTS, INSULIN AND COMBINATION THERAPIES Type 2 diabetes mellitus is characterized by insulin resistance and progressive beta cell failure.While the usual therapy when diet and exercise have failed is to start with a single oral antihyperglycemic agent of any class, the use of early combination therapy is an option in the management of type 2 diabetes with oral antihyperglycemic agents. The stepwise approach described in the 1998 Clinical Practice Guidelines for the Management of Diabetes in Canada implied that it was acceptable to wait for up to 8 to 16 months before implementing aggressive therapy to treat hyperglycemia (1). However, shortterm hyperglycemia can result in vascular changes, the diagnosis of type 2 diabetes is often delayed and 20 to 50% of people with type 2 diabetes present with microvascular and macrovascular complications at the time of diagnosis (2,3). Therefore, it is now recommended that the management regimens of patients with type 2 diabetes be tailored to the individual patient, aiming for glycemic targets as close to normal as possible and, in most people, as early as possible. The initial use of combinations of submaximal doses of oral antihyperglycemic agents produces more rapid and improved glycemic control compared to monotherapy with the maximal dose of 1 agent, without a significant increase in side effects (4). Furthermore, many patients on monotherapy and with late addition of combination therapy may not attain target blood glucose (BG) levels (5). Multiple therapies may be required to achieve glycemic targets because of the progressive deterioration of glycemic control in type 2 diabetes (5).The choice of antihyperglycemic agent(s) should be based on the individual patient and the factors outlined in Table 1 (3,6-33) and Figure 1. The lag period before adding other antihyperglycemic agent(s) should be kept to a minimum, taking into account the pharmacokinetics of the different agents. With timely adjustments to and/or additions of antihyperglycemic agents, the target glycosylated hemoglobin (A1C) level should be attainable within 6 to 12 months. A combination of oral antihyperglycemic agents and insulin often effectively controls BG levels in adults with type 2 The initial draft of this chapter was prepared by Amir Hanna MB BCh FRCPC FACP;VincentWoo MD FRCPC; Keith G. Dawson MD PhD FRCPC; Stewart B. Harris MD MPH FCFP FACPM. diabetes. When insulin is added to oral antihyperglycemic agent(s), a single injection of intermediate-acting or long-acting insulin (3,34), or extended long-acting insulin analogue (insulin glargine [Lantus], approved, but not yet available, in Canada) (14) may be added at bedtime.This approach may result in better glycemic control with a smaller dose of insulin (35) and may induce less weight gain and less hypoglycemia than the use of insulin alone (36). The combination of bedtime insulin with a biguanide (metformin) leads to less weight gain than insulin plus a sulfonylurea or twice-daily NPH insulin (11). In individuals with type 2 diabetes, insulin therapy (without the concomitant use of oral antihyperglycemic agents) is generally used when diet, exercise, lifestyle and oral antihyperglycemic agents are not effective or are contraindicated. However, insulin may be used as the initial therapy (3), especially in the presence of marked hyperglycemia (A1C 9.0%). Insulin can be used temporarily during illness, pregnancy, stress, a medical procedure or surgery. There is no evidence that exogenous insulin accelerates the risk of macrovascular complications of diabetes, and its appropriate use should be encouraged (37).When insulin is used in type 2 diabetes, the insulin regimen should be tailored to achieve good metabolic control without a significant risk of hypoglycemia.With intensive glycemic control, there is an increased risk of hypoglycemia, but this risk is lower in people with type 2 diabetes than in those with type 1 diabetes.The number of insulin injections (1 to 4/day) and the time of injections may vary depending on each individuals situation (38).There is an increased risk of weight gain with insulin compared to sulfonylureas in type 2 diabetes (3).The reduction in A1C achieved with insulin therapy depends on the dosage and type of insulin. HYPOGLYCEMIA Drug-induced hypoglycemia is the most common cause of hypoglycemia. It is estimated that hypoglycemia of any severity occurs annually in approximately 20% of patients taking insulin secretagogues (39). Although these hypoglycemic episodes are rarely fatal, they can be associated with serious clinical sequelae. Therefore, it is important to prevent, recognize and treat hypoglycemic episodes secondary to the use of insulin secretagogues. Few large, randomized clinical trials have compared the rates of hypoglycemia between these agents. In the United Kingdom Prospective Diabetes Study (UKPDS), the proportion of adults with type 2 diabetes who
S38 Table 1. Antihyperglycemic agents for use in type 2 diabetes

Class Expected decrease Therapeutic considerations in A1C with monotherapy (%)
0.50.8 Not recommended as initial therapy in people with severe hyperglycemia (A1C 9.0%) Mostly used in combination with other oral antihyperglycemic agents Gastrointestinal side effects Treat hypoglycemia with dextrose tablets, milk or honey Contraindicated in patients with renal or hepatic dysfunction, or cardiac failure Use Cockcroft-Gault formula (see Nephropathy, p. S66) to calculate creatinine clearance (<60 mL/min indicates caution or contraindicates the use of metformin) Associated with less weight gain than sulfonylureas and does not cause hypoglycemia Gastrointestinal side effects When initiating insulin, consider adding bedtime intermediate-acting insulin, long-acting insulin or extended long-acting insulin analogue to daytime oral antihyperglycemic agents (although other regimens can be used) Intensive insulin therapy regimen recommended if above fails to attain glycemic targets Causes greatest reduction in A1C and has no maximal dose Increased risk of weight gain relative to sulfonylureas and metformin All insulin secretagogues reduce overall glycemia similarly (except nateglinide) Postprandial glycemia is especially reduced by nateglinide and repaglinide Hypoglycemia and weight gain are especially common with glyburide Consider using other class(es) of antihyperglycemic agents first in patients at high risk of hypoglycemia (e.g. the elderly) If a sulfonylurea must be used in such individuals, gliclazide and glimepiride are associated with less hypoglycemia than glyburide Nateglinide and repaglinide are associated with less hypoglycemia in the context of missed meals
Alpha-glucosidase inhibitor acarbose (Prandase) (6-8)
Biguanide metformin (Glucophage, generic) (9,10)
1.01.5
Insulin (3,11-14)
Depends on regimen
Insulin secretagogues 1.01.5 sulfonylureas: gliclazide (Diamicron, Diamicron 0.5 (for nateglinide) MR, generic) (15,16) glimepiride (Amaryl) (17-19) glyburide (Diabeta, Euglucon, generic) (3) (note: chlorpropamide and tolbutamide are still available in Canada, but rarely used) nonsulfonylureas: nateglinide (Starlix) (20) repaglinide (GlucoNorm) (21-23) Insulin sensitizers (TZDs) (24-32) pioglitazone (Actos) rosiglitazone (Avandia) 1.01.5
Contraindicated in patients with hepatic dysfunction (ALT >2.5 times ULN) or significant cardiac failure Between 6 and 12 weeks required to achieve full BG-lowering effect Triple therapy: addition of TZD to metformin plus sulfonylurea is acceptable May induce mild edema, fluid retention When used in combination with insulin, may increase risk of edema and CHF.The combination of a TZD plus insulin is currently not an approved indication in Canada See rosiglitazone and metformin
Combined formulation of rosiglitazone and metformin (Avandamet) Antiobesity agent orlistat (Xenical) (33)
1.01.5
0.5
Associated with weight loss Gastrointestinal side effects
Physicians should refer to the most current Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, ON) and product monographs for detailed prescribing information. A1C = glycosylated hemoglobin ALT = alanine transaminase BG = blood glucose CHF = congestive heart failure TZD = thiazolidinedione ULN = upper limit of normal
M A N AG E M E N T
S39 Figure 1. Management of hyperglycemia in type 2 diabetes

Clinical assessment and initiation of nutrition therapy and physical activity
Mild to moderate hyperglycemia (A1C <9.0%)
Marked hyperglycemia (A1C 9.0%)
Overweight (BMI 25 kg/m2)
Non-overweight (BMI <25 kg/m2)
Biguanide alone or in combination with 1 of: insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor
1 or 2 antihyperglycemic agents from different classes biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor If not at target
2 antihyperglycemic agents from different classes biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor
Basal and/or preprandial insulin
If not at target
If not at target
If not at target
Add a drug from a different class or Use insulin alone or in combination with: biguanide insulin secretagogue insulin sensitizer* alpha-glucosidase inhibitor
Add an oral antihyperglycemic agent from a different class or insulin*
Intensify insulin regimen or add: biguanide insulin secretagogue** insulin sensitizer* alpha-glucosidase inhibitor
Timely adjustments to and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A1C within 6 to 12 months
THERAPEUTIC NOTES Key adverse effects Gastrointestinal upset, loose bowels biguanide Hypoglycemia insulin, insulin secretagogues (less with gliclazide, glimepiride, nateglinide and repaglinide than with glyburide) Edema, fluid retention insulin sensitizers, rarely with insulin Moderate weight gain insulin, insulin secretagogues, insulin sensitizers Key precautions/contraindications Hepatic disease glyburide, biguanide, insulin sensitizers Significant renal insufficiency biguanide, sulfonylureas Significant cardiac failure biguanide, insulin sensitizers Sulfa allergy sulfonylureas
Recommendations 1 to 6 for grading and level of evidence regarding components of this figure. *When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination of an insulin sensitizer and insulin is currently not an approved indication in Canada. **If using preprandial insulin, do not add an insulin secretagogue. May be given as a combined formulation: rosiglitazone and metformin (Avandamet). Physicians should refer to the most current Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, ON) and product monographs for detailed prescribing information. A1C = glycosylated hemoglobin BMI = body mass index CHF = congestive heart failure
See
S40 RECOMMENDATIONS
1. In people with type 2 diabetes, if glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agents should be initiated [Grade A, Level 1A (3)]. In the presence of marked hyperglycemia (A1C 9.0%), antihyperglycemic agents should be initiated concomitant with lifestyle counselling [Grade D, Consensus]. 2. If glycemic targets are not attained when a single antihyperglycemic agent is used initially, an antihyperglycemic agent or agents from other classes should be added.The lag period before adding other agent(s) should be kept to a minimum, taking into account the pharmacokinetics of the different agents.Timely adjustments to and/or additions of antihyperglycemic agents should be made in order to attain target A1C within 6 to 12 months [Grade D, Consensus]. 3.The choice of antihyperglycemic agent(s) should take into account the individual and the following factors: Unless contraindicated, a biguanide (metformin) should be the primary drug used in overweight patients [Grade A, Level 1A (9)]; and Other classes of antihyperglycemic agents may be used either alone or in combination to attain glycemic targets, with consideration given to the information in Table 1 and Figure 1 [Grade D, Consensus for the order of antihyperglycemic agents listed in Figure 1]. 4. In people with type 2 diabetes, if individual treatment goals have not been reached with a regimen of nutrition therapy, physical activity and sulfonylurea [Grade A, Level 1A (42)], sulfonylurea plus metformin [Grade A, Level 1A (34)] or other oral antihyperglycemic agents [Grade D, Consensus], insulin therapy should be initiated to improve glycemic control. 5. Combining insulin and the following oral antihyperglycemic agents (listed in alphabetical order) has been shown to be effective in people with type 2 diabetes: alpha-glucosidase inhibitors (acarbose) [Grade A, Level 1A (6,43)] biguanide (metformin) [Grade A, Level 1A (11,44,45)] insulin secretagogues (sulfonylureas) [Grade A, Level 1A (12)] insulin sensitizers (thiazolidinediones) [Grade A, Level 1A (46)]. (The combination of an insulin sensitizer plus insulin is currently not an approved indication in Canada.) 6. Insulin may be used as initial therapy in type 2 diabetes [Grade A, Level 1A (3)], especially in cases of marked hyperglycemia (A1C 9.0%) [Grade D, Consensus]. 7.To safely achieve optimal postprandial glycemic control, mealtime insulin lispro or insulin aspart is preferred over regular insulin [Grade B, Level 2 (47,48)]. 8.When insulin given at night is added to oral antihyperglycemic agents, insulin glargine may be preferred over NPH to reduce overnight hypoglycemia [Grade B, Level 2 (14,49)] and weight gain [Grade B, Level 2 (14)]. 9.All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counselled about the recognition and prevention of drug-induced hypoglycemia [Grade D, Consensus].
experienced a severe hypoglycemic episode per year was significantly higher in the intensive group than in the conventional group (3), particularly for patients using insulin therapy. Although the risk of hypoglycemia was less than in the Diabetes Control and Complications Trial, each year approximately 3% of patients treated with insulin in the UKPDS experienced a severe hypoglycemic episode and 40% had a hypoglycemic episode of any severity (3). Lower rates of hypoglycemia have been observed in patients with type 2 diabetes treated with insulin lispro (Humalog) compared to those treated with regular insulin (40,41), with more significant reductions in overnight hypoglycemia despite similar reductions in A1C. OTHER RELEVANT GUIDELINES Insulin Therapy in Type 1 Diabetes, p. S32 Hypoglycemia, p. S43 Management of Obesity in Diabetes, p. S46 Type 2 Diabetes in Children and Adolescents, p. S91 Pre-existing Diabetes and Pregnancy, p. S94 Gestational Diabetes Mellitus, p. S99 Diabetes in the Elderly, p. S106
RELEVANT APPENDIX Appendix 9: Insulin Initiation Options in People With Type 2 Diabetes, p. S135 REFERENCES
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18.
19.
S42 insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1992;327:1426-1433. 35. Johnson JL, Wolf SL, Kabadi UM. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. A metaanalysis of the randomized placebo-controlled trials. Arch Intern Med. 1996;156:259-264. 36. United Kingdom Prospective Diabetes Study Group. United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med. 1998;128:165-175. 37. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 1998; 21:2180-2184. 38. Abraira C, Colwell JA, Nuttall FQ, et al. Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Diabetes Care. 1995;18:1113-1123. 39. Jennings AM, Wilson RM, Ward JD. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care. 1989;12:203-208. 40. Anderson JH Jr, Brunelle RL, Keohane P, et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997;157:1249-1255. 41. Anderson JH Jr, Brunelle RL, Koivisto VA, et al. Improved mealtime treatment of diabetes mellitus using an insulin analogue. Clin Ther. 1997;19:62-72. 42. Shank ML, Del Prato S, DeFronzo RA. Bedtime insulin/daytime glipizide. Effective therapy for sulfonylurea failures in NIDDM. Diabetes. 1995;44:165-172. 43. Coniff RF, Shapiro JA, Seaton TB, et al. A double-blind placebocontrolled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring type II diabetes. Diabetes Care. 1995;18:928-932. 44. Ponssen HH, Elte JWF, Lehert P, et al. Combined metformin and insulin therapy for patients with type 2 diabetes mellitus. Clin Ther. 2000;22:709-718. 45. Avils-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131:182-188. 46. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care. 2001;24: 1226-1232. 47. Ross SA, Zinman B, Campos RV, et al. A comparative study of insulin lispro and human regular insulin in patients with type 2 diabetes mellitus and secondary failure of oral hypoglycemic agents. Clin Invest Med. 2001;24:292-298. 48. Rosenfalck AM,Thorsby P, Kjems L, et al. Improved postprandial glycaemic control with insulin aspart in type 2 diabetic patients treated with insulin. Acta Diabetol. 2000;37:41-46. 49. Yki-Jrvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care. 2000;23:1130-1136.
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Hypoglycemia
INTRODUCTION Drug-induced hypoglycemia is a major obstacle for individuals (especially those with type 1 diabetes) trying to achieve glycemic targets. Hypoglycemia can be severe and result in confusion, coma or seizure requiring the assistance of other individuals. Significant risk of hypoglycemia often necessitates less stringent glycemic goals. The negative social and emotional impact of hypoglycemia may make patients reluctant to intensify therapy. As such, it is important to prevent, recognize and treat hypoglycemic episodes secondary to the use of insulin or insulin secretagogues. See Insulin Therapy in Type 1 Diabetes, p. S32, and Pharmacologic Management of Type 2 Diabetes, p. S37, for further discussion of drug-induced hypoglycemia. DEFINITION OF HYPOGLYCEMIA Hypoglycemia is defined by: 1) the development of autonomic or neuroglycopenic symptoms (Table 1); 2) a low plasma glucose (PG) level (the Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada propose 4.0 mmol/L as an operational clinical cutoff for patients treated with insulin or an insulin secretagogue); and 3) symptoms responding to the administration of carbohydrate (1). The severity of hypoglycemia is defined by clinical manifestations (Table 2). COMPLICATIONS OF SEVERE HYPOGLYCEMIA IN ADULTS Short-term risks of hypoglycemia include the dangerous situations that can arise while an individual is hypoglycemic, whether at home or work (e.g. driving, operating machinery). In addition, prolonged coma is sometimes associated with transient neurological symptoms such as paresis, convulsions and encephalopathy. The potential long-term complications of severe hypoglycemia are mild intellectual impairment and permanent neurologic sequelae such as hemiparesis and pontine dysfunction.The latter are rare and have been reported only in case studies. In adults, retrospective studies have suggested a link between frequent severe hypoglycemia (5 episodes since The initial draft of this chapter was prepared by Jean-Franois Yale MD CSPQ.
diagnosis) and a decrease in intellectual performance. These changes were small but, depending on an individuals occupation, could be clinically meaningful. In contrast, prospective studies have not found an association between intensive insulin therapy and cognitive function (2,3).
Table 1. Symptoms of hypoglycemia Neurogenic (autonomic) Neuroglycopenic
Trembling Palpitations Sweating Anxiety Hunger Nausea Tingling Difficulty concentrating Confusion Weakness Drowsiness Vision changes Difficulty speaking Headache Dizziness Tiredness
Table 2. Severity of hypoglycemia

Mild: Autonomic symptoms are present.The individual is able to self-treat. Moderate: Autonomic and neuroglycopenic symptoms are present.The individual is able to self-treat. Severe: Individual requires assistance of another person. Unconsciousness may occur. PG is typically <2.8 mmol/L. PG = plasma glucose
TREATMENT OF HYPOGLYCEMIA The goals of treatment for hypoglycemia are to detect and treat a low blood glucose (BG) level promptly by using an intervention that provides the fastest rise in BG to a safe level, to eliminate the risk of injury and to relieve symptoms quickly. It is also important to avoid overtreatment, since this can result in rebound hyperglycemia and weight gain. Recent evidence suggests that 15 g of glucose (monosaccharide) is required to produce an increase in BG of approximately 2.1 mmol/L within 20 minutes, with adequate symptom relief for most people (Table 3) (4-8).This has not been well studied in patients with gastropathy. A 20-g oral glucose dose will produce a BG increment of approximately 3.6 mmol/L at 45 minutes (5,6). Other choices such as milk and orange juice are slower to increase BG levels and provide symptom relief (5,6). Glucose gel is quite slow (<1.0 mmol/L increase at 20 minutes) and must be swallowed to have a
S44 RECOMMENDATIONS
1. In hospitalized patients, efforts must be made to ensure that patients using insulin have ready access to an appropriate form of glucose at all times, particularly when NPO or during diagnostic procedures [Grade D, Consensus]. 2. In adults, mild to moderate hypoglycemia should be treated by the oral ingestion of 15 g of carbohydrate, preferably as glucose or sucrose tablets or solution. These are preferable to orange juice and glucose gels [Grade B, Level 2 (4)]. Patients should be encouraged to wait 15 minutes, retest BG and retreat with another 15 g of carbohydrate if the BG level remains <4.0 mmol/L. In smaller children (<5 years of age or <20 kg), 10 g of carbohydrate may be used initially [Grade D, Consensus]. 3. Severe hypoglycemia in a conscious adult should be treated by the oral ingestion of 20 g of carbohydrate, preferably as glucose tablets or equivalent. Patients should be encouraged to wait 15 minutes, retest BG and retreat with another 15 g of glucose if the BG level remains <4.0 mmol/L [Grade D, Consensus]. 4. Severe hypoglycemia in an unconscious individual 5 years of age, in the home situation, should be treated with 1 mg of glucagon subcutaneously or intramuscularly. In children <5 years of age, a dose of 0.5 mg of glucagon should be given. Caregivers or support persons should call for emergency services and the episode should be discussed with the diabetes healthcare team as soon as possible [Grade D, Consensus]. 5. In the home situation, support persons should be taught how to administer glucagon by injection [Grade D, Consensus]. 6. For severe hypoglycemia with unconsciousness in adults, when intravenous (IV) access is available, glucose 10 to 25 g (20 to 50 cc of D50W) should be given over 1 to 3 minutes.The pediatric dose of glucose for IV treatment is 0.5 to 1 g/kg [Grade D, Consensus]. 7. In hospitalized patients, a PRN order for glucagon should be considered for any patient at risk for severe hypoglycemia (i.e. requiring insulin and hospitalized for concurrent illness) when IV access is not readily available [Grade D, Consensus]. 8.To prevent repeated hypoglycemia, once the hypoglycemia has been reversed, the person should have the usual meal or snack that is due at that time of the day. If a meal is >1 hour away, a snack (including 15 g of carbohydrate and a protein source) is recommended in the absence of complicating factors [Grade D, Consensus].
Table 3. Examples of 15 g of carbohydrate for the treatment of mild to moderate hypoglycemia

15 g of glucose in the form of glucose tablets 15 mL (3 teaspoons) or 3 packets of table sugar dissolved in water 175 mL (3/4 cup) of juice or regular soft drink 6 Life Savers (1=2.5 g of carbohydrate) 15 mL (1 tablespoon) of honey
OTHER RELEVANT GUIDELINES Targets for Glycemic Control, p. S18 Monitoring Glycemic Control, p. S21 Insulin Therapy in Type 1 Diabetes, p. S32 Pharmacologic Management of Type 2 Diabetes, p. S37 Type 1 Diabetes in Children and Adolescents, p. S84 Pre-existing Diabetes and Pregnancy, p. S94 Diabetes in the Elderly, p. S106 RELATED GUIDELINES Begg IS, Yale J-F, Houlden RL, et al. Canadian Diabetes Associations clinical practice guidelines for diabetes and private and commercial driving. Can J Diabetes. 2003;27:128-140. Available at: http://www.diabetes.ca/ Files/Diabetes%20and%20Driving%20Guidelines-June%202003--FINAL.pdf. Accessed November 7, 2003. REFERENCES
1. Hepburn DA. Symptoms of hypoglycaemia. In: Frier BM, Fisher BM, eds. Hypoglycaemia and Diabetes: Clinical and Physiological Aspects. London, UK: Edward Arnold; 1993:93-103. 2. The Diabetes Control and Complications Trial Research Group. Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Ann Intern Med. 1996;124:379-388. 3. Reichard P, Pihl M. Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study. Diabetes. 1994; 43:313-317. 4. Slama G,Traynard P-Y, Desplanque N, et al.The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Arch Intern Med. 1990;150:589-593. 5. Wiethop BV, Cryer PE.Alanine and terbutaline in treatment of hypoglycemia in IDDM. Diabetes Care. 1993;16:1131-1136. 6. Brodows RG, Williams C, Amatruda JM. Treatment of insulin reactions in diabetics. JAMA. 1984;252:3378-3381. 7. Special problems. In: Skyler JS, ed. Medical Management of Type 1 Diabetes. 3rd ed. Alexandria, VA: American Diabetes Association; 1998:134-143. 8. Canadian Diabetes Association. The role of dietary sugars in diabetes mellitus. Beta Release. 1991;15:117-123. 9. Monoject insulin reaction gel [product monograph]. Montreal, QC: Schering Canada Inc.; 1999.
significant effect (4,9,10). (Patients taking an alpha-glucosidase inhibitor [acarbose (Prandase)] must use glucose [dextrose] tablets or, if unavailable, milk or honey to treat hypoglycemia [11].) Glucagon 1 mg subcutaneously or intramuscularly produces a significant increase in BG (from 3.0 to 12.0 mmol/L) within 60 minutes (12).
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S45 10. Gunning RR, Garber AJ. Bioactivity of instant glucose. Failure of absorption through oral mucosa. JAMA. 1978;240:1611-1612. 11. Prandase (acarbose) [product monograph]. Toronto, ON: Bayer Inc.; 2001. 12. Cryer PE, Fisher JN, Shamoon H. Hypoglycemia. Diabetes Care. 1994;17:734-755.
S46
Management of Obesity in Diabetes

INTRODUCTION An estimated 80 to 90% of persons with type 2 diabetes mellitus are overweight or obese. Obesity is also a growing problem in children with type 1 diabetes (1). Furthermore, intensive insulin therapy is associated with weight gain (2). Weight loss has been shown to improve glycemic control by increasing insulin sensitivity and glucose uptake, and diminishing hepatic glucose output (3,4).The risk of death from all causes, cardiovascular disease (CVD) and some forms of cancer increases with excessive body fat (5). This relationship between increasing body fat accumulation and adverse health outcomes exists throughout the range of overweight and obese men and women in all age groups, including those 75 years of age (6).While the relationship between increasing adiposity and adverse health effects has not been extensively examined in people with diabetes, it is likely that similar, if not greater, benefits are conferred to people with diabetes with lower body fat content or body mass index (BMI). ASSESSMENT OF BODY WEIGHT The initial assessment of people with diabetes should include height and weight measurements, calculation of BMI (kg/m2) (Table 1), and waist circumference to assess the degree of abdominal fat (7). Metabolic comorbidities, such as hypertension, dyslipidemia and CVD, should also be assessed since they are highly correlated with increasing BMI (8,9). Excessive upper body fat, or abdominal obesity, is a strong independent predictor of metabolic comorbidities (10,11). Waist circumference values 102 cm (40 inches) in men and 88 cm (35 inches) in women are associated with substantially increased abdominal fat accumulation and health risks (Table 2) (7). TREATMENT OF OBESITY The goals of therapy for overweight and obese people with diabetes are to reduce body fat, attain and maintain a healthy or lower body weight for the long term, and prevent weight regain. In general, obese people with diabetes have greater difficulty with weight loss compared to similarly obese people without diabetes (12). A modest weight loss of 5 to 10% of initial body weight can substantially improve insulin The initial draft of this chapter was prepared by David C.W. Lau MD PhD FRCPC; Rjeanne Gougeon PhD.
sensitivity, glycemic control, high blood pressure (BP) and dyslipidemia (13-17).The optimal rate of weight loss is 1 to 2 kg/month (2 to 4 lb/month). A negative energy balance of 500 kcal/day is required to achieve a weight loss of 0.45 kg/week (1 lb/week) (18). Lifestyle interventions for weight loss Lifestyle intervention is recommended for weight loss in order to improve health status and quality of life (18,19). In people with diabetes who are overweight or obese, achieving a healthy weight through an active lifestyle promotes a general sense of well-being and cardiovascular (CV) fitness, along with other benefits, such as reducing CVD, morbidity, mortality and other complications attributable to obesity (20). Lifestyle interventions that combine dietary modification, increased and regular physical activity and behaviour therapy are the most effective (21-23). Structured interdisciplinary
Table 1. Canadian Guidelines for Body Weight Classification in Adults using BMI (7) Classification BMI* category Risk of developing (kg/m2) health problems
Underweight Normal weight Overweight Obese Class I Class II Class III <18.5 18.524.9 25.029.9 30.0 30.034.9 35.039.9 40.0 Increased Least Increased High Very high Extremely high
*BMI values are age and gender independent, and may not be correct for all ethnic populations BMI = body mass index
Table 2. WC and risk of developing health problems (7) WC cutoff points Risk of developing health problems
Men 102 cm (40 inches) Women 88 cm (35 inches) WC = waist circumference Increased Increased
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programs have demonstrated the best short- and long-term results (22). Ongoing follow-up with the healthcare team is important to plan individualized dietary and activity changes to facilitate weight loss. Adjustments to antihyperglycemic agents may be required as the individual with diabetes loses weight (24). All weight-loss diets must be well balanced and nutritionally adequate to ensure optimal health. In general, a carbohydrate intake of at least 100 g/day is required to spare protein breakdown and muscle wasting, and to avoid large shifts in fluid balance and ketosis. High-fibre foods that take longer to eat and digest are associated with greater satiety. Adequate protein intake is required to maintain lean body mass and other essential physiological processes. Reduced intake of saturated fat and energy-dense foods should be emphasized to achieve the required daily energy deficit to promote weight loss. Very low-calorie diets with <900 kcal/day are not recommended, except under medical supervision. The efficacy and safety of low-carbohydrate diets, such as the Atkins Diet, with relatively high intake of protein and fat, have recently been studied (25-28). A systematic review concluded that the weight loss experienced with low-carbohydrate diets was mainly due to decreased caloric intake and increased diet duration (25). In a 12-month, randomized, controlled trial, low-carbohydrate diets resulted in greater weight loss than did low-fat diets (absolute difference of 4% of body weight) in the first 6 months, but the differences were not significant at 12 months (27). Another randomized trial in class III, severely obese subjects with a high prevalence of the metabolic syndrome or type 2 diabetes observed a 3-fold greater weight loss with low-carbohydrate diets than with low-fat diets, and greater improvement in triglyceride levels, fasting serum glucose levels and insulin sensitivity at 6 months (28). A third trial of similar duration also confirmed greater weight and fat losses with a low-carbohydrate diet (26).While no deleterious effects were noted with low-carbohydrate diets, longterm follow-up and assessment of CV outcomes are required before such diets can be recommended for weight loss. Pharmacologic therapy Pharmacotherapy for overweight people with diabetes not only improves glycemic control, but also results in a significant
reduction in the dosages of oral antihyperglycemic agents (24). Pharmacotherapy is an acceptable adjunct in the short- and long-term management of obesity when lifestyle measures fail to achieve the desired weight loss after an adequate trial of 3 to 6 months (18,29). Drug therapy can be considered for patients with BMI 30.0 kg/m2 with no obesity-related comorbidities or risk factors, or BMI 27.0 kg/m2 with obesityrelated comorbidities or risk factors (18). Antiobesity drug therapy may be considered as an adjunct to nutrition therapy, physical activity and behaviour modification to achieve a target weight loss of 5 to 10% of initial body weight and for weight maintenance (18,29). Two drugs, orlistat (Xenical) and sibutramine (Meridia), have been approved in Canada for long-term management of obesity (Table 3). Drug therapy leads to even greater weight loss when coupled with lifestyle intervention and behaviour therapy. Both drugs have been shown to be effective in obese people with type 2 diabetes, improving glycemic and metabolic control, and resulting in favourable changes in lipid levels, BP profiles and fat distribution (24,30,31). In obese people with impaired glucose tolerance (IGT), orlistat also improves glucose tolerance and reduces the progression from IGT to type 2 diabetes (32). Clinical trials with antiobesity agents have confirmed a smaller degree of weight loss in people with diabetes compared with obese people who do not have diabetes (12,24). Other available antiobesity drugs, such as diethylpropion (Tenuate) and phentermine (Ionamin), are sympathomimetic noradrenergic appetite suppressants that are approved only for short-term use of a few weeks. They are not recommended because of modest efficacy and frequent adverse side effects. Surgery Patients who are candidates for surgical procedures should be carefully selected after evaluation by an interdisciplinary team with medical, surgical, psychiatric and nutritional expertise. Surgery is usually reserved for people with class III obesity (BMI 40.0 kg/m2), or class II obesity (BMI=35.0 to 39.9 kg/m2) in the presence of comorbidities (33) and the inability to achieve weight-loss goals following an adequate trial of lifestyle intervention (18). Long-term, if not lifelong, medical surveillance after surgical therapy is necessary for most
Table 3. Antiobesity agents for use in type 2 diabetes Class Generic (trade) name Action
Gastrointestinal lipase inhibitor Orlistat (Xenical) Nonsystemic pancreatic lipase inhibitor that exerts its therapeutic activity in the stomach and gastrointestinal tract by reducing dietary fat digestion and absorption by about 30% Enhances satiety and decreases hunger by inhibiting norepinephrine and serotonin reuptake May also increase thermogenesis and prevent the decline in energy expenditure following weight loss
Norepinephrine and serotonin reuptake inhibitor
Sibutramine (Meridia)
S48
patients. Gastric restrictive or bypass procedures could be considered for well-informed and motivated patients with acceptable operative risks (34).The Roux-en-Y gastric bypass appears to be the most successful and preferred procedure (18,35,36).
RECOMMENDATIONS
1. An interdisciplinary program of lifestyle modification, including regular physical activity or exercise and calorie reduction, should be implemented to promote longterm weight loss, weight maintenance and prevention of weight gain [Grade D, Consensus]. 2. A weight-loss goal of 5 to 10% of initial body weight over a 6-month period should be recommended to improve overall metabolic and glycemic control in obese people with type 2 diabetes [Grade C, Level 3 (14)].The recommended energy deficit should be approximately 500 kcal/day, which can lead to an expected weight loss of 1 to 2 kg/month (2 to 4 lb/month) [Grade D, Consensus]. 3. In obese people with type 2 diabetes, medical therapy with the antiobesity agent orlistat (gastrointestinal lipase inhibitor) [Grade A, Level 1A (24)] or sibutramine (norepinephrine and serotonin reuptake inhibitor) [Grade B, Level 2 (31)] may be considered as an adjunct to lifestyle modification to expedite achievement of weight-loss goals and weight maintenance. 4. For individuals with class III obesity (BMI 40.0 kg/m2) or class II obesity (BMI=35.0 to 39.9 kg/m2) with comorbidities who are unable to achieve weight-loss goals following an adequate trial of lifestyle intervention, bariatric surgery may be considered to reduce metabolic comorbidities [Grade C, Level 3 (37)].
OTHER RELEVANT GUIDELINES Screening and Prevention, p. S10 Physical Activity and Diabetes, p. S24 Nutrition Therapy, p. S27 RELATED WEBSITE Office of Nutrition Policy and Promotion, Health Canada. Available at: http://www.hc-sc.gc.ca/hpfb-dgpsa/onppbppn/index_e.html. Accessed November 7, 2003. REFERENCES
1. Hyppnen E, Virtanen SM, Kenward MG, et al. Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care. 2000;23:1755-1760. 2. The Diabetes Control and Complications Trial Research Group. Influence of intensive diabetes treatment on body weight and composition of adults with type 1 diabetes in the Diabetes Control and Complications Trial. Diabetes Care. 2001;24:1711-1721. 3. Ruderman N, Chisholm D, Pi-Sunyer X, et al. The metabolically obese, normal-weight individual revisited. Diabetes. 1998;47:699-713.
4. Markovic TP, Jenkins AB, Campbell LV, et al.The determinants of glycemic responses to diet restriction and weight loss in obesity and NIDDM. Diabetes Care. 1998;21:687-694. 5. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003; 348:1625-1638. 6. Stevens J, Cai J, Pamuk ER, et al.The effect of age on the association between body-mass index and mortality. N Engl J Med. 1998;338:1-7. 7. Health Canada. Canadian Guidelines for Body Weight Classification in Adults. Ottawa, ON: Health Canada; 2003. Publication H49-179/2003E. Available at: http://www.hc-sc.gc.ca/ hpfb-dgpsa/onpp-bppn/weight_book_tc_e.html. Accessed November 7, 2003. 8. Rabkin SW, Chen Y, Leiter L, et al. Risk factor correlates of body mass index. CMAJ. 1997;157(suppl 1):S26-S31. 9. World Health Organization. Obesity:Preventing and Managing the Global EpidemicReport of a WHO Consultation on Obesity, 35 June 1997, Geneva. Geneva, Switzerland: World Health Organization; 1998. 10. Reeder BA, Senthilselvan A, Desprs J-P, et al.The association of cardiovascular disease risk factors with abdominal obesity in Canada. CMAJ. 1997;157(suppl 1):S39-S45. 11. Desprs J-P, Lemieux I, Prudhomme D.Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ. 2001;322:716-720. 12. Wing RR, Marcus MD, Epstein LH, et al. Type II diabetic subjects lose less weight than their overweight nondiabetic spouses. Diabetes Care. 1987;10:563-566. 13. Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56:320-328. 14. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord. 1992;16:397-415. 15. Elmer PJ, Grimm R Jr, Laing B, et al. Lifestyle intervention: results of the Treatment of Mild Hypertension Study (TOMHS). Prev Med. 1995;24:378-388. 16. Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344:1343-1350. 17. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 18. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adultsthe evidence report. Obes Res. 1998;6(suppl 2): 51S-209S. 19. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl J Med. 1999;341:427-434. 20. Williamson DF, Thompson TJ, Thun M, et al. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care. 2000;23:1499-1504.
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S49 21. Pavlou KN, Krey S, Steffee WP. Exercise as an adjunct to weight loss and maintenance in moderately obese subjects. Am J Clin Nutr. 1989;49:1115-1123. 22. Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr. 2001;21:323-341. 23. Wing RR, Goldstein MG, Acton KJ, et al. Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity. Diabetes Care. 2001;24:117-123. 24. Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care. 1998;21:1288-1294. 25. Bravata DM, Sanders L, Huang J, et al. Efficacy and safety of low-carbohydrate diets: a systematic review. JAMA. 2003; 289:1837-1850. 26. Brehm BJ, Seeley RJ, Daniels SR, et al. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab. 2003;88:1617-1623. 27. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med. 2003; 348:2082-2090. 28. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348:2074-2081. 29. National Task Force on the Prevention and Treatment of Obesity. Long-term pharmacotherapy in the management of obesity. JAMA. 1996;276:1907-1915. 30. Scheen AJ, Lefbvre PJ. Antiobesity pharmacotherapy in the management of type 2 diabetes. Diabetes Metab Res Rev. 2000;16:114-124. 31. Finer N, Bloom SR, Frost GS, et al. Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double-blind, placebo-controlled study. Diabetes Obes Metab. 2000;2:105-112. 32. Heymsfield SB, Segal KR, Hauptman J, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med. 2000;160:1321-1326. 33. Melissas J, Christodoulakis M, Spyridakis M, et al. Disorders associated with clinically severe obesity: significant improvement after surgical weight reduction. South Med J. 1998; 91:1143-1148. 34. Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement. Am J Clin Nutr. 1992;55:615S-619S. 35. Hall JC,Watts JM, OBrien PE, et al. Gastric surgery for morbid obesity.The Adelaide Study. Ann Surg. 1990;211:419-427. 36. MacLean LD, Rhode BM, Sampalis J, et al. Results of the surgical treatment of obesity. Am J Surg. 1993;165:155-162. 37. Sjstrm CD, Lissner L, Wedel H, et al. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. 1999;7:477-484.
S50
Psychological Aspects of Diabetes

INTRODUCTION Diabetes mellitus is a psychologically and behaviourally demanding disease, and psychosocial factors are relevant to nearly all aspects of its management (1). ADJUSTMENT PROBLEMS Stress (2), inadequate social and family support (3,4), and poor coping skills (5) may have a negative impact on self-care and glycemic control. Beliefs regarding how serious and controllable diabetes is also influence self-care and glycemic control (6). Many children have adjustment problems soon after the diagnosis of diabetes (7,8). Although most children resolve these problems within the first year after diagnosis, those who do not are at risk for poor adaptation to diabetes, including regimen adherence problems, poor glycemic control and continued psychosocial difficulties (9,10). In view of this, individuals (adults and children) as well as their families (particularly families of children with diabetes) should be regularly screened for adjustment disorders and preventive psychological interventions should be incorporated into standard care. Healthcare professionals should explore the potential role of psychological factors by asking open-ended questions about stress in patients lives, the availability and quality of social support, behaviours that could impair glycemic control and patients beliefs regarding the cause of their diabetes, their risk of complications and the efficacy of their treatment. Direct questioning should be used to determine the amount of psychological distress associated with the problem, as well as the degree to which the problem interferes with normal functioning. Specific psychological issues identified should be addressed using psychosocial services available within diabetes healthcare teams or more generally in the community. DEPRESSION Depression is twice as common in people with diabetes as in the general population (11,12), and major depression is present in at least 15% of patients with diabetes (13). Depression is associated with poorer glycemic control, health complications, decreased quality of life and increased healthcare The initial draft of this chapter was prepared by Robyn Houlden MD FRCPC; Helen Jones RN MSN CDE;T. MichaelVallis PhD.
costs (1,9,12). People with diabetes should be screened for depression regularly, either with direct questioning (e.g. During the past month, have you often been bothered by feeling down, depressed, or hopeless? and During the past month, have you often been bothered by little interest or pleasure in doing things?) (14) or with a standardized questionnaire (e.g. Beck Depression Inventory [15], the Problem Areas in Diabetes scale [16]). ANXIETY There has been less focus on anxiety disorders (excessive worry that interferes with quality of life and/or behaviour) in people with diabetes than depression, but there is limited evidence to suggest that the prevalence of phobic disorders (17) and generalized anxiety disorders (8) is elevated in those with type 1 diabetes. Needle phobias (18) and fear of hypoglycemia (19) are not uncommon in those with diabetes and, when present, can have a negative impact on diabetes control and care. People with diabetes should be regularly screened for anxiety disorders, especially fear of needles and hypoglycemia, as well as for generalized anxiety about diabetes control and complications. EATING DISORDERS Eating disorders are frequently observed in young women and adolescent females with type 1 diabetes (20,21) and are associated with poorer glycemic control (22,23) and an increased risk of long-term complications (24). Therefore, these individuals should be regularly screened for eating disorders.Those with an identified or suspected eating disorder should be referred to a medical team or professional knowledgeable in treating such disorders. INTERVENTIONS A variety of psychological and educational interventions have been shown to enhance psychological adjustment to diabetes. Effective interventions include psychosocial support and reinforcement (25-28), coping skills training (29), cognitive-behaviour therapy (30), and family behaviour therapy (31,32). Approaches that increase patient participation in decision making regarding care and education have been shown to be more effective than a do as I say approach in enhancing psychological adjustment to diabetes and potentially preventing psychological distress (27,33,34).
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Healthcare professionals should therefore encourage patients with diabetes to participate in healthcare decision making. Antidepressant medication and cognitive-behaviour therapy have been shown to be specifically effective in treating depression in people with diabetes (35,36).
RECOMMENDATIONS
1. Individuals with diabetes should be regularly screened for psychosocial problems, depression and anxiety disorders [Grade D, Consensus] by direct questioning or with a standardized questionnaire [Grade B, Level 2 (15)]. Those diagnosed with depression should be offered treatment with cognitive-behaviour therapy [Grade B, Level 2 (36)] and/or antidepressant medication [Grade B, Level 2 (35)]. 2. Individuals with diabetes should be regularly screened for psychological problems by open-ended questioning about stress, social support, beliefs about their disease and behaviour that could impair glycemic control [Grade D, Consensus]. Interventions including ongoing psychological support and reinforcement, coping skills training and family behaviour therapy should be offered as appropriate [Grade B, Level 2 (25,29,31)]. 3. Interventions that increase patients participation in healthcare decision making should be offered to adults with diabetes [Grade B, Level 2 (27)].
8.
9.
10.
11.
12.
13.
14.
15.
OTHER RELEVANT GUIDELINES Organization and Delivery of Care, p. S14 Type 1 Diabetes in Children and Adolescents, p. S84 Type 2 Diabetes in Children and Adolescents, p. S91 REFERENCES
1. Delamater AM, Jacobson AM, Anderson B, et al. Psychosocial therapies in diabetes. Report of the Psychosocial Therapies Working Group. Diabetes Care. 2001;24:1286-1292. 2. Lloyd CE, Dyer PH, Lancashire RJ, et al. Association between stress and glycemic control in adults with type 1 (insulindependent) diabetes. Diabetes Care. 1999;22:1278-1283. 3. Schafer LC, McCaul KD, Glasgow RE. Supportive and nonsupportive family behaviors: relationships to adherence and metabolic control in persons with type I diabetes. Diabetes Care. 1986;9:179-185. 4. Skinner TC, Hampson SE. Social support and personal models of diabetes in relation to self-care and well-being in adolescents with type I diabetes mellitus. J Adolesc. 1998;21:703-715. 5. Peyrot MF, McMurry JF Jr. Stress buffering and glycemic control: the role of coping styles. Diabetes Care. 1992;15:842-846. 6. Lewis KS, Bradley C. Measures of diabetes-specific health beliefs. In: Bradley C, ed. Handbook of Psychology and Diabetes:A Guide to Psychological Measurement in Diabetes Research and Practice. Chur, Switzerland: Harwood Academic Publishers; 1994:247-289. 7. Jacobson AM, Hauser ST, Wertlieb D, et al. Psychological
16.
17.
18.
19.
20.
21.
22.
23.
adjustment of children with recently diagnosed diabetes mellitus. Diabetes Care. 1986;9:323-329. Kovacs M, Goldston D, Obrosky DS, et al. Psychiatric disorders in youths with IDDM: rates and risk factors. Diabetes Care. 1997;20:36-44. Grey M, Cameron ME, Lipman TH, et al. Psychosocial status of children with diabetes in the first 2 years after diagnosis. Diabetes Care. 1995;18:1330-1336. Jacobson AM, Hauser ST, Lavori P, et al. Family environment and glycemic control: a four-year prospective study of children and adolescents with insulin-dependent diabetes mellitus. Psychosom Med. 1994;56:401-409. Anderson RJ, Freedland KE, Clouse RE, et al.The prevalence of comorbid depression in adults with diabetes: a metaanalysis. Diabetes Care. 2001;24:1069-1078. Egede LE, Zheng D, Simpson K. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care. 2002;25:464-470. Garvard JA, Lustman PJ, Clouse RE. Prevalence of depression in adults with diabetes: an epidemiological evaluation. Diabetes Care. 1993;16:1167-1178. Whooley MA, Avins AL, Miranda J, et al. Case-finding instruments for depression.Two questions are as good as many. J Gen Intern Med. 1997;12:439-445. Lustman PJ, Clouse RE, Griffith LS, et al. Screening for depression in diabetes using the Beck Depression Inventory. Psychosom Med. 1997;59:24-31. Welch GW, Jacobson AM, Polonsky WH.The Problem Areas in Diabetes scale.An evaluation of its clinical utility. Diabetes Care. 1997;20:760-766. Popkin MK, Callies AL, Lentz RD, et al. Prevalence of major depression, simple phobia, and other psychiatric disorders in patients with long-standing type I diabetes mellitus. Arch Gen Psychiatry. 1988;45:64-68. Mollema ED, Snoek FJ, Adr HJ, et al. Insulin-treated diabetes patients with fear of self-injecting or fear of self-testing: psychological comorbidity and general well-being. J Psychosom Res. 2001;51:665-672. Hepburn DA, Deary IJ, MacLeod KM, et al. Structural equation modeling of symptoms, awareness and fear of hypoglycemia, and personality in patients with insulin-treated diabetes. Diabetes Care. 1994;17:1273-1280. Jones JM, Lawson ML, Daneman D, et al. Eating disorders in adolescent females with and without type 1 diabetes: cross sectional study. BMJ. 2000;320:1563-1566. Daneman D. Eating disorders in adolescent girls and young adult women with type 1 diabetes. Diabetes Spectrum. 2002; 15:83-105. Daneman D, Olmsted M, Rydall A, et al. Eating disorders in young women with type 1 diabetes. Prevalence, problems and prevention. Horm Res. 1998;50(suppl 1):79-86. Affenito SG, Backstrand JR, Welch GW, et al. Subclinical and clinical eating disorders in IDDM negatively affect metabolic control. Diabetes Care. 1997;20:182-184.
S52 24. Rydall AC, Rodin GM, Olmsted MP, et al. Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. N Engl J Med. 1997;336:1849-1854. 25. Piette JD,Weinberger M, McPhee SJ.The effect of automated calls with telephone nurse follow-up on patient-centered outcomes of diabetes care: a randomized, controlled trial. Med Care. 2000;38:218-230. 26. Surwit RS, van Tilburg MAL, Zucker N, et al. Stress management improves long-term glycemic control in type 2 diabetes. Diabetes Care. 2002;25:30-34. 27. Norris SL, Engelgau MM, Narayan KMV. Effectiveness of selfmanagement training in type 2 diabetes: a systematic review of randomized controlled trials. Diabetes Care. 2001;24:561-587. 28. Jones H, Edwards L,Vallis TM, et al. Changes in diabetes selfcare behaviors make a difference in glycemic control: the Diabetes Stages of Change (DiSC) study. Diabetes Care. 2003; 26:732-737. 29. Grey M, Boland EA, Davidson M, et al. Short-term effects of coping skills training as adjunct to intensive therapy in adolescents. Diabetes Care. 1998;21:902-908. 30. Fosbury JA, Bosley CM, Ryle A, et al. A trial of cognitive analytic therapy in poorly controlled type I patients. Diabetes Care. 1997;20:959-964. 31. Wysocki T, Harris MA, Greco P, et al. Randomized, controlled trial of behavior therapy for families of adolescents with insulin-dependent diabetes mellitus. J Pediatric Psychol. 2000; 25:23-33. 32. Anderson BJ, Brackett J, Ho J, et al. An office-based intervention to maintain parent-adolescent teamwork in diabetes management: impact on parent involvement, family conflict, and subsequent glycemic control. Diabetes Care. 1999;22:713-721. 33. Anderson RM, Funnell MM, Butler PM, et al. Patient empowerment: results of a randomized controlled trial. Diabetes Care. 1995;18:943-949. 34. Greenfield S, Kaplan SH,Ware JE Jr, et al. Patients participation in medical care: effects on blood sugar control and quality of life in diabetes. J Gen Intern Med. 1988;3:448-457. 35. Lustman PJ, Freedland KE, Griffith LS, et al. Fluoxetine for depression in diabetes: a randomized double-blind placebocontrolled trial. Diabetes Care. 2000;23:618-623. 36. Lustman PJ, Griffith LS, Freedland KE, et al. Cognitive behavior therapy for depression in type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med. 1998;129:613-621.
M A N AG E M E N T
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Influenza and Pneumococcal Immunization

INTRODUCTION Few randomized, controlled trials have evaluated the use and benefit of influenza or pneumococcal immunization in adults or children with diabetes (1). Most of the published literature focusses on epidemiologic cohort studies. While individuals with diabetes are sometimes noted as a subgroup, the numbers are usually small. As there is overwhelming evidence supporting the benefit of immunization for both influenza and pneumococcus in high-risk individuals, it is unlikely that there will ever be a randomized, controlled trial specifically evaluating the efficacy and impact in the diabetes population. Clinical practice recommendations for individuals with diabetes must therefore be extrapolated from recommendations for individuals at high risk for complications associated with these infectious diseases (2). ANNUAL INFLUENZA IMMUNIZATION IN ADULTS The majority of studies on influenza immunization rely on observational reports of increased death rates in individuals with diabetes during influenza epidemics (3-6). One casecontrol study of people with diabetes showed a 6-fold increased risk of hospitalization during influenza outbreaks compared to nonepidemic years (6). A retrospective case-control study demonstrated the effectiveness of influenza vaccination in reducing rates of hospitalization of people with diabetes for influenza, pneumonia or diabetes-related events during 2 influenza epidemics in Leicestershire, England, United Kingdom (7).The study detected a 79% reduction in hospitalization rates during the 2 epidemics in people with diabetes who had been immunized for influenza during the period immediately preceding the epidemic. Several studies have demonstrated appropriate influenzaspecific antibody response in both serum and oral fluids in people with diabetes (8), supporting the safety and efficacy of immunization in this population.
PNEUMOCOCCAL IMMUNIZATION IN ADULTS Numerous studies have demonstrated the efficacy of immunization in reducing pneumococcal bacteremia in the general population (9-12). There are few studies evaluating the immunologic response of people with diabetes to the pneumococcal vaccine. However, as there is widespread acceptance that people with diabetes are at least as susceptible to pneumococcal infection as other people with chronic diseases (1), the use of the pneumococcal vaccine is encouraged in this population. A one-time revaccination is recommended for individuals >65 years of age if the original vaccine was administered when they were <65 years of age and >5 years earlier. Other indications for revaccination that may be relevant for patients with diabetes include nephrotic syndrome, chronic renal disease and other immunocompromised states such as post-organ transplantation (13).
RECOMMENDATION
1. Adults with diabetes should receive an annual influenza vaccine to reduce the risk of complications associated with these epidemics [Grade D, Consensus]. Adults with diabetes should also be considered for immunization against pneumococcus [Grade D, Consensus].
The initial draft of this chapter was prepared by Stewart B. Harris MD MPH FCFP FACPM; Heather Dean MD FRCPC.
INFLUENZA AND PNEUMOCOCCAL IMMUNIZATION IN CHILDREN Infants and toddlers are at greatest risk for influenza- and pneumococcal-related morbidity. Children with diabetes are included as a high-risk group by the National Advisory Committee on Immunization of Health Canada (14), the American Academy of Pediatrics (15) and the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (16), and current national guidelines recommend influenza and pneumococcal immunization for children with type 1 diabetes (14-17).While the recommendations for influenza immunization in Canada were written before the identification of type 2 diabetes in children, and there are no studies evaluating the usefulness of the influenza or pneumococcal vaccine in this population, there is no reason not to manage these children according to the recommendations for children with type 1 diabetes. In addition, some children with type 2 diabetes may have other factors
S54
(e.g. Aboriginal heritage) that may place them at higher risk of increased influenza- and pneumococcal-related morbidity.
RECOMMENDATION
2. Children with diabetes should receive influenza and pneumococcal immunization according to national guidelines [Grade D, Consensus].
RELATED WEBSITE National Advisory Committee on Immunization. Canadian Immunization Guide. 6th ed. Ottawa, ON: Canadian Medical Association; 2002. Available at: http://www.hc-sc.gc. ca/pphb-dgspsp/publicat/cig-gci/index.html. Accessed November 7, 2003. REFERENCES
1. Smith SA, Poland GA. Use of influenza and pneumococcal vaccines in people with diabetes. Diabetes Care. 2000;23:95-108. 2. Casey JI. Host defense abnormalities in diabetic patients. In: Rifkin H, Raskin P, eds. Diabetes Mellitus. Vol 5. Bowie, MD: Robert J. Brady Company; 1981:219-223. 3. Eickhoff TC, Sherman IL, Serfling RE. Observations on excess mortality associated with epidemic influenza. JAMA. 1961; 176:104-110 4. Martin WJ. Recent changes in the death rate from influenza. Br Med J. 1950;1:267-268. 5. Stocks P, Camb MD. Influenza epidemics on the certified causes of death. Lancet. 1935;ii:386-395. 6. Bouter KP, Diepersloot RJA, van Romunde LKJ, et al. Effect of epidemic influenza on ketoacidosis, pneumonia and death in diabetes mellitus: a hospital register survey of 19761979 in The Netherlands. Diabetes Res Clin Pract. 1991;12:61-68. 7. Colquhoun AJ, Nicholson KG, Botha JL, et al. Effectiveness of influenza vaccine in reducing hospital admissions in people with diabetes. Epidemiol Infect. 1997;119:335-341. 8. Pozzilli P, Gale EAM,Visalli N, et al.The immune response to influenza vaccination in diabetic patients. Diabetologia. 1986; 29:850-854. 9. Bolan G, Broome CV, Facklam RR, et al. Pneumococcal vaccine efficacy in selected populations in the United States. Ann Intern Med. 1986;104:1-6. 10. Forrester HL, Jahnigen DW, LaForce FM. Inefficacy of pneumococcal vaccine in a high-risk population. Am J Med. 1987; 83:425-430. 11. Schwartz JS. Pneumococcal vaccine: clinical efficacy and effectiveness. Ann Intern Med. 1982;96:208-220. 12. Shapiro ED, Clemens JD.A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections. Ann Intern Med. 1984;101:325-330. 13. Advisory Committee on Immunization Practices (ACIP). Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997;46(RR-08):1-24.
14. National Advisory Committee on Immunization. Canadian Immunization Guide. 6th ed. Ottawa, ON: Canadian Medical Association; 2002. 15. Overturf GD. Committee on Infectious Diseases. Technical report: prevention of pneumococcal infections, including the use of pneumococcal conjugate and polysaccharide vaccines and antibiotic prophylaxis. Pediatrics. 2000;106:367-376. 16. Advisory Committee on Immunization Practices (ACIP). Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2000; 49(RR-09):1-38. 17. Gruber WC. Children as a target for immunization. In: Nicholson KG,Webster RG, Hay AJ, eds. Textbook of Influenza. Oxford, UK: Blackwell Science; 1998:435-444.
M A N AG E M E N T
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Pancreas and Islet Transplantation

INTRODUCTION Even with the best efforts, most patients with diabetes mellitus do not succeed in routinely obtaining a normal glycosylated hemoglobin (A1C) level. Ideally, a closed loop with a glucose sensor and insulin delivery system would provide such glycemic control. Currently, the only option available to create an effective closed-loop system is transplantation, either whole pancreas or islet cell. No prospective randomized, controlled trial of either procedure has been reported. WHOLE PANCREAS TRANSPLANTATION The options for performing whole pancreas transplantation are: 1) at the same time as the kidney transplant (simultaneous pancreas/kidney [SPK]); 2) at a time after the kidney transplant (pancreas after kidney [PAK]); or 3) pancreas transplant alone (PTA).With early work, the PTA grafts did not survive as well as the SPK, but this difference is not evident now.The largest centre recently reported their results using modern immunosuppression (tacrolimus [Prograf ] and mycophenolate mofetil [CellCept] with or without daclizumab [Zenapax] induction) (Table 1) (1). Although a technically demanding procedure, a successful pancreas transplant can deliver superb glycemic control (2). However, whole organ pancreas transplantation for nonuremic patients remains a high-risk procedure and should be considered only for the patient with major problems with diabetes control. Efforts at intensive insulin therapy and optimization of diabetes care must have failed prior to consideration of a pancreas alone transplant.
Table 1. Patient and graft survival 1 year after whole pancreas transplantation with, after or without kidney transplantation (1) SPK PAK PTA
1-year patient survival (%) 1-year graft survival (%) 92 79 98 81 100 88
Impact on long-term complications of diabetes Most studies are longitudinal and, by the nature of the progress in the field, there are no prospective randomized studies of the impact of whole pancreas transplants on diabetes complications. However, there is clear evidence of some regression of diabetic lesions on kidney biopsy after a period of successful pancreas transplantation (3). Neuropathy has been found to at least stabilize, if not improve (4,5). If autonomic neuropathy is present, a successful pancreas transplant is associated with lower 5-year mortality (6). Vascular status has also been improved by the euglycemia achieved with pancreas transplantation (7). Retinopathy has been found to stabilize, with some evidence of improvement (8). There is some evidence that quality of life improves (9).
RECOMMENDATION
1. In centres with personnel appropriately skilled in the technical aspects of the surgery, pancreas transplantation is a preferred option for patients whose type 1 diabetes has been difficult to control and who are undergoing kidney transplantation for diabetic nephropathy [Grade D, Consensus].Whole organ pancreas transplant for nonuremic patients remains a high-risk procedure, and should be considered only for the patient with persistent major problems with diabetes control resulting in significant lifestyle disruption despite efforts at intensive insulin therapy [Grade D, Consensus].
PAK = pancreas after kidney PTA = pancreas transplant alone SPK = simultaneous pancreas/kidney
The initial draft of this chapter was prepared by Edmond A. Ryan MD FRCPC.
ISLET TRANSPLANTATION Islet transplantation is a much simpler procedure than whole pancreas transplantation, but until 1999, it had, at best, a 10% 1-year insulin-independence success rate (10).With the Edmonton Protocol, the success rate is now >80% for insulin independence at 1 year (11).The indications for islet transplantation are extreme lability of glycemic control and/or recurrent hypoglycemia, especially if awareness of hypoglycemia is diminished. The major complications associated with the procedure are hepatic hemorrhage (10%) or thrombosis of a peripheral portal vein (4%) (11). Longer-term complications are related to the immunosuppressive drugs and include hyperlipidemia, hypertension and mouth ulcers. It is too early to assess the impact of islet transplantation on long-term complications of
S56
diabetes, but, in the short term, retinal changes requiring laser photocoagulation, related to the acute improvement of glycemic control, have been reported. In addition, if preexisting renal disease was present, the calcineurin inhibitor (tacrolimus) was associated with varying degrees of nephrotoxicity (11). Any long-term immunosuppressive regimen carries a risk of infection and/or cancer. The medical team must consider the success rate of a transplant and weigh the risks of the procedure and immunosuppression against the benefits of improved glycemic control. Islet transplantation data are too new to provide any meaningful long-term information with respect to diabetes complications. For patients with extreme lability of glycemic control or severe problems with decreased awareness of hypoglycemia, islet transplantation is a reasonable option to consider if efforts at optimal diabetes care have failed.
RECOMMENDATION
2. In centres with personnel appropriately skilled in the technical aspects of islet isolation and clinical use of immunosuppression, islet transplantation is an option for patients whose type 1 diabetes has been particularly difficult to control and that is associated with significant lifestyle disruption despite optimal medical therapy [Grade D, Consensus].
9. Piehlmeier W, Bullinger M, Nusser J, et al. Quality of life in type 1 (insulin-dependent) diabetic patients prior to and after pancreas and kidney transplantation in relation to organ function. Diabetologia. 1991;34(suppl 1):S150-S157. 10. Brendel M, Hering B, Shulz A, et al. International Islet Transplant Registry Report. Giessen, Germany: University of Giessen; 1999:1-20. 11. Ryan EA, Lakey JRT, Paty BW, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes. 2002;51:2148-2157.
REFERENCES
1. Sutherland DER, Gruessner RWG, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg. 2001;233:463-501. 2. Robertson RP, Sutherland DER, Lanz KJ. Normoglycemia and preserved insulin secretory reserve in diabetic patients 1018 years after pancreas transplantation. Diabetes. 1999;48: 1737-1740. 3. Fioretto P, Steffes MW, Sutherland DER, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med. 1998;339:69-75. 4. Kennedy WR, Navarro X, Goetz FC, et al. Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med. 1990; 322:1031-1037. 5. Allen RDM, Al-Harbi IS, Morris JGL, et al. Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation. 1997;63:830-838. 6. Navarro X, Kennedy WR, Loewenson RB, et al. Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction, and mortality in diabetes mellitus. Diabetes. 1990;39:802-806. 7. Jukema JW, Smets YFC, van der Pijl JW, et al. Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes. Diabetes Care. 2002;25:906-911. 8. Koznarova R, Saudek F, Sosna T, et al. Beneficial effect of pancreas and kidney transplantation on advanced diabetic retinopathy. Cell Transplant. 2000;9:903-908.
C O M P L I C AT I O N S
Complications
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Macrovascular Complications, Dyslipidemia and Hypertension

INTRODUCTION Approximately 80% of people with diabetes mellitus will die as a result of a vascular event (1).Thus, in attempting to reduce this excessive risk, all coronary risk factors in the person with diabetes must be addressed and treated aggressively (2). VASCULAR PROTECTION When deciding on appropriate treatment strategies, it is important to prioritize the treatment goals. Since some of the available treatments, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARBs), have potential uses in controlling blood pressure (BP), as well as reducing the risks for cardiovascular disease (CVD) and nephropathy, it can be challenging to integrate the data to make recommendations for one application over another. Table 1 summarizes the priorities for vascular and renal protection and recommended interventions.
RECOMMENDATION
1.The first priority in the prevention of diabetes complications should be reduction of cardiovascular (CV) risk by vascular protection through a comprehensive multifaceted approach (in alphabetical order): ACE inhibitor and antiplatelet therapy (e.g. acetylsalicylic acid [ASA]) as recommended, optimize BP and glycemic control, lifestyle modifications, optimize lipid control and smoking cessation [Grade D, Consensus].
Risk assessment of patients with diabetes Patients with diabetes should be assessed to determine their risk of a vascular event. Although many are at high risk for a vascular event (3) and should be treated as such, clinical assessment can identify those with diabetes whose risk level might be considered moderate. For example, younger patients with a shorter duration of diabetes and without other risk factors for vascular disease and without other complications of diabetes might be judged by the physician as not falling in the high-risk category. Even in this group, however, it is important to consider that the average patient with newly diagnosed type 2 diabetes may have had the disease for some time prior to diagnosis. There are several computer programs that predict vascular risk in people with diabetes.The United Kingdom Prospective Diabetes Study (UKPDS) risk engine, based on this studys cohort, provides such a calculation using not only traditional risk factors, but also the duration of diabetes and glycemic control (4,5).The Cardiovascular Life Expectancy Model also estimates the short-term CV risk of individual patients and compares this risk to the Canadian population using data from the Canadian Heart Health Survey. It can be used to estimate the change in life expectancy associated with modifying specific risk factors. Most importantly, this model, based on the Lipid Research Clinics Follow-up Cohort, has been validated against lipid trials in patients with and without diabetes (6,7). A risk calculator (available in both French and English) based on the Framingham Heart Study and the Cardiovascular Life Expectancy Model is available online (8). Dyslipidemia in type 2 diabetes The most common dyslipidemia in type 2 diabetes consists of hypertriglyceridemia, low HDL-C and normal low-density lipoprotein cholesterol (LDL-C). Notwithstanding the normal LDL-C, increased numbers of small, dense LDL particles and elevated apolipoprotein (apo) B concentrations are often present. The hypertriglyceridemia is due, in part, to the presence of excess remnants of triglyceride (TG) -rich lipoproteins, while the low HDL-C points to a low number of HDL particles. Measurement of small, dense LDL particles and remnants of TG-rich lipoproteins is still not widely available, but increased numbers of small, dense LDL particles will be reflected in an elevated plasma apo B. Other indices reflect these parameters, including the total cholesterol (TC) to
DYSLIPIDEMIA Diabetes is associated with high risk for vascular disease, and aggressive lipid management is generally necessary.The management of dyslipidemia in patients with type 2 diabetes requires attention to the full lipid profile, since hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) are particularly common. The initial draft of this chapter was prepared by Lawrence A. Leiter MD FRCPC FACP; Jeffrey Mahon MD MSc FRCPC; Teik Chye Ooi MBBS FRCPC FRACP FACE; Steven Grover MD MPA FRCPC; Maria Kraw MD FRCPC; Gary Lewis MD FRCPC; Ronald J. Sigal MD MPH FRCPC; George Steiner MD FRCPC.
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HDL-C ratio (TC:HDL-C), which the Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada recommend as an index of choice.Target levels for LDL-C and TC:HDL-C, and optimal TG and apo B (9) levels are provided in Table 2 and vary according to the persons risk of a vascular event. There are very little clinical trial data to support recommendations on TG target levels. Small, dense LDL particles increase above a breakpoint plasma TG level of approximately 1.5 mmol/L (10,11). Nonetheless, it is uncommon for a patient to have a significant elevation in serum TGs with LDL-C and TC:HDL-C at target levels. Thus, in order to simplify the lipid targets, a specific target TG level is not provided, but a level of <1.5 mmol/L is considered optimal. Recognizing the atherogenicity of small, dense LDL particles and remnant lipoproteins and the important anti-atherogenic role of HDL particles, it is important to improve these metabolic parameters.
Studies have shown that the degree of LDL-C lowering with statins and the beneficial effects of lowering LDL-C apply equally well to people with and without diabetes (12-15). Lifestyle interventions Individuals with type 2 diabetes are often overweight and sedentary. Accordingly, lifestyle modification should be a major component of the management of dyslipidemia in these patients. In individuals with a body mass index (BMI) 25 kg/m2, weight reduction should be strongly recommended. Even a modest weight loss of 5 to 10% of initial body weight can be associated with an improvement in the lipid profile of individuals with dyslipidemia and diabetes. An energyrestricted, well-balanced diet is essential. Regular aerobic exercise helps individuals lose weight and maintain this weight reduction over time (16), and may be associated with TG reductions and elevations in HDL-C. Regular exercise can also improve glycemic control in people with type 2 diabetes (17),
Table 1. Priorities for vascular and renal protection Clinical issue Target population
1.Vascular protection All people with diabetes
Interventions
(in alphabetical order) ACE inhibitor, as indicated Antiplatelet therapy (e.g. ASA), as indicated BP control Glycemic control Lifestyle modification Lipid control Smoking cessation Treat according to hypertension guidelines Treat according to nephropathy guidelines (see Nephropathy, p. S66)
2. Elevated BP 3. Renal protection
All people with diabetes who are hypertensive (regardless of whether nephropathy is present) All people with diabetes who have nephropathy (even in the absence of hypertension)
ACE = angiotensin converting enzyme ASA = acetylsalicylic acid BP = blood pressure
Table 2. Lipid targets and treatment initiation parameters* in diabetes based on risk of a vascular event Risk level LDL-C TC:HDL-C (mmol/L)
High (most patients with diabetes) Moderate (younger age and shorter duration of diabetes and no other complications of diabetes and no other risk factors for vascular disease) <2.5 <3.5 and and <4.0 <5.0
*While TGs are not indicated as a treatment target, almost all individuals with hypertriglyceridemia can be identified as having an elevated TC:HDL-C.The optimal TG level is <1.5 mmol/L Optimal apo B: <0.9 g/L for high-risk individuals and <1.05 g/L for moderate-risk individuals (9) apo = apolipoprotein HDL-C = high-density lipoprotein cholesterol LDL-C = low-density lipoprotein cholesterol TC = total cholesterol TG = triglyceride
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and is associated with substantial reductions in CV morbidity and mortality in both type 1 (18) and type 2 diabetes (19,20). Pharmacologic interventions Large, recently published trials have demonstrated the benefits of statin therapy in both primary and secondary prevention of vascular disease. Subgroup analyses of these studies have shown similar benefits in the subsets of participants with diabetes (12-14). As well, several studies have shown benefits associated with fibrate treatment (21-23). The results of the Heart Protection Study (HPS) provided important new insights (24). In this large study involving >20 000 subjects, a similar benefit in terms of risk ratio reduction was observed in subjects with baseline LDL-C >3.5 mmol/L, 3.0 to 3.5 mmol/L and <3.0 mmol/L. All randomized subjects were included in this analysis. The recently published results in the 5963 subjects with diabetes showed similar risk reductions among people with or without diabetes, irrespective of sex, vascular disease or lipid levels (LDL-C <3.0 mmol/L or 3.0 mmol/L), type of diabetes and glycosylated hemoglobin (A1C) (15).These results led to speculation that whatever the existing serum LDL-C level, lowering it further with the use of a statin (simvastatin in the HPS) is beneficial. However, the HPS did not demonstrate the effect of treating LDL-C to any particular preset targets. In a post-hoc analysis of the entire study sample, the investigators also found similar event reductions in individuals with baseline LDL-C values <2.6 mmol/L, but this post-hoc analysis was not performed in the subset of people with diabetes who had baseline LDL-C values <2.6 mmol/L. The following considerations should guide the choice of pharmacologic agent to treat dyslipidemia (Table 3,Table 4): 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are the drugs of choice to
Table 3. Treatment of dyslipidemia Lipid status Therapy*
LDL-C above target lifestyle modification + statin
RECOMMENDATIONS
2. People with type 1 or type 2 diabetes should be encouraged to adopt a healthy lifestyle to lower their risk of CVD.This entails adopting healthy eating habits, achieving and maintaining a healthy weight, engaging in regular physical activity, and stopping smoking [Grade D, Consensus]. 3. A fasting lipid profile (TC, HDL-C,TG and calculated LDL-C) should be conducted at the time of diagnosis of diabetes and then every 1 to 3 years as clinically indicated. Apo B can also be measured to accurately estimate atherogenic particle number. More frequent testing should be done if treatment for dyslipidemia is initiated [Grade D, Consensus]. 4. Most people with type 1 and type 2 diabetes should be considered at high risk for vascular disease [Grade A, Level 1 (20,27,28)]. However, some people with type 1 or type 2 diabetes may be considered at moderate risk, such as younger patients with shorter duration of disease and without complications of diabetes and without other risk factors [Grade A, Level 1 (4,20,29)]. 5. Patients with diabetes should be treated to achieve the following target lipid goals: for patients at high risk of a vascular event: LDL-C <2.5 mmol/L and TC:HDL-C <4.0; and for patients at moderate risk of a vascular event: LDL-C <3.5 mmol/L and TC:HDL-C <5.0 [Grade D, Consensus]. Although current evidence does not support specific targets for apo B or TG, the optimal TG level is <1.5 mmol/L, and the optimal levels for apo B are <0.9 g/L for high-risk patients and <1.05 g/L for moderate-risk patients [Grade D, Consensus]. 6.The following should be considered when choosing treatments for patients with dyslipidemia: In cases where LDL-C is above target, a statin should be prescribed [Grade A, Level 1A (15)]. In high-risk patients with TG levels of 1.5 to 4.5 mmol/L, HDL-C <1.0 mmol/L, and LDL-C at target, either a statin [Grade A, Level 1A (15)] or fibrate [Grade B, Level 2 (22,23)] can be prescribed. In patients with marked hypertriglyceridemia (TG level >4.5 mmol/L), a fibrate should be prescribed [Grade D, Consensus]. When monotherapy fails to achieve lipid targets, the addition of a second drug from another class should be considered [Grade D, Consensus].
High-risk patients with: lifestyle modification TG level = 1.54.5 mmol/L and + HDL-C <1.0 mmol/L and statin or fibrate LDL-C at target TG level >4.5 mmol/L lifestyle modification + fibrate
*When monotherapy plus lifestyle modification fail to achieve lipid targets, the addition of a second drug from another class should be considered. HDL-C = high-density lipoprotein cholesterol LDL-C = low-density lipoprotein cholesterol TG = triglyceride
lower LDL-C,TC:HDL-C and apo B.At higher doses, they have modest TG-lowering and HDL-C-raising effects, but are usually insufficient to correct these lipid abnormalities. Treatment with a statin can also be considered in patients >40 years of age with an LDL-C level 2.5 mmol/L (15). Bile acid sequestrants (cholestyramine resin and colestipol HCl) may also be used to lower LDL-C and apo B, but they tend to elevate TG levels and are therefore not often very useful in diabetic dyslipidemia.
S61
Treatment with a cholesterol absorption inhibitor (ezetimibe), either as monotherapy or in combination with a statin, may be considered to lower LDL-C. Fibrates are recommended to lower TGs, raise HDL-C and improve TC:HDL-C. Fibrates also shift the size of LDL particles from small to large, and may paradoxically raise LDL-C levels in 10 to 15% of patients.They may also raise creatinine and homocysteine levels. Nicotinic acid (niacin) is an alternative drug that increases HDL-C and lowers TG levels. It is also an effective LDL-C-lowering and apo B-lowering agent. Although it should be used with some caution because it can increase insulin resistance and cause deterioration of glycemic control (25), there is now evidence that the adverse effects of niacin on glycemia may have been overemphasized (26).
HYPERTENSION BP targets The recommended BP targets are 130/80 mm Hg. Systolic BP >130 mm Hg and diastolic BP >80 mm Hg are the thresholds recommended to initiate treatment and apply regardless of whether nephropathy is present. Vascular protection and control of hypertension are more important than measures aimed solely at protecting renal function (Table 1) (see Nephropathy, p. S66). Results of the Hypertension Optimal Treatment (HOT) and UKPDS 38 trials provide strong evidence for the diastolic BP target of 80 mm Hg (30,31). Both trials demonstrated clinically important reductions in microvascular and macrovascular complications (30,31), CV death (30) and diabetes-related death (31) in patients with diabetes who were randomized to treatments yielding diastolic BP as low as 81 mm Hg.
Table 4. Indications to guide choice of lipid medication (in alphabetical order by class) Drug class, generic name Effect(s) Other considerations (trade name)
Bile acid sequestrants cholestyramine resin (Questran, Questran Light, generic) colestipol HCl (Colestid) Cholesterol absorption inhibitor ezetimibe (Ezetrol) Lowers LDL-C Inhibits intestinal cholesterol absorption May be considered to lower LDL-C either as monotherapy or in combination with a statin Lower LDL-C Tend to elevate TGs and are therefore not very useful in diabetic dyslipidemia
Fibrates bezafibrate (Bezalip, generic) fenofibrate (micronized/microcoated) (Lipidil Micro/Lipidil Supra, generic) gemfibrozil (Lopid, generic) Nicotinic acid (niacin)
Lower TGs May paradoxically raise LDL-C levels in Raise HDL-C 1015% of patients Lower TC:HDL-C May also raise creatinine and Shift LDL from smaller to larger particles homocysteine levels
Raises HDL-C Lowers TG Lowers LDL-C Lowers apo B
Can aggravate insulin resistance and cause deterioration of glycemic control, although effects on glycemia may have been overemphasized At higher doses, have modest TG-lowering effects and HDL-C-raising effects, but are usually insufficient to correct these lipid abnormalities
Statins (HMG-CoA reductase inhibitors) atorvastatin (Lipitor) fluvastatin (Lescol ) lovastatin (Mevacor , generic) pravastatin (Pravachol , generic) rosuvastatin (Crestor ) simvastatin (Zocor )
Lower LDL-C Improve TC:HDL-C Lower apo B
apo = apolipoprotein HDL-C = high-density lipoprotein cholesterol HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A LDL-C = low-density lipoprotein cholesterol TC = total cholesterol TG = triglyceride
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The evidence for a systolic BP target of 130 mm Hg is less strong and includes 2 prospective cohort studies (27,28) and the normotensive Appropriate Blood Pressure Control in Diabetes (ABCD) trial (32). In the cohort studies, direct relationships were observed between higher systolic BP levels and death, coronary artery disease, nephropathy and proliferative retinopathy (27,28). Although this relationship extended to systolic BP as low as 110 mm Hg, the Canadian Diabetes Association Clinical Practice Guidelines Expert Committee did not judge the evidence to be sufficient to recommend a systolic BP target lower than 130 mm Hg. Results of the normotensive ABCD trial also support the systolic BP target of 130 mm Hg (32), but, again, not to a level that justified a Grade A recommendation. Stronger evidence for the optimal systolic BP target awaits completion of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in which thousands of people with diabetes are being randomized to systolic BP targets of <120 mm Hg or <140 mm Hg. Treatment of hypertension If BP cannot be controlled with lifestyle intervention in people with diabetes without nephropathy, any 1 of the following drugs is recommended as the initial choice of therapy, in the following order:ACE inhibitor,ARB, cardioselective beta blocker or thiazide-like diuretic. This recommendation reflects the results of studies that have compared, as a prespecified primary goal, clinically important vascular outcomes in people with diabetes who were randomized to either a drug from the studied class or to placebo (33,34), or to an active comparator control group (35-37). Because the efficacy of long-acting calcium channel blockers (CCBs) has not been proven in similarly designed trials, but was demonstrated in post-hoc analyses of randomized trials (38), CCBs remain an attractive option for patients unable to use drugs from any of the 4 aforementioned classes. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), >12 000 people with diabetes were randomized to treatment with a CCB, ACE inhibitor, thiazide-like diuretic or alpha-adrenergic blocker (36,37), and CV outcomes were compared over 5 years. Early termination of the alpha-adrenergic blocker arm occurred because of excess heart failure relative to the diuretic arm (37). This is the reason to avoid alpha-adrenergic blockers, at least as first-line therapy, for the treatment of hypertension. More recently, the primary ALLHAT results were reported (36). No differences were observed in people with diabetes among the 3 remaining drug classes with respect to the primary outcome (fatal coronary heart disease or nonfatal myocardial infarction [MI]), but a lower rate of prespecified secondary vascular outcomes, including heart failure, occurred among those randomized to the thiazide-like diuretic. Although glycemic control was also worse in this group relative to the ACE inhibitor and CCB groups (36), the lack of differences in the primary outcome, the lower
incidence of selected secondary outcomes in the diuretic group, and the lower cost of diuretics suggest that diuretics should be used before the other ALLHAT drug classes for patients with diabetes, hypertension and no nephropathy (36). However, a complete description of the ALLHAT results in the subgroup with diabetesincluding whether there were any differences among the 3 drug classes in their effects on microvascular outcomes, such as nephropathy, or on macrovascular outcomes in those with nephropathy at baselinewas not available at the time of development of the Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Therefore, a thiazide-like diuretic was not recommended as first-line therapy before the other drug choices. Multiple drugs will often be required to approach, if not meet, the recommended BP targets. For example, in the UKPDS, 29% of subjects randomized to tight BP control required at least 3 antihypertensive drugs by the trials end (31). The issue of which drug to use first may therefore be less important than the need to use more than 1 drug to control BP in most people with diabetes.The prospect of prescribing several antihypertensive drugs to patients with diabetes can be discouraging, particularly when the same people are likely to need several other drugs to reach the stringent lipid and glycemic targets that are now advocated. For each patient, treatment decisions will have to weigh the potential benefits of lowered BP against the potential adverse effects of polypharmacy.This judgement can be guided by the fact that a direct relationship exists between the size of the incremental BP reduction and subsequent reduction in hypertensionrelated complications (27,28). While any reduction in BP is associated with a lower risk of complications, small reductions in BP are associated with small reductions in risk.Thus, it may be reasonable to be less aggressive (e.g. not adding a third or fourth antihypertensive drug) in patients whose BP is already close to 130/80 mm Hg and for whom the clinician is especially concerned about possible side effects from additional drug therapy. Larger BP reductions are associated with larger reductions in riskjustifying a more aggressive approach in the patient with diabetes whose BP levels are particularly high.
RECOMMENDATIONS
7. Lifestyle interventions to reduce BP, including achieving and maintaining a healthy weight, and limiting sodium and alcohol intake, should be considered [Grade D, Consensus]. 8. BP should be measured at every diabetes visit. Patients with systolic BP >130 mm Hg or diastolic BP >80 mm Hg should have their BP remeasured on a separate visit [Grade D, Consensus]. Continued
S63
Recommendationscontinued 9. Persons with diabetes should be treated to target a systolic BP <130 mm Hg [Grade C, Level 3 (27,28,32)] and a diastolic BP 80 mm Hg [Grade A, Level 1A (30)]. Systolic BP >130 mm Hg and diastolic BP >80 mm Hg are the thresholds recommended to initiate treatment [Grade D, Consensus]. 10. For people with diabetes, no diabetic nephropathy, and BP levels >130 mm Hg and/or >80 mm Hg despite lifestyle modification, any 1 of the following drugs is recommended as the initial choice of therapy, in the following order [Grade D, Consensus for the order]. ACE inhibitor [Grade A, Level 1A (33)]; ARB [Grade A, Level 1A for co-existent left ventricular hypertrophy (LVH) (34); Grade B, Level 2 if LVH is not present (34)]; cardioselective beta blocker [Grade B, Level 2 (35)]; thiazide-like diuretic [Grade A, Level 1A (36)]; or long-acting CCB [Grade B, Level 2 (38)]. 11. If BP targets cannot be reached despite the use of 1 of the above drug choices as monotherapy, use of 1 or more of these or other antihypertensive drugs in combination should be considered [Grade D, Consensus]. 12. Alpha-adrenergic blockers are not recommended as first-line agents for the treatment of hypertension in persons with diabetes [Grade A, Level 1A (37)].
controlled hypertension (30). Patients who cannot tolerate ASA should substitute an alternate antiplatelet agent such as clopidogrel (Plavix). Due to the increase in platelet turnover and thromboxane synthesis in people with diabetes, it has been suggested that multiple daily dosing of ASA may be preferred in this population, although no clinical endpoint data have confirmed this hypothesis.Antiplatelet agents should not be used in patients with inherited or acquired bleeding disorders, recent gastrointestinal bleeding or serious renal or hepatic failure. ASA should not be used in patients <21 years of age due to an increased risk of Reye syndrome.
RECOMMENDATION
13. Unless contraindicated, low-dose ASA therapy (80 to 325 mg/day) is recommended in all patients with diabetes with evidence of CVD, as well as for those individuals with atherosclerotic risk factors that increase their likelihood of CV events [Grade A, Level 1A (30,42,44,45)].
ANTIPLATELET THERAPY People with diabetes have a 2- to 4-fold increased morbidity and mortality due to CVD. Platelet dysfunction in diabetes may contribute to this increased risk. Patients with diabetes have a variety of alterations in platelet function that can predispose them to increased platelet activation and thrombosis, including increased platelet turnover (39), enhanced aggregation (40) and increased thromboxane synthesis (41). A number of prevention trials have shown a reduction in MI with ASA therapy, although no benefit was seen in stroke prevention (30,42-44). The Antithrombotic Trialists Collaboration reported a meta-analysis of 195 randomized trials of antiplatelet therapy published up to 1997, including 9 trials with almost 5000 patients with diabetes. Although there was a significant proportional reduction in vascular events (standard error) of 222% among all high-risk patients using antiplatelet therapy, patients with diabetes showed only a nonsignificant 78% proportional reduction (45). ASA appears to be as effective as other antiplatelet agents (45) and is the preferred choice, given that it is the most widely studied and the most economical.The lowest effective dose (80 to 325 mg/day) should be used to limit both gastrointestinal toxicity and potential adverse effects of prostaglandin inhibition on renal function or BP control. ASA therapy does not increase the risk of vitreous hemorrhage in patients with diabetic retinopathy (43) nor does it increase stroke or fatal bleeds in patients with adequately
OTHER RELEVANT GUIDELINES Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories, p. S7 Screening and Prevention, p. S10 Targets for Glycemic Control, p. S18 Physical Activity and Diabetes, p. S24 Nutrition Therapy, p. S27 Management of Obesity in Diabetes, p. S46 RELATED WEBSITES Canadian Hypertension Society. Available at: http://www. chs.md. Accessed November 7, 2003. Cardiovascular Risk Profile. Available at: http://www. chiprehab.com/CVD/. Accessed November 7, 2003. UKPDS Risk Engine, Diabetes Trials Unit, The Oxford Centre for Diabetes, Endocrinology & Metabolism. Available at: http://www.dtu.ox.ac.uk/riskengine/. Accessed November 7, 2003. REFERENCES
1. Barrett-Connor E, Pyrl K. Long-term complications: diabetes, coronary heart disease, stroke and lower extremity arterial disease. In: ko J-M, Zimmet P,Williams R, eds. The Epidemiology of Diabetes Mellitus: An International Perspective. Chichester, UK: John Wiley & Sons, Ltd.; 2001:301-319. 2. Gde P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393. 3. Haffner SM, Lehto S, Rnnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234. 4. Stevens RJ, Kothari V, Adler AI, et al.The UKPDS risk engine:
S64 a model for the risk of coronary heart disease in type II diabetes (UKPDS 56). Clin Sci (Lond). 2001;101:671-679. Diabetes Trials Unit, The Oxford Centre for Diabetes, Endocrinology & Metabolism. UKPDS Risk Engine. Available at: http://www.dtu.ox.ac.uk/riskengine/. Accessed November 7, 2003. Grover SA, Paquet S, Levinton C, et al. Estimating the benefits of modifying risk factors of cardiovascular disease: a comparison of primary vs secondary prevention. Arch Intern Med. 1998;158:655-662. Grover SA, Coupal L, Zowall H, et al. Cost-effectiveness of treating hyperlipidemia in the presence of diabetes: who should be treated? Circulation. 2000;102:722-727. Cardiovascular Risk Profile. Available at: http://www. chiprehab.com/CVD/. Accessed November 7, 2003. Walldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-2033. Griffin BA, Freeman DJ,Tait GW, et al. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis. 1994;106:241-253. Packard CJ, Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism. Arterioscler Thromb Vasc Biol. 1997;17:3542-3556. Pyrl K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20:614-620. Sacks FM, Pfeffer MA, Moye LA, et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebocontrolled trial. Lancet. 2003;361:2005-2016. Wing RR. Weight loss in the management of type 2 diabetes. In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:252-276. Boul NG, Haddad E, Kenny GP, et al. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA. 2001; 286:1218-1227. Moy CS, Songer TJ, LaPorte RE, et al. Insulin-dependent diabetes mellitus, physical activity, and death. Am J Epidemiol. 1993;137:74-81. Wei M, Gibbons LW, Kampert JB, et al. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med. 2000;132:605-611. Hu FB, Stampfer MJ, Solomon CG, et al. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Arch Intern Med. 2001;161:1717-1723. Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Marys, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care. 1998;21:641-648. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001;357:905-910. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7-22. Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease. The ADMIT study: a randomized trial. JAMA. 2000;284:1263-1270. Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial. Arch Intern Med. 2002;162:1568-1576. Orchard TJ, Forrest KY-Z, Kuller LH, et al. Lipid and blood pressure treatment goals for type 1 diabetes: 10-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2001;24:1053-1059. Adler AI, Stratton IM, Neil HAW, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419. Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulindependent diabetes mellitus. Am J Cardiol. 1987;59:750-755. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713. Schrier RW, Estacio RO, Esler A, et al. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61:1086-1097.
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S65 33. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259. 34. Lindholm LH, Ibsen H, Dahlf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359:1004-1010. 35. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713-720. 36. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997. 37. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;283:1967-1975. 38. Tuomilehto J, Rastenyte D, Birkenhger WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med. 1999;340:677-684. 39. DiMinno G, Silver MJ, Cerbone AM, et al. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood. 1986;68:886-891. 40. Halushka PV, Rogers RC, Loadholt CB, et al. Increased platelet thromboxane synthesis in diabetes mellitus. J Lab Clin Med. 1981;97:87-96. 41. Dav G, Catalano I, Averna M, et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990;322:1769-1774. 42. Steering Committee of the Physicians Health Study Research Group. Final report on the aspirin component of the ongoing Physicians Health Study. N Engl J Med. 1989;321:129-135. 43. ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. JAMA. 1992;268:1292-1300. 44. Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106. 45. Antithrombotic Trialists Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
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Nephropathy
INTRODUCTION Diabetic nephropathy (defined clinically as the presence of microalbuminuria or overt nephropathy in patients with diabetes who lack indicators of other renal diseases) is the most common cause of renal failure in the Western World (1). Dialysis and renal transplantation are costly (2), and can have a devastating effect on quality and length of life (1,3). Diabetic nephropathy progresses from subclinical disease, through the earliest clinically detectable stage, characterized by microalbuminuria (urinary albumin 30 to 300 mg/day), to overt nephropathy with macroalbuminuria (urinary albumin >300 mg/day) (4-6). Renal dysfunction is typically identified in the macroalbuminuria stage, and can progress over time to end stage renal disease (7). Detection of microalbuminuria identifies individuals at high risk of progression to later stages of renal disease (8,9), cardiovascular events and death (10).The diagnosis of nephropathy only requires a kidney biopsy when clinical indicators leave doubt as to the diagnosis. SCREENING The purpose of screening for diabetic nephropathy is to delay or prevent loss of renal function through early detection and initiation of effective therapies, and to manage complications in those identified with renal disease. Screening for microalbuminuria should be performed using the random urine test for albumin to creatinine ratio (ACR) (Figure 1) (11). (See Type 1 Diabetes in Children and Adolescents, p. S84, for considerations regarding the pediatric population.) A urine dipstick test should also be performed on the urine specimen, either in the laboratory or at the point of care, as a screen for nondiabetic renal disease. While 24-hour or timed overnight urine collections have been the gold standard for clinical trials, these tests are difficult to perform correctly in routine practice and may yield false results (12-14).The random urine ACR accurately predicts the urinary protein level detected by 24-hour collections, and is easier to perform and more agreeable to patients than timed collections (15). The initial draft of this chapter was prepared by Philip McFarlane MD FRCPC; Sheldon Tobe MD FRCPC; Robyn Houlden MD FRCPC; Stewart B. Harris MD MPH FCFP FACPM.
People with overt nephropathy (urinary albumin >300 mg/day, equivalent to ACR >20.0 mg/mmol in men and >28.0 mg/mmol in women) typically progress over time to more severe stages of nephropathy and rarely have normalization of urinary protein without directed therapy. Patients with microalbuminuria (urinary albumin 30 to 300 mg/day, equivalent to ACR 2.0 to 20.0 mg/mmol in men and 2.8 to 28.0 mg/mmol in women) have a variable course. While microalbuminuria is a significant risk factor for progression of nephropathy, some will experience a spontaneous normalization of urinary protein (5,16).To confirm the presence of nephropathy in those with microalbuminuria, patients should undergo up to 2 additional random urine tests for ACR. A patient is considered to have nephropathy if any 2 of the 3 urine samples have an ACR >2.0 mg/mmol in men or >2.8 mg/mmol in women.The 2 confirmatory tests should be performed between 1 week and 2 months apart. Patients with overt nephropathy (ACR >20.0 mg/mmol for men and >28.0 mg/mmol for women) should undergo a 24-hour urine collection for creatinine clearance as follow-up within 2 to 3 months. Table 1 illustrates the degree of proteinuria associated with various stages of diabetic nephropathy and highlights the fact that conventional urine dipstick tests fail to identify individuals with early nephropathy. As ACR may be elevated with conditions other than diabetic nephropathy, such as recent major exercise (17), fever (18), urinary tract infection, congestive heart failure (19), acute severe elevations of blood pressure (BP) or blood glucose (BG) (20,21), or menstruation, screening for microalbuminuria should be delayed in the presence of these conditions. Patients with diabetes can develop renal diseases other than diabetic nephropathy (Table 2) (22-26). Further nephrologic investigations, or referral to a renal disease specialist, may be considered if 1 or more of the conditions listed in Table 2 are present. Creatinine clearance, an estimate of the kidneys ability to filter toxins from the blood, should be determined by a formula such as the Cockcroft-Gault formula (Table 3) rather than by serum creatinine, which may falsely indicate that a persons renal function is normal (27,28). Individuals can lose up to 50% of their creatinine clearance before serum creatinine levels rise into the abnormal range (29). Patients may remain asymptomatic until as much as 75% of renal
S67 Figure 1. Screening for diabetic nephropathy and nondiabetic renal disease C O M P L I C AT I O N S
Type 1 diabetes: Annually in postpubertal individuals with duration of diabetes 5 years Type 2 diabetes: At diagnosis and annually thereafter 1) Random urine ACR and 2) Random urine dipstick (at laboratory or point of care)
Suspicion of nondiabetic renal disease? Workup or referral for nondiabetic renal disease
Yes
No
Check ACR results
Normal <2.0 mg/mmol for men <2.8 mg/mmol for women Repeat screen in 1 year
Microalbuminuria 2.020.0 mg/mmol for men 2.828.0 mg/mmol for women
Macroalbuminuria >20.0 mg/mmol for men >28.0 mg/mmol for women Diabetic nephropathy* diagnosed
Up to 2 repeat random urine ACRs performed between 1 week and 2 months apart
Only 1 abnormal ACR Repeat screen in 1 year
Any 2 abnormal out of 3 ACRs Diabetic nephropathy* diagnosed
*Diabetic nephropathy = microalbuminuria or overt nephropathy (macroalbuminuria) ACR = albumin to creatinine ratio
Table 1. Stages of renal involvement according to the urinary albumin level Stage of nephropathy
Normal Microalbuminuria Overt nephropathy (macroalbuminuria)
Urine dipstick for protein

Negative Negative Positive
Urine ACR (mg/mmol)

<2.0 (men) <2.8 (women) 2.020.0 (men) 2.828.0 (women) >20.0 (men) >28.0 (women) >66.7 (men) >93.3 (women)
24-hour urine collection for albumin*

<30 mg/day 30300 mg/day >300 mg/day >1000 mg/day
*Values are for urinary albumin, not total urinary protein, which will be higher than urinary albumin levels ACR results may be elevated with conditions other than diabetic nephropathy. See text and Table 2. ACR = albumin to creatinine ratio
S68
function is lost. As the identification of subclinical renal dysfunction may have management consequences (e.g. drug selection or dosing, or the use of contrast dye during radiologic or cardiologic investigations) and implications regarding the timing for referral to a renal disease specialist, a more accurate assessment of renal function should be performed periodically. The Cockcroft-Gault formula is a sufficiently accurate estimation of renal function in adults for most clinical purposes (30), and should be performed annually in those patients with diabetes without nephropathy and at least every 6 months in those with nephropathy. Alternatively, one could use other validated equations, such as the formula developed from the Modification of Diet in Renal Disease (MDRD) study, for estimating glomerular filtration rate (GFR) (31). TREATMENT AND FOLLOW-UP The development of nephropathy has been associated with smoking (32), hyperlipidemia (33) and poor control of BG (34) and BP. Once nephropathy is diagnosed, intensive glycemic control (35) and optimization of BP will help prevent its progression (36). BP targets (i.e. 130/80 mm Hg) should be the same as those for people with diabetes and hypertension. Vascular protection and control of hypertension are more important than measures aimed solely at protecting renal
function. Patients with vascular risk or hypertension should be treated to reduce these risks (Table 4) (see Macrovascular Complications, Dyslipidemia and Hypertension, p. S58), but may require additional therapies if they remain proteinuric. The presence of proteinuria may influence drug selection in hypertensive individuals. Table 5 summarizes treatment approaches for nephropathy in people with diabetes. Disruption of the reninangiotensin system with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (ARBs) is the preferred method of protecting renal function in people with diabetes, even in the absence of hypertension (37).
Table 2. Possible indicators of nondiabetic causes of renal disease in persons with diabetes
Lack of retinopathy (23) or neuropathy (24) Persistent hematuria (microscopic or macroscopic) (22) Signs or symptoms of systemic disease (25) Rapidly rising creatinine (26) High creatinine with little or no proteinuria (24) Family history of nondiabetic renal disease (e.g. polycystic kidney disease or Alport syndrome) Short duration of diabetes (24)
Table 3. Calculation of creatinine clearance in adults using the Cockcroft-Gault formula*

Creatinine clearance (mL/min) = (140age in years) x actual** weight (kg) serum creatinine (mol/L) Multiply the result by 1.2 for men Normal range is >90 mL/min, >1.5 mL/s An online version of this calculation is available at http://www.nephron.com *Estimates of creatinine clearance are inaccurate when the serum creatinine is changing rapidly **Extremes of overweight and underweight will result in underestimates and overestimates of renal function using this formula
Table 4. Priorities for vascular and renal protection Clinical issue Target population
1.Vascular protection All people with diabetes
Interventions
(in alphabetical order) ACE inhibitor, as indicated Antiplatelet therapy (e.g. ASA), as indicated BP control Glycemic control Lifestyle modification Lipid control Smoking cessation Treat according to hypertension guidelines (See Macrovascular Complications, Dyslipidemia and Hypertension, p. S58) Treat according to nephropathy guidelines
2. Elevated BP
All people with diabetes who are hypertensive (regardless of whether nephropathy is present) All people with diabetes who have nephropathy (even in the absence of hypertension)
3. Renal protection
ACE = angiotensin converting enzyme ASA = acetylsalicylic acid BP = blood pressure
S69 Table 5. Treatment of diabetic nephropathy Treatment group Preferred agent

Type 1 diabetes ACE inhibitor Type 2 diabetes Creatinine clearance >60 mL/min ACE inhibitor or ARB Creatinine clearance 60 mL/min ARB ACE = angiotensin converting enzyme ARB = angiotensin II receptor antagonist
RECOMMENDATIONS
1.The best possible glycemic control and, if necessary, intensive diabetes management should be instituted in people with type 1 or type 2 diabetes for the prevention, onset and delay in progression of early nephropathy [Grade A, Level 1A (35,50,51)]. 2. Screening for diabetic nephropathy should be conducted using a random urine ACR [Grade D, Consensus]. Postpubertal individuals with type 1 diabetes of 5 years duration should be screened annually. Individuals with type 2 diabetes should be screened at diagnosis of diabetes and yearly thereafter [Grade D, Consensus]. 3. Serum creatinine levels should be measured and creatinine clearance estimated annually in those patients with diabetes without albuminuria and at least every 6 months in those with albuminuria [Grade D, Consensus]. 4. Individuals with albuminuria should receive treatment to protect renal function, even in the absence of hypertension: In people with type 1 diabetes and albuminuria, an ACE inhibitor should be given to reduce urinary albumin and prevent progression of nephropathy [Grade A, Level 1A (39)]. An ARB should be considered in patients unable to tolerate an ACE inhibitor [Grade D, Consensus]. In people with type 2 diabetes, albuminuria and creatinine clearance >60 mL/minute, an ACE inhibitor [Grade A, Level 1A (40)] or an ARB [Grade A, Level 1A (41)] should be given to reduce urinary albumin and prevent progression of nephropathy [Grade A, Level 1A (40,41)]. In people with type 2 diabetes, albuminuria and creatinine clearance 60 mL/minute, an ARB should be given to prevent progression of nephropathy [Grade A, Level 1A (42,43)]. 5. Patients placed on an ACE inhibitor or an ARB should have their serum creatinine and potassium levels checked within 2 weeks of initiation of therapy and periodically thereafter [Grade D, Consensus]. 6.The use of nondihydropyridine CCBs (diltiazem, verapamil) may be considered to reduce urinary albumin excretion in proteinuric hypertensive patients [Grade B, Level 2 (38)]. 7.A referral to a nephrologist or internist with an expertise in diabetic nephropathy should be considered if the ACR is >75 mg/mmol, there is persistent hyperkalemia, there is a >30% increase in serum creatinine within 3 months of starting an ACE inhibitor or ARB, or the creatinine clearance is <60 mL/minute [Grade D, Consensus].
Second-line renal-protective agents include the nondihydropyridine calcium channel blockers (CCBs) (diltiazem, verapamil) (38). In type 1 diabetes, ACE inhibitors have been shown to decrease albuminuria and prevent worsening of nephropathy (39). In type 2 diabetes, ACE inhibitors and ARBs have been shown to decrease albuminuria and prevent worsening of nephropathy (40,41), and ARBs have been shown to delay the time to dialysis in those with renal dysfunction at baseline (ACR >1000 mg/mmol and creatinine clearance 60 mL/minute) (42,43). An ACE inhibitor and an ARB can be used safely in combination (44-46). Patients starting therapy with an ACE inhibitor or an ARB should be monitored after 1 to 2 weeks of treatment for significant worsening of renal function or the development of significant hyperkalemia. Periodic monitoring should continue in those whose serum creatinine or potassium level increases above normal laboratory limits until these values have stabilized. Serum creatinine typically increases up to 30% above baseline after initiation of an ACE inhibitor or ARB, and usually stabilizes after 2 to 4 weeks of treatment (47). Those patients who develop mild to moderate hyperkalemia should receive nutrition counselling regarding a potassiumrestricted diet, and consideration should be given to the use of non-potassium-sparing diuretics, reduction of the dose of the ACE inhibitor or ARB, or discontinuation of the ACE inhibitor or ARB. If an ACE inhibitor or ARB is not tolerated due to severe hyperkalemia or a >30% increase in serum creatinine, the drug should be withdrawn, and other ACE inhibitors or ARBs should not be substituted; instead, consideration should be given to the use of a second-line agent (48). There is no upper limit of the serum creatinine level for initiation of ACE inhibitor or ARB therapy, but if the creatinine clearance is <30 mL/minute, these agents should be started with care or referral for specialized nephrologic care should be considered (47,49). Second-line renal-protective agents (nondihydropyridine CCBs, such as diltiazem or verapamil) can be considered in those unable to tolerate an ACE inhibitor or an ARB (38). Patients started on diltiazem or verapamil should be monitored clinically for development of bradycardia. As all nephroprotective drugs are also antihypertensives, patients should be monitored for development of hypotension. See
Appendix 11 for an algorithm summarizing the approach to therapeutics in diabetic nephropathy. ACR should be remeasured 3 months after initiation of a renal-protective agent and annually thereafter with the goal of a decreased or stable value.
S70
Consideration should be given to referring patients with a creatinine clearance (measured or calculated) of <60 mL/minute to a nephrologist or internist with an expertise in diabetic nephropathy. OTHER RELEVANT GUIDELINES Macrovascular Complications, Dyslipidemia and Hypertension, p. S58 Type 1 Diabetes in Children and Adolescents, p. S84 Pre-existing Diabetes and Pregnancy, p. S94 RELEVANT APPENDICES Appendix 10: Level of Urinary Albumin by Various Test Methods and Stage of Diabetic Nephropathy, p. S136 Appendix 11: Approach to Therapeutics in Diabetic Nephropathy, p. S137 RELATED WEBSITES National Kidney Foundation. Kidney Disease Outcomes Quality Initiative. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease. Guideline 4. Estimation of GFR. Available at: http://www.kidney. org/professionals/doqi/kdoqi/p5_lab_g4.htm. Accessed November 7, 2003. Nephron Information Center. Chronic kidney disease worksheet (includes Cockcroft-Gault calculator, MDRD GFR calculator, GFR calculations in children, and total body volume and body surface area calculator). Available at: http://www.nephron.com. Accessed November 7, 2003. REFERENCES
1. Canadian Organ Replacement Registry (CORR). 2001 Annual Report. Ottawa, ON, Canada: Canadian Institute for Health Information; 2001. 2. Goeree R, Manalich J, Grootendorst P, et al. Cost analysis of dialysis treatments for end-stage renal disease (ESRD). Clin Invest Med. 1995;18:455-464. 3. Churchill DN,Torrance GW,Taylor DW, et al. Measurement of quality of life in end-stage renal disease: the time trade-off approach. Clin Invest Med. 1987;10:14-20. 4. Mathiesen ER, Ronn B, Storm B, et al. The natural course of microalbuminuria in insulin-dependent diabetes: a 10-year prospective study. Diabet Med. 1995;12:482-487. 5. Warram JH, Gearin G, Laffel L, et al. Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. J Am Soc Nephrol. 1996;7:930-937. 6. Lemley KV, Abdullah I, Myers BD, et al. Evolution of incipient nephropathy in type 2 diabetes mellitus. Kidney Int. 2000; 58:1228-1237. 7. Marre M, Bouhanick B, Berrut G. Microalbuminuria. Curr Opin Nephrol Hypertens. 1994;3:558-563.
8. Gall M-A, Hougaard P, Borch-Johnsen K, et al. Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study. BMJ. 1997;314:783-788. 9. Messent JWC, Elliott TG, Hill RD, et al. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study. Kidney Int. 1992;41:836-839. 10. Gerstein HC, Mann JFE,Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421-426. 11. Ahn CW, Song YD, Kim JH, et al.The validity of random urine specimen albumin measurement as a screening test for diabetic nephropathy. Yonsei Med J. 1999;40:40-45. 12. Kouri TT, Viikari JSA, Mattila KS, et al. Microalbuminuria. Invalidity of simple concentration-based screening tests for early nephropathy due to urinary volumes of diabetic patients. Diabetes Care. 1991;14:591-593. 13. Rodby RA, Rohde RD, Sharon Z, et al. The urine protein to creatinine ratio as a predictor of 24-hour urine protein excretion in type 1 diabetic patients with nephropathy. Am J Kidney Dis. 1995;26:904-909. 14. Chaiken RL, Khawaja R, Bard M, et al. Utility of untimed urinary albumin measurements in assessing albuminuria in black NIDDM subjects. Diabetes Care. 1997;20:709-713. 15. Bakker AJ. Detection of microalbuminuria. Receiver operating characteristic curve analysis favors albumin-to-creatinine ratio over albumin concentration. Diabetes Care. 1999;22:307-313. 16. Perkins BA, Ficociello LH, Silva KH, et al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 2003; 348:2285-2293. 17. Huttunen NP, Kr M-L, Puukka R, et al. Exercise-induced proteinuria in children and adolescents with type 1 (insulin dependent) diabetes. Diabetologia. 1981;21:495-497. 18. Slling J, Slling K, Mogensen CE. Patterns of proteinuria and circulating immune complexes in febrile patients. Acta Med Scand. 1982;212:167-169. 19. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med. 1999;341:1127-1133. 20. Wiseman M,Viberti G, Mackintosh D, et al. Glycaemia, arterial pressure and micro-albuminuria in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1984;26:401-405. 21. Ravid M, Savin H, Lang R, et al. Proteinuria, renal impairment, metabolic control, and blood pressure in type 2 diabetes mellitus. A 14-year follow-up report on 195 patients. Arch Intern Med. 1992;152:1225-1229. 22. Hommel E, Carstensen H, Sktt P, et al. Prevalence and causes of microscopic haematuria in type 1 (insulin-dependent) diabetic patients with persistent proteinuria. Diabetologia. 1987;30:627-630. 23. El-Asrar AM, Al-Rubeaan KA, Al-Amro SA, et al. Retinopathy as a predictor of other diabetic complications. Int Ophthalmol. 2001;24:1-11. 24. Amoah E, Glickman JL, Malchoff CD, et al. Clinical identification of nondiabetic renal disease in diabetic patients with
S71 type I and type II disease presenting with renal dysfunction. Am J Nephrol. 1988;8:204-211. Clinical path conference. Unusual renal complications in diabetes mellitus. Minn Med. 1967;50:387-393. VenkataRaman TV, Knickerbocker F, Sheldon CV. Unusual causes of renal failure in diabetics: two case studies. J Okla State Med Assoc. 1990;83:164-168. Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum creatinine. Nephron. 1992;62:249-256. Bending JJ, Keen H, Viberti GC. Creatinine is a poor marker of renal failure. Diabet Med. 1985;2:65-66. Shemesh O, Golbetz H, Kriss JP, et al. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int. 1985;28:830-838. Trollfors B, Alestig K, Jagenburg R. Prediction of glomerular filtration rate from serum creatinine, age, sex and body weight. Acta Med Scand. 1987;221:495-498. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461-470. Mhlhauser I, Overmann H, Bender R, et al. Predictors of mortality and end-stage diabetic complications in patients with type 1 diabetes mellitus on intensified insulin therapy. Diabet Med. 2000;17:727-734. Ravid M, Neumann L, Lishner M. Plasma lipids and the progression of nephropathy in diabetes mellitus type II: effect of ACE inhibitors. Kidney Int. 1995;47:907-910. Ballard DJ, Humphrey LL, Melton LJ III, et al. Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota. Diabetes. 1988;37:405-412. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet. 1993;341:1306-1309. Maki DD, Ma JZ, Louis TA, et al. Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med. 1995;155:1073-1080. Kasiske BL, Kalil RSN, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a metaregression analysis. Ann Intern Med. 1993;118:129-138. Bakris GL, Copley JB, Vicknair N, et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int . 1996;50:1641-1650. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462. Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med. 1993;118:577-581. Parving H-H, Lehnert H, Brchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-878. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and noninsulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000;321:1440-1444. Jacobsen P, Andersen S, Rossing K, et al. Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy. Nephrol Dial Transplant. 2002;17:1019-1024. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685-693. Andersen S,Tarnow L, Rossing P, et al. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int. 2000;57:601-606. Mendelssohn DC, Barrett BJ, Brownscombe LM, et al. Elevated levels of serum creatinine: recommendations for management and referral. CMAJ. 1999;161:413-417. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47:1703-1720. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-853.
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Neuropathy
INTRODUCTION Detectable sensorimotor polyneuropathy will develop within 10 years of the onset of diabetes mellitus in 40 to 50% of people with type 1 or type 2 diabetes. Although <50% of these patients have motor or sensory symptoms, the neuropathic pain associated with symptomatic disease is frequently bothersome (1,2). While neuropathy is uncommon in people with type 1 diabetes within the first 5 years after onset of diabetes, people with type 2 diabetes may have neuropathy very early in the course of their disease (3). Foot ulceration, which depends on the degree of foot insensitivity (4), and amputation are important and costly sequelae of diabetic neuropathy (5). Both somatic and autonomic neuropathy may occur and may require referral to a specialist experienced in managing the affected body system. Mononeuropathy, particularly carpal tunnel syndrome, is common in people with diabetes and can be difficult to diagnose (6). SCREENING FOR PERIPHERAL NEUROPATHY Screening for neuropathy can be accomplished rapidly and reliably using the 10-g Semmes-Weinstein monofilament or 128-Hz tuning fork (7,8). Further examination could include an abbreviated neurologic examination of pinprick sensation (7), distal muscle strength and reflexes. In individuals with significant symptoms of neuropathy or for whom a clinical suspicion of nondiabetic neuropathy exists, referral for additional neurologic evaluation may be helpful. MANAGEMENT OF NEUROPATHY Intensive glycemic control is effective for the primary prevention or secondary intervention of neuropathy in people with type 1 diabetes (2,9,10). In those with type 2 diabetes, lower blood glucose (BG) levels are associated with reduced frequency of neuropathy (1), and thus, intensified therapy is warranted for primary prevention (11,12). Tricyclic antidepressants (13-16), carbamazepine (17), mexiletine (18), gabapentin (19), mild opioid analgesics (20) and isosorbide dinitrate spray (21) are often effective in controlling neuropathic pain. Adverse effects of these The initial draft of this chapter was prepared by Vera Bril MD FRCPC; Bruce Perkins MD MPH FRCPC.
medications, especially gastrointestinal side effects with mexiletine, must be considered before use. The efficacy of topical capsaicin is less clear (22,23). Nonaddictive analgesics may be used to alleviate pain. Although subclinical autonomic neuropathic manifestations are common, symptomatic involvement is infrequent. The diagnosis of symptomatic autonomic neuropathy is based on exclusion of specific cardiovascular, gastrointestinal or genitourinary pathology, usually requiring assessment by a specialist in the affected system. Treatment of autonomic neuropathy is based mainly on expert opinion, but research in this field remains active (24).
RECOMMENDATIONS
1. Screening for peripheral neuropathy should be carried out annually to identify those at high risk of developing foot ulcers. Screening should begin at diagnosis in people with type 2 diabetes and after 5 years duration of type 1 diabetes in postpubertal individuals [Grade D, Consensus]. 2. Detection of peripheral neuropathy should be conducted by assessing loss of sensitivity to the 10-g monofilament at the great toe or loss of sensitivity to vibration at the great toe [Grade A, Level 1 (7)]. 3. People with type 1 diabetes should be treated with intensive glycemic control management to delay the onset and slow the progression of peripheral neuropathy [Grade A, Level 1A (2,9)]. Intensified glycemic control management should be considered for people with type 2 diabetes to prevent the onset and progression of neuropathy [Grade B, Level 2 (12)]. 4.Tricyclic antidepressants and/or anticonvulsants should be considered for relief of painful peripheral neuropathy [Grade A, Level 1A (13,19)]. 5. Carpal tunnel syndrome should be diagnosed on clinical grounds [Grade A, Level 1 (6)] and managed accordingly with supplementary electrophysiological testing as needed in patients with diabetes [Grade D, Consensus]. 6. People with clinically significant autonomic dysfunction should be appropriately assessed and referred to a specialist experienced in managing the affected body system [Grade D, Consensus].
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OTHER RELEVANT GUIDELINES Targets for Glycemic Control, p. S18 Foot Care, p. S74 Type 1 Diabetes in Children and Adolescents, p. S84 REFERENCES
1. Partanen J, Niskanen L, Lehtinen J, et al. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:89-94. 2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986. 3. Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care. 2001;24:1448-1453. 4. Young MJ, Breddy JL,Veves A, et al.The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study. Diabetes Care. 1994;17:557-560. 5. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and amputations in diabetes. In: Diabetes in America. 2nd ed. Bethesda, MD: National Diabetes Data Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:409-428. 6. Perkins BA, Olaleye D, Bril V. Carpal tunnel syndrome in patients with diabetic polyneuropathy. Diabetes Care. 2002; 25:565-569. 7. Perkins BA, Olaleye D, Zinman B, et al. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care. 2001;24:250-256. 8. Rith-Najarian SJ, Stolusky T, Gohdes DM. Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. A prospective evaluation of simple screening criteria. Diabetes Care. 1992;15:1386-1389. 9. Reichard P, Berglund B, Britz A, et al. Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years. J Intern Med. 1991;230:101-108. 10. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122:561-568. 11. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103-117. 12. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-853.
13. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37:589-596. 14. Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991;45:3-9, 1-2. 15. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326:1250-1256. 16. Gomez-Perez FJ, Rull JA, Dies H, et al. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study. Pain. 1985;23:395-400. 17. McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995; 311:1047-1052. 18. Stracke H, Meyer UE, Schumacher HE, et al. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care. 1992;15: 1550-1555. 19. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831-1836. 20. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50:1842-1846. 21. Yuen KCJ, Baker NR, Rayman G.Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray. A doubleblind placebo-controlled cross-over study. Diabetes Care. 2002;25:1699-1703. 22. Low PA, Opfer-Gehrking TL, Dyck PJ, et al. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain. 1995;62:163-168. 23. The Capsaicin Study Group.Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. Arch Intern Med. 1991;151:2225-2229. 24. Bianco A, Pitocco D,Valenza V, et al. Effect of sildenafil on diabetic gastropathy. Diabetes Care. 2002;25:1888-1889.
S74
Foot Care
INTRODUCTION Foot problems are a major cause of morbidity and mortality in people with diabetes mellitus and contribute to increased healthcare costs (1,2). The sequence of events leading to lower extremity amputation is well knownin people with neuropathy (3) or peripheral vascular disease (4), minor trauma to the foot leads to skin ulceration and infection, and to gangrene, resulting in amputation (5-9). Foot complications are a major reason for admission to the hospital for people with diabetes, accounting for approximately 20% of all diabetes-related admissions in the North American population (7,8,10,11).After amputation of 1 limb, the prognosis for the contralateral limb is poor (12,13). MANAGEMENT Appropriate management can prevent or heal diabetic foot ulcers, thereby greatly reducing the amputation rate (6,9,10,14,15).All patients with diabetes should be instructed on proper foot care (see Appendix 12) and should strive to reach recommended glycemic targets. Prevention of amputations necessitates the use of various measures, including regular foot examination and evaluation of amputation risk, patient education, optimal footwear to accommodate foot deformities, early detection and treatment of diabetic foot ulcers, and, if necessary, vascular surgery (10,14-16). Characteristics that have been demonstrated to confer high risk of ulceration include previous ulceration, neuropathy, structural deformity, peripheral vascular disease and microvascular complications (17). Management of established neuropathic foot ulceration requires an interdisciplinary approach that addresses glycemic control, infection, lower extremity vascular status, local wound care, appropriate debridement and off-loading of the ulcer site (18). OTHER RELEVANT GUIDELINES Targets for Glycemic Control, p. S18 Physical Activity and Diabetes, p. S24 Neuropathy, p. S72
RECOMMENDATIONS
1. Foot examinations in adults by both patients and healthcare providers should be an integral component of diabetes management to decrease the risk of foot lesions and amputations [Grade B, Level 2 (15,19)]. Foot examination should include assessment of structural abnormalities, neuropathy, vascular disease, ulcerations and evidence of infection [Grade D, Level 4 (9,19)]. Foot examinations should be performed at least annually in all people with diabetes, commencing at puberty and at more frequent intervals in those at high risk [Grade D, Consensus]. 2. People at high risk of foot ulceration and amputation require foot care education, proper footwear, counselling to avoid foot trauma, smoking cessation and early referrals if problems occur [Grade B, Level 2 (19)]. 3.A person with diabetes who develops a foot ulcer requires therapy by healthcare professionals who have experience in diabetes foot care. Any infection must be treated aggressively [Grade D, Consensus].
RELEVANT APPENDIX Appendix 12: Diabetes and Foot Care: A Patients Checklist, p. S138 REFERENCES
1. American Diabetes Association: clinical practice recommendations 1997. Diabetes Care. 1997;20(suppl 1):S1-S70. 2. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and amputations in diabetes. In: Diabetes in America. 2nd ed. Bethesda, MD: National Diabetes Data Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:409-428. 3. Eastman RC. Neuropathy in diabetes. In: Diabetes in America. 2nd ed. Bethesda, MD: National Diabetes Data Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:339-348. 4. Palumbo PJ, Melton LJ III. Peripheral vascular disease and diabetes. In: Diabetes in America. 2nd ed. Bethesda, MD: National Diabetes Data Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:401-408. 5. Boyko EJ, Lipsky BA. Infection and diabetes. In: Diabetes in America. 2nd ed. Bethesda, MD: National Diabetes Data
The initial draft of this chapter was prepared by Dereck Hunt MD MSc FRCPC; Robyn Houlden MD FRCPC.
S75 Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:485-499. Frykberg RG. Diabetic foot ulcerations. In: Frykberg RG, ed. The High Risk Foot in Diabetes Mellitus. New York, NY: Churchill Livingstone; 1991:151-195. Frykberg RG,Veves A. Diabetic foot infections. Diabetes Metab Rev. 1996;12:255-270. Gibbons GW, Eliopoulos GM, Kozak GP, et al. Infection of the diabetic foot. In: Kozak GP, Campbell DR, Frykberg RG, et al, eds. Management of Diabetic Foot Problems. Philadelphia, PA:WB Saunders; 1995:121. Reiber GE, Pecoraro RE, Koepsell TD. Risk factors for amputation in patients with diabetes mellitus. A case-control study. Ann Intern Med. 1992;117:97-105. Bild DE, Selby JV, Sinnock P, et al. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care. 1989;12:24-31. Reiber GE. Epidemiology of the diabetic foot. In: Levin ME, ONeal LW, Bowker JH, eds. The Diabetic Foot. 5th ed. St. Louis, MO: Mosby; 1993:1-15. Ebskov B, Josephsen P. Incidence of reamputation and death after gangrene of the lower extremity. Prosthet Orthot Int. 1980;4:77-80. Most RS, Sinnock P. The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care. 1983;6:87-91. Assal JP, Mhlhauser I, Pernet A, et al. Patient education as the basis for diabetes care in clinical practice and research. Diabetologia. 1985;28:602-613. Litzelman DK, Slemenda CW, Langefeld CD, et al. Reduction of lower extremity clinical abnormalities in patients with noninsulin-dependent diabetes mellitus.A randomized, controlled trial. Ann Intern Med. 1993;119:36-41. Malone JM, Snyder M,Anderson G, et al. Prevention of amputation by diabetic education. Am J Surg. 1989;158:520-523, 523-524. Boyko EJ, Ahroni JH, Stensel V, et al. A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study. Diabetes Care. 1999;22:1036-1042. Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A metaanalysis. Diabetes Care. 1999;22:692-695. McCabe CJ, Stevenson RC, Dolan AM. Evaluation of a diabetic foot screening and protection programme. Diabet Med. 1998;15:80-84.
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Retinopathy
INTRODUCTION Diabetic retinopathy is the most common cause of new cases of legal blindness in North America in people of working age (1), and the sole or contributing cause of blindness in about 86% of the eyes of people with type 1 diabetes mellitus and in 33% of the eyes of people with type 2 diabetes (2). However, the burden of vision loss attributable to diabetic retinopathy is greater in people with type 2 diabetes because of the greater prevalence of type 2 diabetes.The prevalence rate of proliferative retinopathy is 23% in patients with type 1 diabetes, 14% in people with type 2 diabetes taking insulin and 3% in people with type 2 diabetes not taking insulin (3). Macular edema occurs in 11, 15 and 4% of these groups, respectively (4). Patients with diabetes are also at increased risk of developing cataracts (5). Evidence for increased risk of primary open-angle glaucoma is conflicting (6,7). SCREENING Screening strategies for sight-threatening retinopathy (i.e. severe nonproliferative retinopathy, proliferative retinopathy or macular edema) must reflect differences in the incidence and prevalence of retinopathy in type 1 and type 2 diabetes (Table 1) (8-11). Diabetic retinopathy rarely develops in children <10 years of age with type 1 diabetes, regardless of the duration of diabetes (10). However, the prevalence rate increases sharply after 5 years duration of diabetes in postpubertal individuals with type 1 diabetes (10). Among people <15 years of age, irrespective of age of onset of diabetes, the prevalence of mild nonproliferative retinopathy was 2%, and none had soft exudates, intraretinal microvascular abnormalities, venous beading, macular edema or proliferative retinopathy (10,12,13). In the Wisconsin Epidemiologic Study of Diabetic Retinopathy 4-year incidence study, no person <17 years of age developed proliferative retinopathy or macular edema (8,14). Conversely, in patients with type 2 diabetes, retinopathy may be present in 21 to 39% of patients soon after clinical diagnosis, but is sight-threatening in only about 3% (4,9,11,15). In the United Kingdom Prospective Diabetes Study (UKPDS), few patients without retinopathy
The initial draft of this chapter was prepared by Iain S. Begg MB FRCS (Edin) FRCSC.
at diagnosis of diabetes progressed to photocoagulation in the following 3 to 6 years (16). There are 2 main approaches, used singly or in combination, to screening for diabetic retinopathy: ophthalmoscopy and retinal photography with subsequent grading. However, with ophthalmoscopy there is no permanent record for quality assurance or for monitoring progressive changes. The gold standard for assessing diabetic retinopathy is 7-standard field, stereoscopic-colour fundus photography (17). There is no formal standard for an acceptable level of sensitivity and specificity for screening tests.The benefits of screening begin to decline at sensitivities below 50 to 60% (18). The validity and reliability of any screening method should be explained to patients. The sensitivities and specificities of direct ophthalmoscopy performed by healthcare professionals to detect retinal lesions of retinopathy and to diagnose levels of severity vary widely (19).When fundus examination by direct ophthalmoscopy through dilated pupils is carried out by highly trained personnel (regardless of professional designation), 79% agreement in the detection of proliferative retinopathy can be achieved (20). Examinations performed by inexperienced observers or through undilated pupils fail to detect proliferative retinopathy in about 50% of patients and macular edema in 100% of patients (21-23). Using simple grading and referral criteria, community optometrists in the United Kingdom who were suitably trained and accredited in indirect slit-lamp fundoscopy performed well in the detection of sight-threatening diabetic retinopathy (76% sensitivity and 95% specificity) (24). This method of examination, widely used in clinics, awaits validation. Retina specialists achieved 81% agreement using contact lens fundus biomicroscopy and 84% agreement using high-resolution stereoscopic digital photography to detect clinically significant macular edema (25,26). In screening for sight-threatening retinopathy, the performance of mydriatic and nonmydriatic retinal photography using film or digital images depends on the number of photographic fields, resolution of the camera, proportion of unusable images, ability of the professional who takes the images and the ability of the professional who reads the images to diagnose the severity of retinopathy (19). Better technical methods for capturing adequate stereo images and high-quality consistent protocols for digital images are still being developed (27). The Early Treatment Diabetic Retinopathy Studys (ETDRSs) final
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scale is the best means of categorizing the severity of retinopathy and provides important prognostic information (28,29).
RECOMMENDATIONS
1. In people with type 1 diabetes, screening and evaluation for retinopathy by an experienced professional should be performed annually 5 years after the onset of diabetes in individuals 15 years of age [Grade A, Level 1 (8,10)]. 2. In people with type 2 diabetes, screening and evaluation for retinopathy by an experienced professional should be performed at the time of diagnosis [Grade A, Level 1 (9,11)].The interval for follow-up assessments should be tailored to the severity of the retinopathy. In those with no or minimal retinopathy, the recommended interval is 1 to 2 years [Grade A, Level 1 (9,11)]. 3. Screening for retinopathy should be performed by experienced professionals either in person or through their interpretation of photographs [Grade A, Level 1 (23)].
of vitreous hemorrhage (35,36).The risk of vitreous hemorrhage or foveola blot hemorrhage associated with warfarin therapy is unknown. Increasing age, female sex and proteinuria are risk factors associated with lens extraction (37). Appropriate monitoring intervals for retinopathy should be established. Glycemic, BP and lipid control should be assessed and therapy should be adjusted as required. In addition, screening for other complications of diabetes should be performed. Glycemic control People with type 1 diabetes can delay the onset or slow the progression of retinopathy by improving glycemic control with intensive insulin therapy (38,39). In the primary prevention cohort of the Diabetes Control and Complications Trial (DCCT), intensive therapy reduced the adjusted mean risk of retinopathy progression by 3 or more steps by 76%, and in the secondary intervention cohort by 54%, compared with conventional therapy (38). In type 1 diabetes, improved glycemic control may be associated with transient early worsening of retinopathy during the first 12 months (40). In people with type 2 diabetes, hyperglycemia is an independent risk factor for the incidence and progression of retinopathy (41,42). Intensified glycemic control is recommended to prevent clinically important eye disease in patients with type 2 diabetes (41,43).When compared to conventionally treated participants, intensively treated participants in the UKPDS developed significantly less microvascular disease (defined as retinopathy requiring photocoagulation, vitreous hemorrhage and/or fatal or nonfatal renal failure) (41).
PREVENTION OF ONSET AND PROGRESSION Longer duration of diabetes, higher glycosylated hemoglobin (A1C), more severe retinopathy, higher blood pressure (BP), higher lipid levels, lower hematocrit and pregnancy in women with type 1 diabetes are all important predictors of the progression of retinopathy (8-11,14,28,30-34). Acetylsalicylic acid (ASA) does not increase the risk or severity
Table 1. Screening for retinopathy

When to initiate screening 5 years after diagnosis of type 1 diabetes in all individuals 15 years of age In all individuals at diagnosis of type 2 diabetes Screening methods 7-standard field, stereoscopic-colour fundus photography with interpretation by a trained reader (gold standard) Direct ophthalmoscopy or indirect slit-lamp fundoscopy through dilated pupil Digital fundus photography If retinopathy is present Diagnose retinopathy severity and establish appropriate monitoring intervals (1 year or less) Treat sight-threatening retinopathy with laser therapy Review glycemic, BP and lipid control, and adjust therapy to reach targets as per guidelines* Screen for other diabetes complications If retinopathy is not present Type 1 diabetes: rescreen annually Type 2 diabetes: rescreen every 12 years Review glycemic, BP and lipid control, and adjust therapy to reach targets as per guidelines* Screen for other diabetes complications *See Other Relevant Guidelines BP = blood pressure
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Evidence for transient early worsening of retinopathy associated with improved glycemic control in people with type 2 diabetes is conflicting (44-46). BP control In type 1 and type 2 diabetes, elevated diastolic BP is a risk factor for the development of macular edema (14,47), and elevated systolic BP is a risk factor for vision loss (48). In people with hypertension, the development and progression of retinopathy can be reduced by treatment with antihypertensive agents (49). Lowering BP in normotensive patients with type 2 diabetes reduces the progression of retinopathy (50). Lipid control People with elevated total serum cholesterol, low-density lipoprotein cholesterol or triglyceride levels are more likely to have or develop retinal hard exudate, which can be associated with risk of vision loss, independent of the extent of macular edema (31).
RECOMMENDATION
4.To prevent the onset and delay the progression of diabetic retinopathy, people with diabetes should be treated to achieve optimal control of blood glucose [Grade A, Level 1A (38,41)], BP [Grade A, Level 1A (49)] and lipids [Grade D, Level 4 (31)].
the services in their community that will assist with retraining for employment, encourage independence and improve their quality of life (57,58).
RECOMMENDATIONS
5. Patients with proliferative or severe nonproliferative retinopathy, vitreous hemorrhage or macular edema should be assessed by an ophthalmologist or retina specialist [Grade D, Consensus] and should be considered for laser therapy and/or vitrectomy [Grade A, Level 1A (51,53,55,56)]. 6.Visually disabled people should be referred for low-vision evaluation and rehabilitation [Grade D, Consensus].
OTHER RELEVANT GUIDELINES Targets for Glycemic Control, p. S18 Macrovascular Complications, Dyslipidemia and Hypertension, p. S58 Pre-existing Diabetes and Pregnancy, p. S94 REFERENCES
1. Klein R, Klein BEK.Vision disorders in diabetes. In: Diabetes in America. 2nd ed. Bethesda, MD: National Diabetes Data Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:293-338. 2. Klein R, Klein BEK, Moss SE. Visual impairment in diabetes. Ophthalmology. 1984;91:1-9. 3. Klein R, Klein BEK, Moss SE. Epidemiology of proliferative diabetic retinopathy. Diabetes Care. 1992;15:1875-1891. 4. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984;91:1464-1474. 5. Klein BE, Klein R, Wang Q, et al. Older-onset diabetes and lens opacities. The Beaver Dam Eye Study. Ophthalmic Epidemiol. 1995;2:49-55. 6. Klein BEK, Klein R, Jensen SC. Open-angle glaucoma and older-onset diabetes. The Beaver Dam Eye Study. Ophthalmology. 1994;101:1173-1177. 7. Tielsch JM, Katz J, Quigley HA, et al. Diabetes, intraocular pressure, and primary open-angle glaucoma in the Baltimore Eye Survey. Ophthalmology. 1995;102:48-53. 8. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1989;107:237-243. 9. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol. 1989;107:244-249. 10. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less
TREATMENT Sixty-four percent of eyes undergoing cataract extraction had improved visual acuity postoperatively, and only 15% of operated-on eyes had a significant decrease in visual acuity 1 year after surgery (37). Focal/grid laser treatment for clinically significant macular edema reduces the incidence of moderate visual loss (doubling of initial visual angle [3 lines, 15 letters] on the ETDRS visual acuity chart) by 50% (51). Full implementation of scatter laser treatment and vitrectomy reduces legal blindness by 90% in patients with severe nonproliferative or proliferative retinopathy (52-54). In type 1 diabetes, early vitrectomy performed for nonclearing, severe vitreous hemorrhage provides a better chance of visual recovery than if treatment is deferred (55). In type 2 diabetes, advances in the skill and technology of vitrectomy surgery now challenge the prior conclusions that early vitrectomy has no such benefit and carries a 2-fold higher overall risk of serious untoward events than if deferred for 1 year (55). In people with type 1 or type 2 diabetes, early vitrectomy for advanced active proliferative retinopathy unresponsive to laser treatment achieves significant recovery of visual acuity compared with conventional management (56). Residual vision can often be improved by an accurate spectacle correction and/or magnifying aids (including a magnification addition to insulin syringes) with instructions for use. People with impaired vision should be informed of
S79 than 30 years. Arch Ophthalmol. 1984;102:520-526. 11. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102:527-532. 12. Klein R, Klein BEK, Moss SE, et al. Severe retinopathy in insulin-taking children and young adults. Pediatr Adolesc Endocrinol. 1988;17:146-152. 13. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy.VII. Diabetic nonproliferative retinal lesions. Ophthalmology. 1987;94:1389-1400. 14. Klein R, Moss SE, Klein BEK, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XI. The incidence of macular edema. Ophthalmology. 1989;96:1501-1510. 15. Kohner EM, Aldington SJ, Stratton IM, et al. United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors. Arch Ophthalmol. 1998;116:297-303. 16. Kohner EM, Stratton IM, Aldington SJ, et al. Relationship between the severity of retinopathy and progression to photocoagulation in patients with type 2 diabetes mellitus in the UKPDS (UKPDS 52). Diabet Med. 2001;18:178-184. 17. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographsan extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 1991; 98:786-806. 18. Javitt JC, Canner JK, Frank RG, et al. Detecting and treating retinopathy in patients with type I diabetes mellitus. A health policy model. Ophthalmology. 1990;97:483-495. 19. Hutchinson A, McIntosh A, Peters J, et al. Effectiveness of screening and monitoring tests for diabetic retinopathy a systematic review. Diabet Med. 2000;17:495-506. 20. Moss SE, Klein R, Kessler SD, et al. Comparison between ophthalmoscopy and fundus photography in determining severity of diabetic retinopathy. Ophthalmology. 1985;92:62-67. 21. Nathan DM, Fogel HA, Godine JE, et al. Role of diabetologist in evaluating diabetic retinopathy. Diabetes Care. 1991;14:26-33. 22. Sussman EJ, Tsiaras WG, Soper KA. Diagnosis of diabetic eye disease. JAMA. 1982;247:3231-3234. 23. Buxton MJ, Sculpher MJ, Ferguson BA, et al. Screening for treatable diabetic retinopathy: a comparison of different methods. Diabet Med. 1991;8:371-377. 24. Prasad S, Kamath GG, Jones K, et al. Effectiveness of optometrist screening for diabetic retinopathy using slit-lamp biomicroscopy. Eye. 2001;15:595-601. 25. Kinyoun J, Barton F, Fisher M, et al. Detection of diabetic macular edema. Ophthalmoscopy versus photographyEarly Treatment Diabetic Retinopathy Study report number 5. Ophthalmology. 1989;96:746-751. 26. Rudnisky CJ, Hinz BJ, Tennant MTS, et al. High-resolution stereoscopic digital fundus photography versus contact lens biomicroscopy for the detection of clinically significant macular edema. Ophthalmology. 2002;109:267-274. 27. Klein R, Klein BEK. Screening for diabetic retinopathy, revisited [editorial]. Am J Ophthalmol. 2002;134:261-263. 28. Davis MD, Fisher MR, Gangnon RE, et al. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study report #18. Invest Ophthalmol Vis Sci. 1998;39:233-252. 29. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Ophthalmology. 1991; 98:823-833. 30. Klein BEK, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care. 1990;13:34-40. 31. Chew EY, Klein ML, Ferris FL III, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) report 22. Arch Ophthalmol. 1996;114:1079-1084. 32. Qiao Q, Keinnen-Kiukaanniemi S, Lr E. The relationship between hemoglobin levels and diabetic retinopathy. J Clin Epidemiol. 1997;50:153-158. 33. The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care. 2000;23:1084-1091. 34. Chew EY, Mills JL, Metzger BE, et al. Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. Diabetes Care. 1995;18:631-637. 35. Chew EY, Klein ML, Murphy RP, et al. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report no. 20. Arch Ophthalmol. 1995;113:52-55. 36. Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Ophthalmology. 1991;98:757-765. 37. Chew EY, Benson WE, Remaley NA, et al. Results after lens extraction in patients with diabetic retinopathy: Early Treatment Diabetic Retinopathy Study report number 25. Arch Ophthalmol. 1999;117:1600-1606. 38. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986. 39. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus.The Diabetes Control and Complications Trial. Arch Ophthalmol. 1995;113:36-51. 40. The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998; 116:874-886. 41. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients
S80 with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853. 42. Klein R, Klein BEK, Moss SE, et al. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med. 1994;154:2169-2178. 43. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103-117. 44. Henricsson M, Janzon L, Groop L. Progression of retinopathy after change of treatment from oral antihyperglycemic agents to insulin in patients with NIDDM. Diabetes Care. 1995; 18:1571-1576. 45. Henricsson M, Nilsson A, Janzon L, et al. The effect of glycaemic control and the introduction of insulin therapy on retinopathy in non-insulin-dependent diabetes mellitus. Diabet Med. 1997;14:123-131. 46. Emanuele N, Klein R,Abraira C, et al. Evaluations of retinopathy in the VA Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM). A feasibility study. Diabetes Care. 1996;19:1375-1381. 47. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthalmology. 1995;102:7-16. 48. Moss SE, Klein R, Klein BEK.Ten-year incidence of visual loss in a diabetic population. Ophthalmology. 1994;101:1061-1070. 49. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713. 50. Schrier RW, Estacio RO, Esler A, et al. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61:1086-1097. 51. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103:1796-1806. 52. Ferris FL III. How effective are treatments for diabetic retinopathy? JAMA. 1993;269:1290-1291. 53. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings. Ophthalmology. 1978;85:82-106. 54. Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:505-537. 55. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Study report 5. Arch Ophthalmol. 1990;108:958-964. 56. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial Diabetic Retinopathy Vitrectomy Study report 3. Ophthalmology. 1988;95:1307-1320. 57. Fonda GE. Optical treatment of residual vision in diabetic retinopathy. Ophthalmology. 1994;101:84-88. 58. Bernbaum M, Albert SG. Referring patients with diabetes and vision loss for rehabilitation: who is responsible? Diabetes Care. 1996;19:175-177.
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Erectile Dysfunction
INTRODUCTION Erectile dysfunction (ED) affects approximately 34 to 45% of men with diabetes (1-8). Risk factors include increasing age, duration of diabetes, poor glycemic control, cigarette smoking, hypertension, dyslipidemia and cardiovascular disease (4,6,9,10). Diabetic retinopathy has been shown to correlate directly with the presence of ED (4,6,11). Organic causes include microvascular and macrovascular disease, and neuropathy. Psychological and situational factors may also cause or contribute to ED. In addition, ED is a side effect of many drugs commonly prescribed to men with diabetes, such as antihypertensives (beta blockers and thiazide diuretics) and antidepressants. SCREENING All adult men with diabetes should be periodically screened for ED with a sexual function history. Screening for ED in men with type 2 diabetes should begin at diagnosis of diabetes. TREATMENT While no randomized clinical trial has demonstrated that interventions that improve glycemic control also reduce the incidence and progression of ED, the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study showed that intensive glycemic control was effective for primary prevention of and secondary intervention for neuropathy (12-14). A new class of agents, type 5 phosphodiesterase (PDE5) inhibitors, has the potential to have a major impact on ED therapy and quality of life, and should be offered as first-line therapy to men with diabetes wishing treatment for ED (15-18). Contraindications for the use of PDE5 inhibitors include unstable angina or untreated cardiac ischemia, any form of nitrate use and poor exercise tolerance (19). Referral to a specialist in ED should be offered to men who do not respond to PDE5 inhibitors or for whom the use of PDE5 inhibitors is contraindicated. Second-line therapies (e.g. vacuum constriction devices, intracorporal injection therapy with prostaglandin E1 [PGE1] alone or in combination with papaverine and phentolamine [triple therapy], The initial draft of this chapter was prepared by Sidney B. Radomski MD FRCSC.
intraurethral therapy using PGE1 [MUSE]) or third-line therapy (penile prosthesis) may be considered for these men. EJACULATORY DISORDERS Ejaculatory disorders are another common disorder of sexual function in men with diabetes, occurring in up to 32% (20). They are secondary to autonomic neuropathy, with incomplete closure of the bladder neck during ejaculation leading to retrograde ejaculation or anejaculation.Treatment of these disorders is generally unsuccessful.
RECOMMENDATIONS
1. All adult men with diabetes should be periodically screened for ED with a sexual function history. Screening for ED in men with type 2 diabetes should begin at diagnosis of diabetes [Grade D, Consensus]. 2. A PDE5 inhibitor should be offered as first-line therapy to men with diabetes with ED wishing treatment if there are no contraindications to its use [Grade A, Level 1A (15-18)]. 3. Referral to a specialist in ED should be considered for men who do not respond to PDE5 inhibitors or for whom the use of PDE5 inhibitors is contraindicated [Grade D, Consensus].
OTHER RELEVANT GUIDELINES Diabetes in the Elderly, p. S106 REFERENCES

1. Maatman TJ, Montague DK, Martin LM. Erectile dysfunction in men with diabetes mellitus. Urology. 1987;29:589-592. 2. Rubin A, Babbott D. Impotence and diabetes mellitus. JAMA. 1958;168:498-500. 3. Kolodny RC, Kahn CB, Goldstein HH, et al. Sexual dysfunction in diabetic men. Diabetes. 1974;23:306-309. 4. McCulloch DK, Campbell IW,Wu FC, et al.The prevalence of diabetic impotence. Diabetologia. 1980;18:279-283. 5. Zemel P. Sexual dysfunction in the diabetic patient with hypertension. Am J Cardiol. 1988;61:27H-33H. 6. McCulloch DK,Young RJ, Prescott RJ, et al.The natural history of impotence in diabetic men. Diabetologia. 1984;26:437-440. 7. Bacon CG, Hu FB, Giovannucci E, et al. Association of type and duration of diabetes with erectile dysfunction in a large
S82 cohort of men. Diabetes Care. 2002;25:1458-1463. 8. De Berardis G, Pellegrini F, Franciosi M, et al. Identifying patients with type 2 diabetes with a higher likelihood of erectile dysfunction: the role of the interaction between clinical and psychological factors. J Urol. 2003;169:1422-1428. 9. Naliboff BD, Rosenthal M. Effects of age on complications in adult onset diabetes. J Am Geriatr Soc. 1989;37:838-842. 10. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151:54-61. 11. Klein R, Klein BEK, Lee KE, et al. Prevalence of self-reported erectile dysfunction in people with long-term IDDM. Diabetes Care. 1996;19:135-141. 12. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986. 13. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995; 122:561-568. 14. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-853. 15. Rendell MS, Rajfer J,Wicker PA, et al. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. JAMA. 1999;281:421-426. 16. Boulton AJM, Selam J-L, Sweeney M, et al. Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus. Diabetologia. 2001;44:1296-1301. 17. Goldstein I,Young JM, Fischer J, et al.Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care. 2003; 26:777-783. 18. Senz de Tejada I, Anglin G, Knight JR, et al. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care. 2002;25:2159-2164. 19. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Am J Cardiol. 2000;86:175-181. 20. Dunsmuir WD, Holmes SA.The aetiology and management of erectile, ejaculatory, and fertility problems in men with diabetes mellitus. Diabet Med. 1996;13:700-708.
D I A B E T E S I N S P E C I A L P O P U L AT I O N S
Diabetes in Special Populations
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Type 1 Diabetes in Children and Adolescents

INTRODUCTION Diabetes mellitus is the most common endocrine disease and one of the most common chronic conditions in children and adolescents.This section addresses those areas of diabetes management that are specific to children. Unless otherwise specified, the term child is used for individuals 0 to 18 years of age, and the term adolescent for those 13 to 18 years of age. MANAGEMENT Children and adolescents who present with diabetic ketoacidosis (DKA) require a short period of hospitalization to stabilize the associated metabolic derangements and to initiate insulin therapy. Outpatient education for new-onset diabetes in children and adolescents who are not experiencing DKA has been shown to be less expensive and associated with similar or slightly better outcomes in terms of metabolic control, and rates of rehospitalization, DKA and severe hypoglycemia compared to an inpatient education program (1-6). Children and adolescents with new-onset type 1 diabetes and their families require intensive diabetes education by an interdisciplinary pediatric diabetes healthcare (DHC) team to provide them with the necessary skills and knowledge to manage this disease. The complex physical, developmental and emotional needs of children and their families require specialized care to ensure the best long-term outcomes (7). Education topics must include insulin action and administration, dosage adjustment, blood glucose (BG) testing, sick-day management and prevention of DKA, nutrition therapy, exercise, and prevention and treatment of hypoglycemia. As part of routine care, children and their families should also receive psychoeducational sessions and interventions, as required, on emotional adjustment at each age and stage, behavioural-developmental growth, childhood and adolescent depression, school issues, diabetes camp, substance abuse, drivers licence and career choices.
RECOMMENDATIONS
1. All children and adolescents with diabetes should have access to an experienced DHC team and specialized care starting at the time of diagnosis [Grade D, Level 4 (7)]. 2. For children and adolescents with new-onset type 1 diabetes who are medically stable, initial education and management in an outpatient setting should be considered, providing appropriate personnel and daily telephone consultation service are available in the community [Grade C, Level 3 (3)].
Glycemic targets As improved metabolic control reduces both the onset and progression of diabetes-related complications in adults and adolescents with type 1 diabetes (8,9), aggressive attempts should be made to reach the recommended glycemic targets outlined in Table 1. However, clinical judgement is required to determine which children can reasonably and safely achieve these targets.Treatment goals and strategies must be tailored to the child, with consideration given to individual risk factors. Repeat episodes of severe hypoglycemia appear to increase the risk of cognitive impairment in preschoolaged children (10-17).
RECOMMENDATION
3. Adolescents should employ the same therapeutic strategies and aim for the same glycemic targets as adults [Grade A, Level 1A (8)]. Children 5 to 12 years of age should aim for a glycosylated hemoglobin (A1C) target of 8.0%, with glycemic and A1C targets graduated according to the childs age [Grade D, Consensus]. In children <5 years of age, an A1C of 9.0% is acceptable, and extreme caution should be exercised to avoid hypoglycemia because of the risk of cognitive impairment that may occur in this age group [Grade D, Level 4 (11,15,17)].
The initial draft of this chapter was prepared by Danile Pacaud MD FRCPC; Heather Dean MD FRCPC; Margaret L. Lawson MD MSc FRCPC; Denis Daneman MB BCh FRCPC; Sarah Lawrence MD FRCPC.
Insulin therapy Insulin therapy is the mainstay of medical management of type 1 diabetes. A variety of insulin regimens can be employed, but few have been studied specifically in children and adolescents with new-onset diabetes. The initial insulin
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regimen in children and adolescents with new-onset type 1 diabetes should include at least 2 daily injections of intermediate- and fast-acting insulin. The choice of insulin regimen will depend on other factors, including the childs age, family lifestyle, socioeconomic factors, and individual family, patient and physician preferences. Regardless of the insulin regimen used, all children should be treated to meet glycemic targets. Most children will require intensification of their regimen over time. Two major methods of intensive diabetes management have been employed to achieve recommended glycemic targets: multiple daily injection routines and continuous subcutaneous insulin infusion (CSII, insulin pump therapy). CSII is a safe and effective way of delivering intensive diabetes management in children and adolescents with type 1 diabetes, and can be initiated at any age. Rapid-acting insulin analogues are the insulins of choice for pump users (18).When used as part of a multidimensional approach to therapy, improvements in metabolic control may be achieved without increased risk of severe hypoglycemia (19-21). Enhanced attention to meal planning, BG monitoring and insulin pump function are essential components of this therapy. Insulin glargine (Lantus), an extended long-acting insulin analogue approved, but not yet available, in Canada, has been approved and is in use in Europe and the United States.The only 2 published reports of its use in children and adolescents both confirmed improved fasting blood glucose levels and fewer episodes of nocturnal hypoglycemia (22,23).
RECOMMENDATION
4. Consideration should be given to increasing the frequency of injections or changing the type of intermediate-acting insulin and fast-acting insulin, or changing to CSII (insulin pump) therapy when the 2 or 3 daily insulin injection regimen fails to optimize metabolic control and/or for quality of life reasons [Grade D, Consensus].
RECOMMENDATION
6.Adolescent females with type 1 diabetes should receive counselling on contraception and sexual health in order to avoid unplanned pregnancy [Grade D, Consensus].
Eating disorders Adolescent females with type 1 diabetes have a 2-fold increased risk of developing an eating disorder compared to their peers without diabetes (28). Furthermore, in adolescents with type 1 diabetes, eating disorders are associated with poor metabolic control and earlier onset and more rapid progression of microvascular complications (29) and should be suspected in those adolescent and young adult females with type 1 diabetes who are unable to achieve and maintain metabolic targets. It is important to identify those patients with eating disorders because different management strategies are required to optimize metabolic control and prevent microvascular complications (30). Screening should be conducted by health professionals by asking appropriate nonjudgemental questions about weight and shape concerns, dieting, binge episodes and insulin omission for the purpose of weight control (28).
RECOMMENDATION
7.Adolescent females and young women with type 1 diabetes should be regularly screened for eating disorders using nonjudgemental questions about weight and shape concerns, dieting, binge eating and insulin omission for weight loss [Grade B, Level 2 (28)].
Table 1. Glycemic targets for children and adolescents Age A1C Preprandial Considerations (years) (%) PG (mmol/L)
<5 9.0 6.012.0 Extreme caution is required to avoid severe hypoglycemia because of the risk of cognitive impairment in this age group Targets should be graduated to the childs age Appropriate for most patients Consider for patients in whom these targets can be achieved safely
Smoking prevention and cessation In view of the importance of smoking as a modifiable risk factor for both macrovascular and microvascular complications of diabetes, antismoking counselling should be part of diabetes management (24-27).
RECOMMENDATION
5. Formal smoking prevention and cessation counselling should be part of diabetes management for adolescents with diabetes [Grade D, Consensus].
512
8.0
4.010.0
1318
7.0 6.0
4.07.0 4.06.0
Contraception and sexual health counselling As pregnancy in adolescent females with type 1 diabetes with poor metabolic control results in higher risks of maternal and fetal complications, unplanned pregnancies should be avoided (see Pre-existing Diabetes and Pregnancy, p. S94).
A1C = glycosylated hemoglobin PG = plasma glucose
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DKA DKA occurs in 15 to 67% of patients with new-onset diabetes, depending on geographic location (31-33), and with a frequency of 1 to 10 episodes per 100 patient years in those with established diabetes (31,32). In the patient with established diabetes, DKA results from failing to take insulin or poor sick-day management. Special caution should be exercised in children with DKA and new-onset diabetes or a greater degree of acidosis and dehydration because of the increased risk of cerebral edema (CE). While most cases of DKA are corrected without event, 0.7 to 3.0% of cases are complicated by CE (34-37), which is associated with significant morbidity (21 to 35%) and mortality (21 to 24%) (38). Although the cause of CE is still unknown, several factors are associated with increased risk, including age <5 years, newonset diabetes, high initial serum urea nitrogen, low initial partial pressure of arterial carbon dioxide (pCO2), rapid administration of hypotonic fluids, failure of serum sodium to rise during treatment, and use of bicarbonate (34-36,38-41). Detailed clinical protocols for the management of DKA in children to reduce the risk of CE have been published (42), and others are available through some provincial ministries of health (43) and medical colleges (44).
COMPLICATIONS There are important age-related considerations regarding the initiation of surveillance for diabetes complications and the interpretations of investigations (Table 2). Nephropathy A first morning urine albumin to creatinine ratio (ACR) has high sensitivity and specificity for the detection of microalbuminuria (45,46), the first clinical marker of diabetic nephropathy.Although screening with a random ACR is associated with greater compliance than with a first morning sample, its specificity may be compromised in adolescents due to their higher frequency of exercise-induced proteinuria and benign postural proteinuria. Due to the false-positive rate and low positive predictive value for the random ACR, especially in adolescents, confirmation of microalbuminuria is required (47) using a first morning ACR, or a timed overnight or 24-hour split urine collection for determination of the albumin excretion rate. At least 1 month should elapse between the abnormal screening test and the confirmatory test. Microalbuminuria is rare in prepubertal children, regardless of the duration of diabetes or metabolic control (48), so prepubertal children need not be screened. Furthermore,
Table 2. Screening for complications in children and adolescents with type 1 diabetes Complication Indications and intervals for screening Screening test
Nephropathy Yearly screening commencing at puberty in those with duration of type 1 diabetes 5 years First morning ACR If compliance prohibits a first morning urine sample, Postpubertal adolescents should be screened yearly a random ACR should be obtained after 5 years duration of type 1 diabetes Abnormal screening tests require confirmation with a first morning ACR or timed overnight or 24-hour split urine collection for determination of the albumin excretion rate. At least 1 month should elapse between sampling, and repeat sampling should be conducted every 3 to 4 months over a 12-month period to demonstrate persistence and/or progression 7-standard field, stereoscopic-colour fundus photography with interpretation by a trained reader (gold standard), or Direct ophthalmoscopy or indirect slit-lamp fundoscopy through dilated pupil, or Digital fundus photography Neuropathy Dyslipidemia Postpubertal adolescents should be screened yearly None, other than routine clinical assessment after 5 years duration of type 1 diabetes Screening necessary only in those with BMI >95th percentile, family history of hyperlipidemia or premature CAD, or poor metabolic control Routine Fasting lipid profile
Retinopathy
Yearly screening should commence 5 years after diagnosis of diabetes in individuals 15 years of age Follow-up screening should occur annually or be tailored to severity of retinopathy, if present
Hypertension
Use appropriate cuff size
ACR = albumin to creatinine ratio BMI = body mass index CAD = coronary artery disease
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the likelihood of transient or intermittent microalbuminuria is higher during the early peripubertal years (49,50). It is not known if individuals with transient or intermittent microalbuminuria are at risk of progression to overt nephropathy.As it can take 12 to 18 months of observation to determine whether the microalbuminuria is going to resolve, persist or progress, annual screening should begin with onset of puberty in order to follow the natural history of the microalbuminuria. Abnormal screening results require confirmation and follow-up to demonstrate persistence and/or progression (i.e. to demonstrate that the patient has nephropathy). Prior to initiating treatment, persistence and/or progression of microalbuminuria must be demonstrated by repeat sampling conducted every 3 to 4 months over a 12-month period. Treatment is indicated only for those adolescents with persistent and/or progressive microalbuminuria.There are no long-term intervention studies assessing the effectiveness of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists in delaying progression to overt nephropathy in adolescents with microalbuminuria. Therefore, treatment of adolescents with persistent and/or progressive microalbuminuria is based on the effectiveness of various interventions in adults with type 1 diabetes (51-53). A short-term randomized, controlled trial in adolescents demonstrated that ACE inhibitors were effective in reducing microalbuminuria compared to placebo (54).
RECOMMENDATIONS
8. In children with duration of type 1 diabetes of 5 years, screening for microalbuminuria should commence at onset of puberty and be performed yearly thereafter. Postpubertal adolescents should be screened yearly after 5 years duration of type 1 diabetes. Prepubertal children need not be screened [Grade D, Consensus]. 9. Screening for microalbuminuria in adolescents with type 1 diabetes should be conducted using a first morning urine test for determination of the ACR [Grade B, Level 2 (45)]. If compliance prohibits a first morning urine test, a random urine ACR should be obtained. Abnormal results require confirmation [Grade B, Level 2 (47)] with a first morning ACR, or a timed overnight or 24-hour split urine collection [Grade D, Consensus] for determination of the albumin excretion rate. At least 1 month should elapse between the abnormal screening test and the confirmatory test [Grade D, Consensus]. 10. Prior to initiating treatment, persistence and/or progression of microalbuminuria must be demonstrated by repeat sampling conducted every 3 to 4 months over a 12-month period [Grade D, Consensus].
Neuropathy When present, neuropathy is mostly subclinical in children (55,56). While prospective nerve conduction studies and autonomic neuropathy assessment studies have demonstrated increased prevalence of abnormalities over time (55,57-59), persistence of abnormalities is an inconsistent finding (56). With the exception of intensifying diabetes management to achieve and maintain glycemic targets, no other treatment modality has been reported in children and adolescents. It is therefore not necessary to use formal investigations other than routine clinical assessment of neuropathy in postpubertal adolescents with type 1 diabetes of 5 years duration. Dyslipidemia Children and adolescents with type 1 diabetes have a higher frequency of dyslipidemia compared to their peers and siblings without diabetes (60,61). Dyslipidemia in adolescents and adults with type 1 diabetes is associated with a higher frequency of progressive microalbuminuria, retinopathy and macrovascular disease. There are, however, no intervention trials for dyslipidemia in children or adolescents. In general, the dyslipidemia found in type 1 diabetes is associated with poor metabolic control and can be reversed with intensification of therapy and achievement of metabolic targets. In a small proportion of individuals, pharmacologic lipid-lowering therapy may be indicated, although experience with these medications in children and adolescents is limited.
RECOMMENDATION
11. Only those children and adolescents with type 1 diabetes and other risk factors, such as severe obesity (body mass index >95th percentile), and/or a family history of hyperlipidemia or premature coronary artery disease, or those with poor metabolic control should be screened for dyslipidemia [Grade D, Level 4 (60,61)].
Hypertension Children and adolescents with type 1 diabetes should have routine blood pressure (BP) measurement using an appropriate cuff size. Those with BP readings persistently above the 95th percentile for age should be referred for assessment and possible treatment. TRANSITION TO ADULT CARE Regular medical follow-up within a trusting and collaborative patient-doctor relationship or patient-DHC team relationship is very important to achieving metabolic targets.The change of physician or DHC team can have a major impact on disease management and metabolic control in the person with diabetes. Between 25 and 65% of young adults have no medical follow-up during the transition from pediatric to adult diabetes care services (62,63).Those with no follow-up are more likely to experience hospitalization for DKA during this period.
Retinopathy In children with type 1 diabetes of at least 5 years duration, screening for retinopathy should begin at age 15 years, and occur yearly thereafter (see Retinopathy, p. S76).
S88 RECOMMENDATION
12.To ensure ongoing and adequate metabolic control, pediatric and adult diabetes care services should collaborate to prepare adolescents and young adults for the transition to adult diabetes care [Grade D, Consensus].
COMORBID CONDITIONS IN CHILDREN WITH TYPE 1 DIABETES Autoimmune thyroid disease, Addisons disease and celiac disease can occur with increased frequency in children with diabetes. For a brief discussion on the prevalence of these comorbid conditions and indications for screening in children with type 1 diabetes, see Appendix 13. OTHER RELEVANT GUIDELINES Organization and Delivery of Care, p. S14 Targets for Glycemic Control, p. S18 Monitoring Glycemic Control, p. S21 Insulin Therapy in Type 1 Diabetes, p. S32 Hypoglycemia, p. S43 Psychological Aspects of Diabetes, p. S50 Influenza and Pneumococcal Immunization, p. S53 Nephropathy, p. S66 Retinopathy, p. S76 Type 2 Diabetes in Children and Adolescents, p. S91 Pre-existing Diabetes and Pregnancy, p. S94 RELEVANT APPENDIX Appendix 13: Comorbid Conditions in Children With Type 1 Diabetes, p. S139 REFERENCES
1. Curtis J, Hamilton J, Beck C, et al. Diagnosis and short-term clinical consequences of diabetes in children and adolescents. In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:107-123. 2. Charron-Prochownik D, Maihle T, Siminerio L, et al. Outpatient versus inpatient care of children newly diagnosed with IDDM. Diabetes Care. 1997;20:657-660. 3. Siminerio LM, Charron-Prochownik D, Banion C, et al. Comparing outpatient and inpatient diabetes education for newly diagnosed pediatric patients. Diabetes Educ. 1999; 25:895-906. 4. Chase HP, Crews KR, Garg S, et al. Outpatient management vs in-hospital management of children with new-onset diabetes. Clin Pediatr (Phila). 1992;31:450-456. 5. Daneman D, Frank M. Defining quality of care for children and adolescents with type 1 diabetes. Acta Paediatr Suppl. 1998;425:11-19. 6. Dougherty G, Schiffrin A, White D, et al. Home-based management can achieve intensification cost-effectively in type I diabetes. Pediatrics. 1999;103:122-128.
7. Glasgow AM, Weissberg-Benchell J, Tynan WD, et al. Readmissions of children with diabetes mellitus to a childrens hospital. Pediatrics. 1991;88:98-104. 8. Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr. 1994;125:177-188. 9. The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995;44:968-983. 10. Rovet J, Alvarez M. Attentional functioning in children and adolescents with IDDM. Diabetes Care. 1997;20:803-810. 11. Rovet JF, Ehrlich RM. The effect of hypoglycemic seizures on cognitive function in children with diabetes: a 7-year prospective study. J Pediatr. 1999;134:503-506. 12. Hershey T, Bhargava N, Sadler M, et al. Conventional versus intensive diabetes therapy in children with type 1 diabetes: effects on memory and motor speed. Diabetes Care. 1999; 22:1318-1324. 13. Bjrgaas M, Gimse R,Vik T, et al. Cognitive function in type 1 diabetic children with and without episodes of severe hypoglycaemia. Acta Paediatr. 1997;86:148-153. 14. Hershey T, Craft S, Bhargava N, et al. Memory and insulin dependent diabetes mellitus (IDDM): effects of childhood onset and severe hypoglycemia. J Int Neuropsychol Soc. 1997;3:509-520. 15. Northam EA, Anderson PJ, Jacobs R, et al. Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset. Diabetes Care. 2001;24:1541-1546. 16. Yale J-F, Begg I, Gerstein H, et al. 2001 Canadian Diabetes Association clinical practice guidelines for the prevention and management of hypoglycemia in diabetes. Can J Diabetes. 2001;26:22-35. 17. Ryan C,Vega A, Drash A. Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics. 1985;75:921-927. 18. Zinman B, Tildesley H, Chiasson J-L, et al. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes. 1997;46:440-443. 19. Maniatis AK, Klingensmith GJ, Slover RH, et al. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics. 2001; 107:351-356. 20. Boland EA, Grey M, Oesterle A, et al. Continuous subcutaneous insulin infusion.A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care. 1999;22:1779-1784. 21. Conrad SC, McGrath MT, Gitelman SE. Transition from multiple daily injections to continuous subcutaneous insulin infusion in type 1 diabetes mellitus. J Pediatr. 2002;140:235-240. 22. Schober E, Schoenle E, Van Dyk J, et al. Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes [letter]. Diabetes Care. 2001; 24:2005-2006.
S89 23. Mohn A, Strang S, Wernicke-Panten K, et al. Nocturnal glucose control and free insulin levels in children with type 1 diabetes by use of the long-acting insulin HOE 901 as part of a three-injection regimen [letter]. Diabetes Care. 2000;23:557-559. 24. Chase HP, Garg SK, Marshall G, et al. Cigarette smoking increases the risk of albuminuria among subjects with type I diabetes. JAMA. 1991;265:614-617. 25. Microalbuminuria Collaborative Study Group, United Kingdom. Risk factors for development of microalbuminuria in insulin dependent diabetic patients: a cohort study. BMJ. 1993;306:1235-1239. 26. Sinha RN, Patrick AW, Richardson L, et al. A six-year follow-up study of smoking habits and microvascular complications in young adults with type 1 diabetes. Postgrad Med J. 1997;73:293-294. 27. Scott LJ, Warram JH, Hanna LS, et al. A nonlinear effect of hyperglycemia and current cigarette smoking are major determinants of the onset of microalbuminuria in type 1 diabetes. Diabetes. 2001;50:2842-2849. 28. Jones JM, Lawson ML, Daneman D, et al. Eating disorders in adolescent females with and without type 1 diabetes: cross sectional study. BMJ. 2000;320:1563-1566. 29. Rydall AC, Rodin GM, Olmsted MP, et al. Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. N Engl J Med. 1997;336:1849-1854. 30. Crow SJ, Keel PK, Kendall D. Eating disorders and insulindependent diabetes mellitus. Psychosomatics. 1998;39:233-243. 31. Lvy-Marchal C, Patterson CC, Green A. Geographical variation of presentation at diagnosis of type I diabetes in children: the EURODIAB study. Diabetologia. 2001;44(suppl 3):B75-B80. 32. Smith CP, Firth D, Bennett S, et al. Ketoacidosis occurring in newly diagnosed and established diabetic children. Acta Paediatr. 1998;87:537-541. 33. Pinkey JH, Bingley PJ, Sawtell PA, et al. Presentation and progress of childhood diabetes mellitus: a prospective populationbased study. Diabetologia. 1994;37:70-74. 34. Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344:264-269. 35. Edge JA, Hawkins MM, Winter DL, et al. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child. 2001;85:16-22. 36. Harris GD, Fiordalisi I, Harris WL, et al. Minimizing the risk of brain herniation during treatment of diabetic ketoacidemia: a retrospective and prospective study. J Pediatr. 1990;117:22-31. 37. Bello FA, Sotos JF. Cerebral oedema in diabetic ketoacidosis in children [letter]. Lancet. 1990;336:64. 38. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care. 1990;13:22-33. 39. Duck SC, Wyatt DT. Factors associated with brain herniation in the treatment of diabetic ketoacidosis. J Pediatr. 1988; 113:10-14. 40. Harris GD, Fiordalisi I. Physiologic management of diabetic ketoacidemia. A 5-year prospective pediatric experience in 231 episodes. Arch Pediatr Adolesc Med. 1994;148:1046-1052. 41. Hale PM, Rezvani I, Braunstein AW, et al. Factors predicting cerebral edema in young children with diabetic ketoacidosis and new onset type I diabetes. Acta Paediatr. 1997;86:626-631. 42. American Diabetes Association. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care. 2003;26(suppl 1): S109-S117. 43. Emergency guidelines for the management of the child with type 1 diabetes.Toronto, ON: Ontario Ministry of Health and Long-term Care; 2001. Publication 7610-2133205 (English), 7610-3133212 (French). 44. The College of Physicians and Surgeons of Manitoba. Initial fluid and electrolyte management of diabetic ketoacidosis (DKA) in childhood 902. 1997. Available at: http://www. umanitoba.ca/colleges/physicians_and_surgeons/Guidelines _and_Statements/902.html. Accessed November 7, 2003. 45. Shield JPH, Hunt LP, Baum JD, et al. Screening for diabetic microalbuminuria in routine clinical care: which method? Arch Dis Child. 1995;72:524-525. 46. Gatling W, Knight C, Hill RD. Screening for early diabetic nephropathy: which sample to detect microalbuminuria? Diabet Med. 1985;2:451-455. 47. Houlihan CA, Tsalamandris C, Akdeniz A, et al. Albumin to creatinine ratio: a screening test with limitations. Am J Kidney Dis. 2002;39:1183-1189. 48. Lawson ML, Sochett EB, Chait PG, et al. Effect of puberty on markers of glomerular hypertrophy and hypertension in IDDM. Diabetes. 1996;45:51-55. 49. Danne T, Kordonouri O. Controversies on the pathogenesis of diabetic angiopathy: which treatment for normotensive adolescents with microalbuminuria and type 1 diabetes? J Pediatr Endocrinol Metab. 1998;11(suppl 2):347-363. 50. Rudberg S, Dahlquist G. Determinants of progression of microalbuminuria in adolescents with IDDM. Diabetes Care. 1996;19:369-371. 51. The Microalbuminuria Captopril Study Group. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabetologia. 1996;39:587-593. 52. Laffel LMB, McGill JB, Gans DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. Am J Med. 1995;99:497-504. 53. Mathiesen ER, Hommel E, Hansen HP, et al. Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ. 1999;319:24-25. 54. Cook J, Daneman D, Spino M, et al. Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus. J Pediatr. 1990;117:39-45. 55. Duck SC,Wei FF, Parke J, et al. Role of height and glycosylated hemoglobin in abnormal nerve conduction in pediatric patients with type I diabetes mellitus after 49 yr of disease. 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S90 56. Donaghue KC, Fung ATW, Fairchild JM, et al. Prospective assessment of autonomic and peripheral nerve function in adolescents with diabetes. Diabet Med. 1996;13:65-71. 57. Karachaliou F, Karavanaki K, Greenwood R, et al. Consistency of pupillary abnormality in children and adolescents with diabetes. Diabet Med. 1997;14:849-853. 58. Olsen BS, Sjlie A-K, Hougaard P, et al. A 6-year nationwide cohort study of glycaemic control in young people with type 1 diabetes. Risk markers for the development of retinopathy, nephropathy, and neuropathy. J Diabetes Complications. 2000; 14:295-300. 59. Solders G,Thalme B, Aguirre-Aquino M, et al. Nerve conduction and autonomic nerve function in diabetic children. A 10year follow-up study. Acta Paediatr. 1997;86:361-366. 60. Abraha A, Schultz C, Konopelska-Bahu T, et al. Glycaemic control and familial factors determine hyperlipidaemia in early childhood diabetes. Diabet Med. 1999;16:598-604. 61. Lipman TH, Hayman LL, Fabian CV, et al. Risk factors for cardiovascular disease in children with type I diabetes. Nurs Res. 2000;49:160-166. 62. Frank M. Factors associated with non-compliance with a medical follow-up regimen after discharge from a pediatric diabetes clinic. Can J Diabetes Care. 1996;20(3):13-20. 63. Pacaud D, McConnell B, Huot C, et al. Transition from pediatric to adult care for insulin-dependent diabetes patients. Can J Diabetes Care. 1996;20(4):14-20.
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Type 2 Diabetes in Children and Adolescents

INTRODUCTION Type 2 diabetes mellitus in children and adolescents has been documented in Aboriginal and other populations in North America (1-8). Understanding of the natural history, complications and treatment strategies is evolving. The prevalence of type 2 diabetes in Canadian Aboriginal children 5 to 18 years of age has been documented to be as high as 1%, with the highest prevalence in the Plains Cree people of Central Canada (2-7). Data from the United States (US) suggest a 10- to 30-fold increase in the number of children with type 2 diabetes over the past 10 to 15 years (8). Most of these children are from ethnic groups at high risk for type 2 diabetes, namely, of African, Hispanic and Asian descent.There are no data on these populations in Canada. Unless otherwise specified, the term child is used for individuals 0 to 18 years of age, and the term adolescent for those 13 to 18 years of age. SCREENING Although not proven in children, it is generally assumed that earlier diagnosis will lead to interventions that will normalize glycemia and reduce the short- and long-term complications of diabetes (9). Children with type 2 diabetes from high-risk ethnic groups, such as Hispanic, African and Asian, in the US and Japan have been identified in school-based screening studies (10,11), but most have been reported as part of case series (8). Risk factors for the development of type 2 diabetes in children and adolescents include history of type 2 diabetes in a first- or second-degree relative, being a member of a highrisk population (e.g. people of Aboriginal, Hispanic, South Asian, Asian or African descent) (11), overweight (12-15), impaired glucose tolerance (IGT), polycystic ovary syndrome (PCOS) (16,17), exposure to diabetes in utero (18,19), acanthosis nigricans (11,20), hypertension and dyslipidemia. While the currently recommended screening test for children is the same as that for adults (namely, a fasting plasma glucose [FPG] test), studies have shown that the oral glucose tolerance test (OGTT) has a higher detection rate (12).
The diagnostic criteria for diabetes in children are the same as for adults (9).
RECOMMENDATION
1. Obese children 10 years of age should be considered for screening for type 2 diabetes every 2 years using an FPG test if they meet 2 of the following criteria: member of a high-risk ethnic group; family history of type 2 diabetes, especially if the child was exposed to diabetes in utero; acanthosis nigricans; PCOS; hypertension; or dyslipidemia. An OGTT may also be considered as a screening test [Grade D, Consensus].
CLASSIFICATION AND DIAGNOSIS In most children, the mode of presentation and early course of the disease usually indicate whether the child has type 1 or type 2 diabetes. However, in some children and adolescents, differentiation may be difficult.Testing for islet autoantibodies may be useful (21-23). Fasting insulin levels are not helpful because these levels are most often low (13,14). Youth with type 2 diabetes can present with diabetic ketoacidosis (DKA), so this cannot be used to classify the type of diabetes (24,25). In youth without classical features of type 1 diabetes and without features of insulin resistance, especially without morbid obesity and acanthosis nigricans, DNA diagnostic testing for genetic defects in beta cell function may be considered in some populations (26,27). PREVENTION Obesity is a major modifiable risk factor for the development of type 2 diabetes, yet studies on prevention of obesity in children are limited (28). Lifestyle counselling, as part of routine pediatric care, is recommended for obese schoolaged children and adolescents. The treatment of obese adolescents with metformin to reduce insulin resistance and, theoretically, to reduce the risk of glucose intolerance and type 2 diabetes has recently been investigated (29,30). Also investigated was the use of metformin in obese girls with PCOS to reduce insulin resistance,
The initial draft of this chapter was prepared by Heather Dean MD FRCPC; Denis Daneman MB BCh FRCPC.
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and associated hyperandrogenemia, and to prevent or delay glucose intolerance and diabetes (31-33). In contrast to infertile adult women with PCOS, pregnancy is not a therapeutic goal in adolescents. It is currently premature to recommend metformin for use in PCOS in this population. Intensive counselling for lifestyle modification should be implemented to promote weight loss.The effect of behaviour modification plus therapy with antiobesity agents in adolescents has not been reported. Breastfeeding has been shown to be protective against type 2 diabetes in some Aboriginal populations (19). MANAGEMENT Children with type 2 diabetes should receive care in conjunction or consultation with an interdisciplinary pediatric diabetes healthcare team.While there are very few data pertaining to successful management of type 2 diabetes in children, adult management principles apply equally to this population, including consideration of the sociocultural environment associated with obesity (34). In addition, psychoeducational issues, such as depression, self-destructive behaviour patterns and smoking cessation, may need to be addressed, and interventions offered as required. Intensive lifestyle intervention in obese youth with type 2 diabetes should be the first line of therapy, unless there is severe metabolic decompensation. In Aboriginal children, this approach has been found to improve glycemic control to within the normal range in <2 weeks (35). Insulin is required in those with severe metabolic decompensation at diagnosis (e.g. DKA, glycosylated hemoglobin [A1C] 9.0%, symptoms of severe hyperglycemia). While there is only anecdotal support for the long-term efficacy of metformin, it may be useful in the short term to improve glycemic control in adolescents with type 2 diabetes. In 1 study, metformin was shown to be safe in adolescents for up to 16 weeks of treatment, lowering FPG and A1C by 1.0 to 2.0% without any unique side effects (36). Metformin must be avoided in children if there is evidence of renal, hepatic or nonalcoholic fatty liver disease (37). More research and experience using oral antihyperglycemic agents in adolescents is required.
RECOMMENDATION
2. Adolescents with type 2 diabetes should receive intensive counselling regarding lifestyle modification. If glycemic targets are not achieved using lifestyle modification alone, metformin [Grade B, Level 2 (36)] or insulin should be considered [Grade D, Consensus].
adolescents with type 2 diabetes at diagnosis, but it is prudent to consider screening for retinopathy at diagnosis until the natural history is better understood. There is good evidence to support screening for renal disease at diagnosis. Aboriginal youth in Canada are at increased risk of renal diseases not associated with diabetes (39). Documentation of albuminuria at diagnosis indicates underlying primary renal disease requiring referral to a pediatric nephrologist. Since most adolescents with type 2 diabetes show clinical evidence of insulin resistance, surveillance for comorbid features of the metabolic syndrome should occur at diagnosis. Although there is no evidence to recommend specific interventions for dyslipidemia or hypertension in individuals in this age group with type 2 diabetes, these conditions should be treated judiciously, with consideration of the approaches used in adults. See Type 1 Diabetes in Children and Adolescents, p. S84, for additional information on screening for complications. OTHER RELEVANT GUIDELINES Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories, p. S7 Screening and Prevention, p. S10 Macrovascular Complications, Dyslipidemia and Hypertension, p. S58 Retinopathy, p. S76 Type 1 Diabetes in Children and Adolescents, p. S84 Type 2 Diabetes in Aboriginal Peoples, p. S110 REFERENCES
1. Savage PJ, Bennett PH, Senter RG, et al. High prevalence of diabetes in young Pima Indians: evidence of phenotypic variation in a genetically isolated population. Diabetes. 1979;28:937-942. 2. Dean HJ, Mundy RL, Moffatt M. Non-insulin-dependent diabetes mellitus in Indian children in Manitoba. CMAJ. 1992;147:52-57. 3. Dean HJ, Young TK, Flett B, et al. Screening for type-2 diabetes in aboriginal children in northern Canada [letter]. Lancet. 1998;352:1523-1524. 4. Harris SB, Perkins BA, Whalen-Brough E. Non-insulindependent diabetes mellitus among First Nations children. New entity among First Nations people of northwestern Ontario. Can Fam Physician. 1996;42:869-876. 5. Smith WG, Gowanlock W, Babcock K.Type 2 diabetes in First Nation children: a collaborative effort to assess and prevent disease. Paediatr Child Health. 2001;6:755-759. 6. Dannenbaum D,Verronneau M,Torrie J, et al. Comprehensive computerized diabetes registry. Serving the Cree of Eeyou Istchee (eastern James Bay). Can Fam Physician. 1999;45:364-370. 7. Delisle HF, ko J-M. Prevalence of non-insulin-dependent diabetes mellitus and impaired glucose tolerance in two Algonquin communities in Quebec. CMAJ. 1993;148:41-47. 8. Fagot-Campagna A. Emergence of type 2 diabetes mellitus in children: epidemiological evidence. J Pediatr Endocrinol Metab. 2000;13(suppl 6):1395-1402.
COMPLICATIONS Evidence suggests that early-onset type 2 diabetes in adolescence is associated with severe and early-onset microvascular complications (9,38). Retinopathy has not been described in
S93 9. Krakoff J, Lindsay RS, Looker HC, et al. Incidence of retinopathy and nephropathy in youth-onset compared with adultonset type 2 diabetes. Diabetes Care. 2003;26:76-81. 10. Owada M, Hanaoka Y, Tanimoto Y, et al. Descriptive epidemiology of non-insulin dependent diabetes mellitus detected by urine glucose screening in school children in Japan. Acta Paediatr Jpn. 1990;32:716-724. 11. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al.Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr. 2000;136:664-672. 12. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346:802-810. 13. McCance DR, Pettitt DJ, Hanson RL, et al. Glucose, insulin concentrations and obesity in childhood and adolescence as predictors of NIDDM. Diabetologia. 1994;37:617-623. 14. Pettitt DJ, Moll PP, Knowler WC, et al. Insulinemia in children at low and high risk of NIDDM. Diabetes Care. 1993;16:608-615. 15. Hanley AJG, Harris SB, Gittelsohn J, et al. Overweight among children and adolescents in a Native Canadian community: prevalence and associated factors. Am J Clin Nutr. 2000; 71:693-700. 16. Lewy VD, Danadian K, Witchel SF, et al. Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome. J Pediatr. 2001;138:38-44. 17. Palmert MR, Gordon CM, Kartashov AI, et al. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87:1017-1023. 18. Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49:2208-2211. 19. Young TK, Martens PJ,Taback SP, et al.Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among Native Canadians. Arch Pediatr Adolesc Med. 2002;156:651-655. 20. Stoddart ML, Blevins KS, Lee ET, et al. Association of acanthosis nigricans with hyperinsulinemia compared with other selected risk factors for type 2 diabetes in Cherokee Indians: the Cherokee Diabetes Study. Diabetes Care. 2002;25:1009-1014. 21. Dabelea D, Palmer JP, Bennett PH, et al. Absence of glutamic acid decarboxylase antibodies in Pima Indian children with diabetes mellitus [letter]. Diabetologia. 1999;42:1265-1266. 22. Sellers E, Eisenbarth G, Young TK, et al. Diabetes-associated autoantibodies in aboriginal children [letter]. Lancet. 2000; 355:1156. 23. Hathout EH,Thomas W, El-Shahawy M, et al. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics. 2001;107:E102. Available at: http://www. pediatrics.org/cgi/content/full/107/6/e102. Accessed November 7, 2003. 24. Pinhas-Hamiel O, Dolan LM, Zeitler PS. Diabetic ketoacidosis among obese African-American adolescents with NIDDM. Diabetes Care. 1997;20:484-486. 25. Sellers EAC, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth [letter]. Diabetes Care. 2000;23:1202-1204. Sellers EAC,Triggs-Raine B, Rockman-Greenberg C, et al.The prevalence of the HNF-1 G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care. 2002; 25:2202-2206. Owen KR, Stride A, Ellard S, et al. Etiological investigation of diabetes in young adults presenting with apparent type 2 diabetes. Diabetes Care. 2003;26:2088-2093. Campbell K,Waters E, OMeara S, et al. Interventions for preventing obesity in children. Cochrane Database Syst Rev. 2002(2):CD001871. Freemark M, Bursey D.The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics. 2001;107:E55.Available at: http://www.pediatrics. org/cgi/content/full/107/4/e55.Accessed November 7, 2003. Kay JP, Alemzadeh R, Langley G, et al. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism. 2001;50:1457-1461. Arslanian SA, Lewy V, Danadian K, et al. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab. 2002;87:1555-1559. Glueck CJ, Wang P, Fontaine R, et al. Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). J Adolesc Health. 2001;29:160-169. Ibez L, Valls C, Ferrer A, et al. Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism. J Clin Endocrinol Metab. 2001;86:3595-3598. Macaulay AC, Harris SB, Lvesque L, et al. Primary prevention of type 2 diabetes: experiences of 2 Aboriginal communities in Canada. Can J Diabetes. 2003;27:464-475. Anderson KA, Dean HJ. The effect of diet and exercise on a native youth with poorly controlled non-insulin dependent diabetes mellitus. Beta Release. 1990;14:105-106. Jones KL, Arslanian S, Peterokova VA, et al. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2002;25:89-94. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30:48-53. Yokoyama H, Okudaira M, Otani T, et al. Existence of earlyonset NIDDM Japanese demonstrating severe diabetic complications. Diabetes Care. 1997;20:844-847. Bulloch B, Postl BD, Ogborn MR. Excess prevalence of non diabetic renal disease in native American children in Manitoba. Pediatr Nephrol. 1996;10:702-704.
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S94
Pre-existing Diabetes and Pregnancy

PRECONCEPTION CARE FOR WOMEN WITH DIABETES Care by an interdisciplinary diabetes healthcare (DHC) team prior to conception and during pregnancy has been shown to minimize maternal and fetal risks in women with diabetes mellitus (1-5). An early working relationship should be established between the woman and the DHC team (composed of diabetes nurse educators, registered dietitians, obstetricians and endocrinologists/internists) to optimize care and assess whether self-care practices and social supports will be adequate during pregnancy (2-4,6).When such care results in optimal glycemic control, the risks of spontaneous abortion, congenital malformations, pre-eclampsia and progression of retinopathy are reduced (1-11).The incidence of congenital anomalies (the most significant fetal complication) decreases as preconception glycemic control improves (5,8-10,12).Women with type 1 or type 2 diabetes should strive to optimize glycemic control (see Targets for Glycemic Control, p. S18, and Table 1) (7,8,13). While an increasing number of women with type 2 diabetes are being managed in pregnancy clinics, they are often referred postconception, still using oral antihyperglycemic agents and with poor metabolic control (14).Whenever possible, women with type 2 diabetes who are planning pregnancy should be referred to the DHC team. Oral antihyperglycemic agents should be discontinued, and an insulin regimen appropriate for pregnancy should be established. Women with poorly controlled diabetes have a 2- to 3-fold increased risk of offspring with all congenital anomalies, including a 1% risk for neural tube defects (15). A folic acid supplement of 1 to 4 mg/day from preconception until 13 weeks gestation may reduce this risk (15,16). Assessment of complications In women with pre-existing diabetes, the risk of progression of any existing complications should be evaluated and discussed, preferably prior to pregnancy, or as early in pregnancy as possible (17-23). The initial draft of this chapter was prepared by Sara J. Meltzer MD FRCPC; Edmond A. Ryan MD FRCPC; Denice S. Feig MD MSc FRCPC; David Thompson MD FRCPC; Jennifer Snyder PDt MSc.
Women with type 1 diabetes (24,25) and type 2 diabetes (26) should have ophthalmologic assessments before conception, during the first trimester, as needed during pregnancy and within the first year postpartum (11). The risk of progression of retinopathy is increased with poor glycemic control during pregnancy and such progression may occur up to 1 year postpartum (11,26). Additional risks for progression include chronic and pregnancy-induced hypertension, preeclampsia and more severe pre-existing retinopathy (17,24,27,28). Pregnancy does not affect the long-term outcome of mild to moderate retinopathy (11). Prior to pregnancy, women should be screened for nephropathy according to the guidelines (see Nephropathy, p. S66). In the presence of early nephropathy, monitoring of renal function using a random albumin to creatinine ratio and/or 24-hour urine collection to assess creatinine clearance should occur each trimester. Microalbuminuria and overt nephropathy are associated with increased risk of maternal and fetal complications (29,30); consequently, glycemic and blood pressure (BP) control should be optimized
Table 1. Recommended glycemic targets preconception and during pregnancy* Glycemic targets
Pre-pregnancy A1C (%) Once pregnant FPG and preprandial PG (mmol/L) 1-hour postprandial PG (mmol/L) or 2-hour postprandial PG (mmol/L) Pre-bedtime snack PG (mmol/L) A1C (%) 3.85.2 5.57.7 5.06.6 4.05.9 6.0 (normal) 7.0 (6.0, if possible)
*In women with type 1 diabetes, attempts to achieve these glycemic targets all the time may be associated with an unacceptable increase in severe hypoglycemic episodes. Glycemic targets may need to be individualized. A1C = glycosylated hemoglobin FPG = fasting plasma glucose PG = plasma glucose
S95
to minimize this risk. Women with a creatinine clearance of 90 mL/minute are at increased risk of long-term worsening of nephropathy; such women should be followed concurrently with a nephrologist whenever possible (21,31). The risk of hypertension is increased in any woman with preconception microalbuminuria or proteinuria (32,33). Significant preconception proteinuria (>300 mg/day) will usually increase during pregnancy despite good BP and glycemic control, but will return to baseline by 6 months postpartum (22). If hypertension is uncontrolled during pregnancy, proteinuria will increase significantly and can be associated with worsening of renal function (21,34,35).Whether from worsening underlying hypertension or superimposed pre-eclampsia, if BP remains uncontrolled, early delivery may need to be considered (21,34). Angiotensin converting enzyme (ACE) inhibitors have been associated with major problems with fetal development, and angiotensin II receptor antagonists (ARBs), due to similar mechanisms of action, may have similar effects. Women using ACE inhibitors and/or ARBs should be changed to alternative antihypertensive medications known to be safe in pregnancy (e.g. methyldopa, calcium channel blockers, thiazide diuretics, beta blockers, hydralazine), preferably prior to conception, but at least as soon as pregnancy is diagnosed (36-38). Although rare, cardiovascular disease (CVD) can occur in women of reproductive age with diabetes. Myocardial infarction in pregnancy is associated with poor maternal and fetal outcomes (20,39).Women with known CVD should be evaluated and counselled about the significant risks associated with pregnancy. MANAGEMENT OF DIABETES DURING PREGNANCY Glycemic control Meticulous glycemic control is required for optimal maternal and fetal outcomes. Glycemic targets recommended during pregnancy are outlined in Table 1 (1,40-42). Hyperglycemia has adverse effects on the fetus throughout pregnancy. Hyperglycemia at conception and during the first trimester increases the risk of fetal malformations; later in pregnancy, it increases the risk of macrosomia and metabolic complications at birth (43). During pregnancy, there is a blunting of normal counterregulatory hormone responses to hypoglycemia (44,45). This, and the risk of recurrent hypoglycemic episodes as a result of striving to reach glycemic targets, may lead to hypoglycemia unawareness. Women with type 1 diabetes may therefore be at high risk of severe hypoglycemia, especially during the first trimester before relative insulin resistance from placental hormones develops, and care should be taken to counsel them about these risks. There do not appear to be significant adverse neonatal effects of hypoglycemia on the fetus (46). However, in the presence of hypoglycemia unawareness, there may be an increased risk of macrosomia
related to erratic glycemic control, as well as an increased risk of maternal seizures (47-49). Monitoring Self-monitoring of blood glucose (SMBG) is essential during pregnancy (2,50). Both preprandial and postprandial testing are recommended to guide therapy in order to achieve glycemic targets (8,13,51). Due to the increased risk of nocturnal hypoglycemia during pregnancy, testing during the night is often necessary (47). Since starvation ketosis is common in pregnancy and may have detrimental effects on the fetus, urine and/or blood monitoring of ketones is warranted to confirm that the diet is adequate (50,52). Lifestyle interventions During pregnancy, women with diabetes should be evaluated and followed by a registered dietitian to ensure that nutrition therapy promotes euglycemia, appropriate weight gain and adequate nutritional intake (53-56). Meal planning should emphasize carbohydrate restriction, especially at breakfast, and distribution over 3 meals and at least 3 snacks (1 of which should be a bedtime snack) (53,55,56). Hypocaloric diets are not recommended, as they result in weight loss and significant ketosis, and are likely inadequate in key nutrients required during pregnancy, such as protein and calcium (52,55-57). Pre-pregnancy body mass is a potent predictor of birth weight and should be considered when making recommendations about energy intake and rate of weight gain (55). Physical activity should be encouraged unless obstetrical contraindications exist or glycemic control is worsened by the activity (2,57). Pharmacologic interventions Insulin Insulin therapy must be individualized and regularly adapted to the changing needs of the pregnancy (2,3,42,58-60). Intensive insulin therapy (multiple daily injections [2,3,42] or continuous subcutaneous insulin infusion [CSII] [2,61]) is recommended to achieve glycemic targets. Women using CSII therapy should be educated about an increased risk of diabetic ketoacidosis (DKA) in the event of insulin pump failure, since DKA is a potentially fatal complication for the fetus (62). Insulin analogues (insulin lispro [Humalog] and insulin aspart [NovoRapid]) may help achieve postprandial glycemic targets without causing severe hypoglycemia (63,64). Insulin lispro does not appear to cross the placenta and can be used safely in pregnancy (65,66). Placental transfer of insulin aspart has not yet been assessed, although insulin aspart has been shown to control postprandial plasma glucose levels in pregnancy (67). The extended long-acting insulin analogue glargine (Lantus) stimulates insulin-like growth factor-1 (IGF-1) receptors significantly more than do other insulins, potentially altering growth, and should not be used in pregnancy until concerns about its safety have been addressed (68,69).
S96 RECOMMENDATIONS
1.Women with pre-existing diabetes should plan their pregnancy, preferably in consultation with an interdisciplinary pregnancy team, to optimize maternal and neonatal outcomes [Grade C, Level 3 (3,5,8)]. 2.Women with type 1 diabetes who are planning a pregnancy should strive to attain a preconception glycosylated hemoglobin (A1C) 7.0% to decrease the risk of spontaneous abortion, congenital malformations [Grade C, Level 3 (5,10)], pre-eclampsia [Grade C, Level 3 (35)], and the progression of retinopathy [Grade A, Level 1A (11)]. 3.Women with type 2 diabetes who are planning pregnancy should be encouraged to attain a preconception A1C 7.0% to reduce the risk of congenital anomalies [Grade D, Consensus]. 4.Women with type 2 diabetes who are planning pregnancy should discontinue oral antihyperglycemic agents prior to conception and attain glycemic targets using insulin, if needed [Grade D, Consensus]. 5. Prior to conception, women with pre-existing diabetes should receive nutrition counselling from a registered dietitian who is part of the DHC team [Grade C, Level 3 (3)] with reassessment as needed during pregnancy and postpartum [Grade D, Consensus]. Recommendations for weight gain during pregnancy should be based on pregravid body mass index [Grade D, Consensus]. 6. If planning pregnancy, women using ACE inhibitors or ARBs should change to other antihypertensives that are safe in pregnancy for BP control [Grade D, Consensus]. 7. Women with type 1 and type 2 diabetes who are planning a pregnancy should have ophthalmologic assessments prior to conception, during the first trimester, as needed during pregnancy and within the first year postpartum [Grade A, Level 1 for type 1 diabetes (11,25); Grade D, Consensus for type 2 diabetes]. 8. Prior to conception, women with diabetes should be screened for nephropathy [Grade A, Level 1 (29)]. If microalbuminuria or overt nephropathy is found, glycemic and BP control should be optimized to minimize maternal and fetal complications and progression of nephropathy [Grade D, Consensus]. 9. During pregnancy, women with type 1 or type 2 diabetes should aim to achieve glycemic targets while avoiding significant hypoglycemia [Grade D, Consensus]. 10.To attain glycemic targets during pregnancy, women with type 1 diabetes should receive intensive insulin therapy using multiple daily injections or CSII [Grade A, Level 1A (1,59,61)]. Insulin regimens for women with type 2 diabetes should be individualized and adjusted to achieve glycemic targets, with consideration given to intensive insulin regimens, as needed [Grade A, Level 1A (59)]. 11. Pregnant women with type 1 or type 2 diabetes should use both preprandial and postprandial SMBG, often 4 times per day, in order to make insulin adjustments to attain glycemic targets [Grade C, Level 3 (2)]. 12. Ketosis should be avoided during pregnancy [Grade C, Level 3 (52)].
Oral antihyperglycemic agents Use of glyburide or metformin during pregnancy does not appear to be associated with an increase in congenital anomalies independent of glycemic control. However, the evidence is inadequate to warrant recommendation of their use in pregnancy (70-73). OTHER RELEVANT GUIDELINES Targets for Glycemic Control, p. S18 Nephropathy, p. S66 Type 1 Diabetes in Children and Adolescents, p. S84 REFERENCES
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Silverman BL, Rizzo TA, Cho NH, et al. Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care. 1998;21(suppl 2): B142-B149. Montaner P, Domnguez R, Corcoy R. Self-monitored blood glucose in pregnant women without gestational diabetes mellitus. Diabetes Care. 2002;25:2104-2105. Churchill JA, Berendes HW, Nemore J. Neuropsychological deficits in children of diabetic mothers. A report from the Collaborative Study of Cerebral Palsy. Am J Obstet Gynecol. 1969;105:257-268. Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2002;25:148-198. Institute of Medicine (U.S.). Subcommittee on Nutritional Status and Weight Gain During Pregnancy. Nutrition During Pregnancy: Part I: Weight Gain, Part II: Nutrient Supplements. Washington, DC: National Academy Press; 1990. Jovanovic L. 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Results of 312 pregnancies among White class B-F mothers in Northern Jutland from 1976 to 1992. Dan Med Bull. 1994;41:115-118. Burkart W, Hanker JP, Schneider HPG. Complications and fetal outcome in diabetic pregnancy. Intensified conventional versus insulin pump therapy. Gynecol Obstet Invest. 1988; 26:104-112. Chauhan SP, Perry KG Jr, McLaughlin BN, et al. Diabetic ketoacidosis complicating pregnancy. J Perinatol. 1996;16:173-175. Anderson JH Jr, Brunelle RL, Koivisto VA, et al. Improved mealtime treatment of diabetes mellitus using an insulin analogue. Clin Ther. 1997;19:62-72. Raskin P, Guthrie RA, Leiter L, et al. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care. 2000;23:583-588. Jovanovic L, Ilic S, Pettitt DJ, et al. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care. 1999;22:1422-1427. Masson EA, Patmore JE, Brash PD, et al. Pregnancy outcome in type 1 diabetes mellitus treated with insulin lispro (Humalog). Diabet Med. 2003;20:46-50. Pettitt DJ, Ospina P, Kolaczynski JW, et al. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care. 2003;26:183-186. Kurtzhals P, Schffer L, Srensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000; 49:999-1005. Bolli GB, Owens DR. Insulin glargine. Lancet. 2000;356:443-445. Glueck CJ, Wang P, Kobayashi S, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002;77:520-525. Glueck CJ,Wang P, Goldenberg N, et al. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod. 2002;17:2858-2864. Langer O, Conway DL, Berkus MD, et al.A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134-1138. Gutzin SJ. The safety of oral hypoglycemic agents in the first trimester of pregnancy: a meta-analysis. Can J Clin Pharm. In press.
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Gestational Diabetes Mellitus

DEFINITION AND PREVALENCE Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy (1). The prevalence of GDM is population-specific and is a reflection of the underlying incidence of diabetes in that population (2). In Canada, the prevalence of GDM is higher than previously thought, varying from 3.5 to 3.8% in the nonAboriginal (but potentially multi-ethnic) population to 8.0 to 18.0% in Aboriginal populations (3-6). SCREENING AND DIAGNOSIS In the year 2003, screening, diagnosis and management of GDM remain controversial and continue to be debated in the medical community. The 1998 Clinical Practice Guidelines for the Management of Diabetes in Canada recommended screening all pregnant women for GDM, with the exception of those identified as being at very low risk (lean Caucasian women <25 years of age, with no personal or family history of diabetes or history of giving birth to a baby with a birth weight >4 kg) (7). However, studies have shown that selective screening still results in missed diagnoses (8-10). In addition, women with GDM are at increased risk for type 2 diabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and lipid abnormalities. Indeed, since GDM may represent an early manifestation of type 2 diabetes (2,11-13), diagnosing these women identifies those who might benefit from interventions to reduce the risk of future diabetes and those who might benefit from cardiovascular risk modification. Furthermore, treatment of GDM, particularly for those women with higher glycemic levels, has been shown to reduce perinatal morbidity (14,15). Morbidity for the baby includes macrosomia (with the risk of fetal and maternal trauma during birth), neonatal hypoglycemia, neonatal hypocalcemia, hyperbilirubinemia, respiratory distress syndrome and potential long-term obesity and glucose intolerance (16-19). Evidence is conflicting about the degree of maternal anxiety associated with the diagnosis of GDM, which has been used as an argument against screening (20,21). The initial draft of this chapter was prepared by Sara J. Meltzer MD FRCPC; Denice S. Feig MD MSc FRCPC; Edmond A. Ryan MD FRCPC; David Thompson MD FRCPC; Jennifer Snyder PDt MSc.
Since 1998, there has been no new high-quality evidence to examine the benefits of universal vs. selective screening for GDM. In the absence of such evidence, and considering the potential benefits of identifying GDM and the risk of missing cases with selective screening, the Canadian Diabetes Association Clinical Practice Guidelines Expert Committee recommends that all pregnant women be screened for GDM between 24 and 28 weeks gestation. Evaluation of risk for GDM (Table 1) should be conducted early in all pregnant women so that hyperglycemia, associated with increased perinatal morbidities, may be treated (15,22-24). Ideally, those women with multiple risk factors should be screened during the first trimester and, if negative, should be reassessed during subsequent trimesters. The screening test for GDM is a 1-hour plasma glucose (1hPG) measurement following a 50-g glucose load given at any time of the day. If the 1hPG is 10.3 mmol/L, GDM is confirmed (25). If the 1hPG is 7.8 to 10.2 mmol/L, a 75-g oral glucose tolerance test (OGTT) should be conducted (Figure 1). Criteria for the diagnosis of GDM continue to be problematic because the cutpoints on the current diagnostic tests do not clearly distinguish pregnancies at high risk of adverse fetal or maternal outcomes from those at low risk. Results are pending from the international Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, which should help to clarify this issue (26). In the absence of firm outcome data, the 75-g OGTT, using the values in the 1998 Clinical Practice Guidelines for the Management of Diabetes in Canada, is recommended (Figure 1). In populations at high risk, a single 75-g OGTT can be used as a definitive screen (14,27,28). A recent review by the Maternal-Fetal Medicine Committee of the
Table 1. Risk factors for GDM
Previous diagnosis of GDM Previous delivery of a macrosomic infant Member of high-risk population (e.g. woman of Aboriginal, Hispanic, South Asian, Asian or African descent) Age 35 years Obesity (BMI 30 kg/m2) Polycystic ovary syndrome and/or hirsutism Acanthosis nigricans Corticosteroid use BMI = body mass index GDM = gestational diabetes mellitus
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Society of Obstetricians and Gynaecologists of Canada highlights ongoing controversies in this area (22).
RECOMMENDATIONS
1.All pregnant women should be screened for GDM between 24 and 28 weeks gestation [Grade D, Consensus]. Plasma glucose (PG) should be measured 1 hour after a 50-g glucose load [Grade B, Level 1 (29)]. Women with multiple risk factors should be screened during the first trimester and, if negative, should be reassessed during subsequent trimesters [Grade D, Consensus]. 2. If the 1hPG in the 50-g glucose screening test is 7.8 to 10.2 mmol/L, a 75-g OGTT should be conducted, and fasting plasma glucose (FPG), 1hPG and 2-hour plasma glucose (2hPG) levels obtained [Grade D, Consensus]. In view of the controversies about diagnostic tests in this area, other accepted methods may be used [Grade D, Consensus].
MANAGEMENT Glycemic targets The glycemic targets associated with the best pregnancy outcomes (19,22,30-34) are outlined in Table 2. Although the lower limits have not been clearly defined, all PG levels should stay within the normal range, and excessively low values (i.e. preprandial <3.3 mmol/L and immediate postprandial <5.0 mmol/L) should be avoided. Monitoring Women with GDM should perform frequent fasting blood glucose (FBG) and postprandial home blood glucose (BG) monitoring to make the necessary meal plan and insulin adjustments to achieve glycemic targets and weight gain goals (32,35). Daily home BG monitoring is more effective than intermittent laboratory monitoring. Daytime preprandial BG values should be obtained when needed to adjust glycemic management strategies (35,36). Since starvation
Figure 1. Screening for and diagnosis of GDM

All pregnant women between 24 and 28 weeks gestation If multiple risk factors for GDM are present, screen during the first trimester of pregnancy and reassess during subsequent trimesters 1hPG following a 50-g glucose load given at any time of day
1hPG 10.3 mmol/L
1hPG=7.810.2 mmol/L 75-g OGTT* Measure FPG, 1hPG and 2hPG levels FPG 5.3 mmol/L 1hPG 10.6 mmol/L 2hPG 8.9 mmol/L
GDM
If 2 values are met or exceeded
IGT of pregnancy
If 1 value is met or exceeded
*In view of the controversies about diagnostic tests, other accepted methods may be used 1hPG = 1-hour plasma glucose 2hPG = 2-hour plasma glucose FPG = fasting plasma glucose GDM = gestational diabetes mellitus IGT = impaired glucose tolerance OGTT = oral glucose tolerance test
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ketosis is common in pregnancy and may have detrimental effects on the fetus, urine and/or blood monitoring of ketones is warranted to confirm that the diet is adequate (18,37). Lifestyle interventions Nutrition therapy is the primary treatment of GDM, although evidence for the optimal diet is lacking (38,39). Women with GDM should be evaluated and followed as needed during pregnancy by a registered dietitian to ensure that the meal plan promotes euglycemia, appropriate weight gain and adequate nutritional intake (31,38,40). Carbohydrate intake should be distributed over 3 meals and at least 3 snacks (1 of which should be at bedtime) (38,40,41). Pre-pregnancy body mass is a potent predictor of birth weight and should be considered when making recommendations regarding energy intake and rate of weight gain (31,42-44). Hypocaloric diets are not recommended, as they result in weight loss and significant ketosis, and are likely inadequate in key nutrients required during pregnancy, such as protein and calcium (31,45,46). Physical activity should be encouraged, with the frequency, type, duration and intensity tailored to individual obstetric risk (47-51). Pharmacologic interventions If women with GDM do not achieve glycemic targets within 2 weeks with nutrition therapy alone, insulin therapy should be initiated (19,52). The use of insulin therapy to achieve glycemic targets has been shown to reduce fetal and maternal morbidities (53,54). A variety of protocols can be used, with multiple injections (up to 4 injections per day) being most effective (19). Insulin should be adjusted based on FBG and postprandial BG values (19,30,32,53,55). Insulin lispro (Humalog) does not appear to cross the placenta and can be used safely in pregnancy (56,57). Placental transfer of insulin aspart (NovoRapid) has not yet been assessed, although insulin aspart has been shown to control postprandial PG levels in pregnancy (58). Due to ongoing safety concerns, insulin glargine (Lantus) should be avoided in pregnancy (59,60). Most oral antihyperglycemic agents cross the placenta and stimulate fetal hyperinsulinism. Glyburide does not appear to cross the placenta and, if started after the first trimester of pregnancy, good glycemic control and pregnancy outcomes
Table 2. Recommended glycemic targets for women with GDM PG (mmol/L)
Preprandial 1-hour postprandial 2-hour postprandial <5.3 <7.8 <6.7
can be achieved (61). However, until further studies demonstrate that glyburide is as safe as insulin during pregnancy, it should not be routinely used in this population (61,62). Early third trimester assessment of fetal growth may help determine a need for more aggressive therapy (e.g. fetal abdominal circumference of 70th percentile for gestational age on ultrasound) to reduce the risk of macrosomia (63-65). Further studies are needed to prove the benefit of this strategy (66). Management of IGT of pregnancy IGT of pregnancy (Figure 1) has been associated with an increased rate of adverse perinatal outcomes (67-69). Although treatment of IGT of pregnancy has not yet been shown to improve outcomes, nutrition therapy and BG monitoring may be justified.
RECOMMENDATIONS
3. Women with GDM should strive to attain the following glycemic targets, as these are associated with the best pregnancy outcomes: Preprandial PG <5.3 mmol/L [Grade D, Consensus]; 1-hour postprandial PG <7.8 mmol/L [Grade A, Level 1 (30)]; and 2-hour postprandial PG <6.7 mmol/L [Grade D, Consensus]. 4. If women with GDM do not achieve glycemic targets within 2 weeks with nutrition therapy alone, insulin therapy should be initiated [Grade D, Consensus].When insulin therapy is initiated, up to 4 injections/day should be considered [Grade A, Level 1A (19)]. 5. Women with GDM should conduct frequent FBG and postprandial home BG monitoring [Grade C, Level 3 (32,35)].
POSTPARTUM FOLLOW-UP As women who have had GDM have an elevated risk of subsequent type 2 diabetes, they should be re-evaluated within 6 months of delivery with a 2hPG in a 75-g OGTT (preferred test) or an FPG test. Breastfeeding, lifelong healthy eating and regular physical activity should be encouraged. In addition, these women should be monitored for development of type 2 diabetes or IGT according to recommended screening guidelines (see Screening and Prevention, p. S10). Long-term maternal risks With the diagnosis of GDM, there is evidence of both impairment of insulin secretion and action (70,71). These defects persist postpartum and increase the risk of IFG, IGT and type 2 diabetes (72-74). At 3 to 6 months postpartum, risks of dysglycemia are in the 16 to 20% range (74), and the cumulative risks increase to a 30 to 50% range depending on the time since the index pregnancy and the population studied (13,73,75). Some women with GDM (especially lean
GDM = gestational diabetes mellitus PG = plasma glucose
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women) have positive islet cell antibodies, making them more likely to progress to type 1 diabetes (76). Insulin resistance is often associated with increased cardiovascular disease risk profiles and is a prominent finding in many women with previous GDM (77,78). Given the elevated future risk of dysglycemia and diabetes in this population (13,75), promoting lifestyle changes in an effort to prevent diabetes is justified (72,79,80).
RECOMMENDATION
6. As women who have had GDM have an elevated risk of subsequent type 2 diabetes, they should be re-evaluated within 6 months of delivery with a 2hPG in a 75-g OGTT (preferred test) or an FPG test, and be counselled on a healthy lifestyle [Grade D, Consensus].
Long-term risks in offspring Many animal studies suggest long-term consequences of in utero hyperglycemia for the offspring, but human studies, by nature of the length of follow-up required, are few. A confounding factor is the genetically increased predisposition to diabetes. Observational studies have shown an increased risk of IGT in offspring, especially at or beyond puberty (17,81,82). This risk applies to the children of both women with GDM and those with pre-existing diabetes. Breastfeeding may lower the risk (83). Under- or overnutrition in utero may be associated with insulin resistance, possibly an underlying factor in the increase of type 2 diabetes in younger people, particularly in certain ethnic groups (81,84). In the Pima Indian population, as many as 70% of offspring exposed to diabetes in utero had type 2 diabetes at age 25 to 35 years (85). Followup observational studies in restricted study groups have also indicated an increased risk of obesity in the offspring of women with diabetes during pregnancy (18,81,85,86). Planning subsequent pregnancies Women with previous GDM (especially if obese), IFG or IGT should plan future pregnancies in consultation with their healthcare providers (87,88). Glucose tolerance should be assessed prior to conception. In an effort to reduce the risk of congenital anomalies and optimize pregnancy outcomes, these women should take a folic acid supplement (45,89) and implement lifestyle modifications to treat any glucose abnormality (45,87,90). OTHER RELEVANT GUIDELINES Screening and Prevention, p. S10 REFERENCES
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Bevier WC, Fischer R, Jovanovic L.Treatment of women with an abnormal glucose challenge test (but a normal oral glucose tolerance test) decreases the prevalence of macrosomia. Am J Perinatol. 1999;16:269-275. 68. Jensen DM, Damm P, Srensen B, et al. Clinical impact of mild carbohydrate intolerance in pregnancy: a study of 2904 nondiabetic Danish women with risk factors for gestational diabetes mellitus. Am J Obstet Gynecol. 2001;185:413-419. 69. Tallarigo L, Giampietro O, Penno G, et al. Relation of glucose tolerance to complications of pregnancy in nondiabetic women. N Engl J Med. 1986;315:989-992. 70. Catalano PM, Drago NM, Amini SB. Longitudinal changes in pancreatic -cell function and metabolic clearance rate of insulin in pregnant women with normal and abnormal glucose tolerance. Diabetes Care. 1998;21:403-408. 71. Ergin T, Lembet A, Duran H, et al. Does insulin secretion in patients with one abnormal glucose tolerance test value mimic gestational diabetes mellitus? Am J Obstet Gynecol. 2002; 186:204-209. 72. Kjos SL, Peters RK, Xiang A, et al. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes. 1995;44:586-591. 73. OSullivan JB. Diabetes mellitus after GDM. Diabetes. 1991;40(suppl 2):131-135. 74. Pallardo F, Herranz L, Garcia-Ingelmo T, et al. Early postpartum metabolic assessment in women with prior gestational diabetes. Diabetes Care. 1999;22:1053-1058. 75. Kaufmann RC, Schleyhahn FT, Huffman DG, et al. Gestational diabetes diagnostic criteria: long-term maternal follow-up. Am J Obstet Gynecol. 1995;172:621-625. 76. Dozio N, Beretta A, Belloni C, et al. Low prevalence of islet autoantibodies in patients with gestational diabetes mellitus. Diabetes Care. 1997;20:81-83. 77. Kousta E, Cela E, Lawrence NJ, et al.The prevalence of polycystic ovaries in women with a history of gestational diabetes. Clin Endocrinol (Oxf ). 2000;53:501-507. 78. Kjos SL, Buchanan TA, Montoro M, et al. Serum lipids within 36 mo of delivery in women with recent gestational diabetes. Diabetes. 1991;40(suppl 2):142-146. 79. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic -cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796-2803. 80. Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344:1343-1350. 81. Pettitt DJ, Aleck KA, Baird HR, et al. Congenital susceptibility to NIDDM. Role of intrauterine environment. Diabetes. 1988;37:622-628. 82. Plagemann A, Harder T, Kohlhoff R, et al. Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes. Diabetologia. 1997;40:1094-1100. 83. Plagemann A, Harder T, Franke K, et al. Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers. Diabetes Care. 2002;25:16-22. 84. Rosenbloom AL, Joe JR,Young RS, et al. Emerging epidemic of type 2 diabetes in youth. Diabetes Care. 1999;22:345-354.
S105 85. Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. J Matern Fetal Med. 2000;9:83-88. 86. Pettitt DJ, Bennett PH, Knowler WC, et al. Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring. Diabetes. 1985;34(suppl 2):119-122. 87. Gaudier FL, Hauth JC, Poist M, et al. Recurrence of gestational diabetes mellitus. Obstet Gynecol. 1992;80:755-758. 88. MacNeill S, Dodds L, Hamilton DC, et al. Rates and risk factors for recurrence of gestational diabetes. Diabetes Care. 2001;24:659-662. 89. Van Allen MI, McCourt C, Lee NS. Preconception Health: Folic Acid for the Primary Prevention of Neural Tube Defects. A Resource Document for Health Professionals, 2002. Ottawa, ON: Minister of Public Works and Government Services Canada; 2002. Publication H39-607/2002E. 90. Schaefer-Graf UM, Buchanan TA, Xiang A, et al. Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol. 2000;182:313-320.
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Diabetes in the Elderly

INTRODUCTION The definition of elderly varies, with some studies defining the elderly population as 60 years of age. Administrative guidelines frequently classify people >65 years of age as elderly. Although there is no definitive definition of elderly, it is generally agreed that this is a concept that reflects an age continuum starting sometime after age 60 and that is characterized by a slow, progressive frailty that continues until the end of life (1). PREVENTION OF DIABETES Lifestyle interventions are effective in the prevention of diabetes mellitus in elderly people at high risk for development of the disease (2). MANAGEMENT Glycemic control As interdisciplinary interventions have been shown to improve glycemic control in elderly individuals with diabetes, these patients should be referred to a diabetes healthcare (DHC) team (3,4). The same glycemic targets apply to otherwise healthy elderly as to younger people with diabetes (5-15). In people with multiple comorbidities, high level of functional dependency and limited life expectancy, the goal should be more conservative, and clinicians should try to avoid symptoms of hyperglycemia and prevent hypoglycemia. Nutrition and physical activity Nutrition education programs can improve metabolic control in ambulatory older people with diabetes (16). Physical training programs can be successfully implemented in older people with diabetes, although comorbid conditions may prevent aerobic physical training in many patients, and increased activity levels may be difficult to sustain.While the effects of aerobic exercise programs on glucose and lipid metabolism are inconsistent (17-20), resistance training has been shown to result in modest improvements in glycemic control as well as an increase in strength (21,22).
Oral antihyperglycemic agents In lean elderly patients with type 2 diabetes, the principal metabolic defect is an impairment in glucose-induced insulin secretion.Therefore, initial therapy for these patients should involve agents that stimulate insulin secretion. In obese elderly patients with type 2 diabetes, the principal metabolic defect is resistance to insulin-mediated glucose disposal, with insulin secretion being relatively preserved (23-25). Initial therapy for obese older people with diabetes should involve agents that improve insulin resistance. Alpha-glucosidase inhibitors (acarbose [Prandase]) are modestly effective oral antihyperglycemic agents in older patients with diabetes, but a substantial percentage of patients cannot tolerate them because of gastrointestinal side effects (26-30). Troglitazone (no longer available) has been shown to have significant effects on glycemic control in older patients with diabetes (31). Few studies with insulin sensitizers (thiazolidinediones) in the elderly are available, but data published in abstract form suggest that the newer thiazolidinediones demonstrate similar efficacy to troglitazone in the elderly. However, these drugs are associated with an increased incidence of fluid retention in older patients and, therefore, must be used with caution in patients with cardiovascular disease. The incidence of hypoglycemia associated with the use of sulfonylureas increases with age and appears to be higher with glyburide (32,33). Gliclazide (Diamicron) and glimepiride (Amaryl) are preferred over glyburide (Diabeta, Euglucon) in the elderly because they are associated with a lower frequency of hypoglycemic events (34,35). A new, long-acting formulation of gliclazide (Diamicron MR) resulted in equivalent glycemic control and the same frequency of hypoglycemic events as regular gliclazide in the elderly (36). The long-acting formulation may be preferred for patients in whom compliance is an issue. Nonsulfonylurea insulin secretagogues (repaglinide [GlucoNorm] and nateglinide [Starlix]) may be associated with a lower frequency of hypoglycemia in the elderly, and would be preferred in patients with irregular eating habits. Insulin therapy In elderly people, the use of premixed insulins as an alternative to mixing insulins minimizes dosage errors (37). Glycemic control may be improved if elderly patients are treated with prefilled insulin pens instead of conventional
The initial draft of this chapter was prepared by Graydon Meneilly MD FRCPC; Daniel Tessier MD MSc.
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syringes (38,39). Rapid-acting insulin analogue mixtures can be used in elderly people and be administered after meals (40). Equivalent glycemic control can be maintained in older people with either BID insulin injections or a combination of a single injection of insulin with an oral antihyperglycemic agent (41). Prevention and treatment of complications Hypertension Treatment of isolated systolic hypertension or combined systolic and diastolic hypertension in elderly patients with diabetes is associated with a significant reduction in cardiovascular (CV) morbidity and mortality (42-45).Treatment of isolated systolic hypertension may also preserve renal function in elderly patients with diabetes (46). Several different classes of antihypertensive agents have been shown to be effective, including thiazide diuretics, calcium channel blockers, beta blockers and angiotensin converting enzyme (ACE) inhibitors (42-45). ACE inhibitors may be particularly valuable for patients with diabetes and 1 other CV risk factor (47). Dyslipidemia The treatment of hypercholesterolemia with statins for both primary and secondary prevention of CV events significantly reduces CV morbidity and mortality in older people without diabetes (48).Although no data are currently available for the treatment of hypercholesterolemia in elderly patients with diabetes, it is reasonable to treat such patients to achieve the same targets as younger patients (49). Erectile dysfunction Type 5 phosphodiesterase inhibitors appear to be effective for the treatment of erectile dysfunction in carefully selected elderly patients with diabetes (50-52). OTHER RELEVANT GUIDELINES Screening and Prevention, p. S10 Organization and Delivery of Care, p. S14 Targets for Glycemic Control, p. S18 Insulin Therapy in Type 1 Diabetes, p. S32 Pharmacologic Management of Type 2 Diabetes, p. S37 Hypoglycemia, p. S43 Macrovascular Complications, Dyslipidemia and Hypertension, p. S58 Erectile Dysfunction, p. S81 REFERENCES
1. Tessier D, Meneilly G. Diabetes management in the elderly. In: Gerstein HC, Haynes RB, eds. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:370-379. 2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
RECOMMENDATIONS
1. Lifestyle interventions, including nutrition therapy and exercise, should be considered as therapeutic interventions to prevent type 2 diabetes in elderly patients at risk [Grade A, Level 1A (2)]. 2. Otherwise healthy elderly people with diabetes should be treated to achieve the same glycemic, blood pressure and lipid targets as younger people with diabetes [Grade D, Consensus]. In people with multiple comorbidities, high level of functional dependency or limited life expectancy, the goals should be more conservative [Grade D, Consensus]. 3.As interdisciplinary interventions have been shown to improve glycemic control in elderly people with diabetes, these patients should be referred to a DHC team [Grade C, Level 3 (3,4)]. 4. Either aerobic exercise or resistance training may benefit elderly people with type 2 diabetes and should be recommended for those individuals in whom it is not contraindicated [Grade B, Level 2 (17,20-22)]. 5.Alpha-glucosidase inhibitors are modestly effective in the elderly with type 2 diabetes [Grade A, Level 1A (30)]. 6. Insulin sensitizers (thiazolidinediones) are effective in elderly patients with type 2 diabetes, but should be used with caution in elderly patients at risk for fluid retention [Grade D, Consensus]. 7. In elderly people with type 2 diabetes, sulfonylureas should be used with caution because the risk of hypoglycemia increases exponentially with age [Grade D, Level 4 (53)]. In general, initial doses of sulfonylureas in the elderly should be half those used for younger people, and doses should be increased more slowly [Grade D, Consensus]. Gliclazide [Grade B, Level 2 (34)] and glimepiride [Grade C, Level 3 (35)] are the preferred sulfonylureas, as they are associated with a reduced frequency of hypoglycemic events compared with glyburide. 8. In elderly people, the use of premixed insulins and prefilled insulin pens as an alternative to mixing insulins should be encouraged to reduce dosages errors and potentially improve glycemic control [Grade B, Level 2 (37-39)]. 9. Isolated systolic hypertension or combined systolic and diastolic hypertension in elderly patients with diabetes should be treated to reduce CV morbidity and mortality [Grade A, Level 1A (42,44)].
3. Kronsbein P, Jrgens V, Mhlhauser I, et al. Evaluation of a structured treatment and teaching programme on non-insulindependent diabetes. Lancet. 1988;2:1407-1411. 4. Wilson W, Pratt C.The impact of diabetes education and peer support upon weight and glycemic control of elderly persons with noninsulin dependent diabetes mellitus (NIDDM). Am J Public Health. 1987;77:634-635.
S108 5. Kuusisto J, Mykknen L, Pyrl K, et al. Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke. 1994;25:1157-1164. 6. Kuusisto J, Mykknen L, Pyrl K, et al. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes. 1994;43:960-967. 7. Nathan DM, Singer DE, Godine JE, et al. Retinopathy in older type II diabetics. Association with glucose control. Diabetes. 1986;35:797-801. 8. Morisaki N, Watanabe S, Kobayashi J, et al. Diabetic control and progression of retinopathy in elderly patients: five-year follow-up study. J Am Geriatr Soc. 1994;42:142-145. 9. Tanaka Y,Atsumi Y, Matsuoka K, et al. Role of glycemic control and blood pressure in the development and progression of nephropathy in elderly Japanese NIDDM patients. Diabetes Care. 1998;21:116-120. 10. Stolk RP, Vingerling JR, de Jong PTVM, et al. Retinopathy, glucose, and insulin in an elderly population. The Rotterdam Study. Diabetes. 1995;44:11-15. 11. Beks PJ, Mackaay AJC, de Neeling JND, et al. Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn study. Diabetologia. 1995;38:86-96. 12. The DECODE study group on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet. 1999;354:617-621. 13. The DECODE study group, on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;161:397-405. 14. Kanaya AM, Grady D, Barrett-Connor E. Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med. 2002;162:1737-1745. 15. Barzilay JI, Spiekerman CF,Wahl PW, et al. Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria. Lancet. 1999;354:622-625. 16. Miller CK, Edwards L, Kissling G, et al. Nutrition education improves metabolic outcomes among older adults with diabetes mellitus: results from a randomized controlled trial. Prev Med. 2002;34:252-259. 17. Tessier D, Mnard J, Flp T, et al. Effects of aerobic physical exercise in the elderly with type 2 diabetes mellitus. Arch Gerontol Geriatr. 2000;31:121-132. 18. Skarfors ET, Wegener TA, Lithell H, et al. Physical training as treatment for type 2 (non-insulin-dependent) diabetes in elderly men. A feasibility study over 2 years. Diabetologia. 1987;30:930-933. 19. Ligtenberg PC, Godaert GLR, Hillenaar EF, et al. Influence of a physical training program on psychological well-being in elderly type 2 diabetes patients. Psychological well-being, physical training, and type 2 diabetes [letter]. Diabetes Care. 1998;21:2196-2197. 20. Ligtenberg PC, Hoekstra JBL, Bol E, et al. Effects of physical training on metabolic control in elderly type 2 diabetes mellitus patients. Clin Sci (Lond). 1997;93:127-135. 21. Dunstan DW, Daly RM, Owen N, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care. 2002;25:1729-1736. 22. Castaneda C, Layne JE, Munoz-Orians L, et al. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes. Diabetes Care. 2002;25:2335-2341. 23. Meneilly GS, Elliott T. Metabolic alterations in middle-aged and elderly obese patients with type 2 diabetes. Diabetes Care. 1999;22:112-118. 24. Meneilly GS, Elliott T,Tessier D, et al. NIDDM in the elderly. Diabetes Care. 1996;19:1320-1325. 25. Arner P, Pollare T, Lithell H. Different aetiologies of type 2 (non-insulin-dependent) diabetes mellitus in obese and nonobese subjects. Diabetologia. 1991;34:483-487. 26. Spengler M, Cagatay M. Evaluation of efficacy and tolerability of acarbose by postmarketing surveillance. Diabetes und Stoffwechsel. 1992;1:218-222. 27. Johnston PS, Lebovitz HE, Coniff RF, et al. Advantages of -glucosidase inhibition as monotherapy in elderly type 2 diabetic patients. J Clin Endocrinol Metab. 1998;83:1515-1522. 28. Orimo H, Akiguchi I, Shiraki M. Usefulness of acarbose in the management of non-insulin-dependent diabetes in the aged. In: Creutzfeldt W, ed. Acarbose. New York, NY: Excerpta Medica; 1982:348-352. 29. Johansen K. Acarbose treatment of sulfonylurea-treated noninsulin dependent diabetics. A double-blind cross-over comparison of an -glocosidase [sic] inhibitor with metformin. Diabete Metab. 1984;10:219-223. 30. Josse RG, Chiasson J-L, Ryan EA, et al. Acarbose in the treatment of elderly patients with type 2 diabetes. Diabetes Res Clin Pract. 2003;59:37-42. 31. Kumar S, Prange A, Schulze J, et al. Troglitazone, an insulin action enhancer, improves glycaemic control and insulin sensitivity in elderly type 2 diabetic patients. Diabet Med. 1998; 15:772-779. 32. Shorr RI, Ray WA, Daugherty JR, et al. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc. 1996;44:751-755. 33. Shorr RI, Ray WA, Daugherty JR, et al. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med. 1997;157:1681-1686. 34. Tessier D, Dawson K, Ttrault JP, et al. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Diabet Med. 1994; 11:974-980. 35. Holstein A, Plaschke A, Egberts E-H. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev. 2001;17:467-473. 36. DiamicronMR Study Group, Drouin P. DiamicronMR once daily is effective and well tolerated in type 2 diabetes: a
S109 double-blind, randomized, multinational study. J Diabetes Complications. 2000;14:185-191. Coscelli C, Calabrese G, Fedele D, et al. Use of premixed insulin among the elderly. Reduction of errors in patient preparation of mixtures. Diabetes Care. 1992;15:1628-1630. Corsi A, Torre E, Coronel G, et al. Pre-filled insulin pen in newly insulin-treated diabetic patients over 60 years old. Diab Nutr Metab. 1997;10:78-81. Coscelli C, Lostia S, Lunetta M, et al. Safety, efficacy, acceptability of a pre-filled insulin pen in diabetic patients over 60 years old. Diabetes Res Clin Pract. 1995;28:173-177. Herz M, Sun B, Milicevic Z, et al. Comparative efficacy of preprandial or postprandial Humalog Mix75/25 versus glyburide in patients 60 to 80 years of age with type 2 diabetes mellitus. Clin Ther. 2002;24:73-86. Wolffenbuttel BHR, Sels J-PJE, Rondas-Colbers GJWM, et al. Comparison of different insulin regimens in elderly patients with NIDDM. Diabetes Care. 1996;19:1326-1332. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA. 1996;276:1886-1892. Wang J-G, Staessen JA, Gong L, et al. Chinese trial on isolated systolic hypertension in the elderly. Arch Intern Med. 2000;160:211-220. Tuomilehto J, Rastenyte D, Birkenhger WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med. 1999;340:677-684. Lindholm LH, Hansson L, Ekbom T, et al. Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension-2. J Hypertens. 2000;18:1671-1675. Voyaki SM, Staessen JA,Thijs L, et al. Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. J Hypertens. 2001;19:511-519. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259. LaRosa JC, He J,Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999;282:2340-2346. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7-22. Wagner G, Montorsi F, Auerbach S, et al. Sildenafil citrate (VIAGRA) improves erectile function in elderly patients with erectile dysfunction: a subgroup analysis. J Gerontol A Biol Sci Med Sci. 2001;56A:M113-M119. Senz de Tejada I,Anglin G, Knight JR, et al. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care. 2002;25:2159-2164. 52. Goldstein I,Young YM, Fischer J, et al.Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care. 2003; 26:777-783. 53. Asplund K, Wiholm B-E, Lithner F. Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia. 1983; 24:412-417. D I A B E T E S I N S P E C I A L P O P U L AT I O N S
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Type 2 Diabetes in Aboriginal Peoples

INTRODUCTION Aboriginal peoples include those of First Nations, Inuit and Mtis heritage. Type 2 diabetes mellitus is an epidemic among Aboriginal peoples in Canada, with the national ageadjusted prevalence 3 to 5 times higher than that of the general population (1-3), and individual communities with age-adjusted rates as high as 26% (4). As in the general population, screening repeatedly uncovers previously undiagnosed cases of diabetes (4,5). These high rates of type 2 diabetes are causing increased rates of cardiovascular risk factors (6,7) and cardiovascular disease (CVD) (3,6,8), hypertension (1,3), peripheral vascular disease (9) and renal disease (1), all of which are contributing to premature death (10). In Manitoba, Canada, it is estimated that between the years 1996 and 2016, there will be a 10-fold increase in CVD, a 10-fold increase in lower extremity amputations and a 5-fold increase in blindness among Aboriginal peoples (11). Other significant statistics include a younger average age of onset of diabetes (2), type 2 diabetes in young children (12) and increased rates of gestational diabetes mellitus (GDM) (13). The disease is considered to be indicative of the negative sociocultural changes occurring in Aboriginal communities. Genetic susceptibility and local genetic mutations are interacting with numerous social stressors and lifestyle changes (14,15). The replacement of traditional foods with highly refined foods and decreased rates of physical activity have resulted in high rates of obesity in adults (16) and children (17). Other predisposing factors include a positive family history, or pregnancy complicated by frank diabetes or GDM (which leads to increased incidence of diabetes in the offspring) (18). Early studies also suggested that bottle-feeding increases the risk of diabetes (19). INTERVENTIONS Healthcare professionals and policymakers face major challenges in trying to provide Aboriginal peoples with diabetes with culturally appropriate and practical treatment. Diabetes cannot always be a priority for communities; geographical isolation, absence of healthcare providers, loss of traditional The initial draft of this chapter was prepared by Ann C. Macaulay MD CCFP FCFP; Catherine L. Cook MD MSc CCFP.
ways, psychosocial issues, substance abuse, sedentary lifestyles and poor eating habits are frequently significant barriers. Much of the responsibility for diabetes care lies with community health representatives, who are already overburdened. These individuals are able to provide better care when they have increased training and can focus on diabetes.A number of communities have provided local lay people with comprehensive diabetes training. This achieves the goal of having a local member of the community knowledgeable in diabetes and sensitive to the culture and issues in their community. Aboriginal people living in urban centres are eligible and encouraged to receive treatment through local physicians and Diabetes Education Centres. Native Friendship Centres, which exist in most large cities, can provide information on good resources for treatment for those with diabetes. Treatment of diabetes and its complications should follow current clinical practice guidelines for adults and children and incorporate new strategies, such as cost-effective retinal photograph, in remote communities (20,21). Ideally, multidisciplinary teams should include community members with local knowledge and expertise. Diabetes education programs should consider various learning styles, incorporate local traditions and culture, promote traditional activities and foods (provided they are safe, acceptable and accessible [22]) and, ideally, be taught in the language of the patient. The new challenge of treating children with type 2 diabetes is currently under investigation. PRIMARY PREVENTION Primary prevention of type 2 diabetes through lifestyle modification, shown to be successful in high-risk populations (23,24), is essential to reduce this epidemic in Aboriginal populations. Primary prevention requires collaboration between community leaders, healthcare professionals and funding agencies. A number of research initiatives with community-researcher partnerships are ongoing in Canada, and include programs to mobilize entire communities and promote environmental changes such as local walking paths. Programs in Kahnawake, Quebec (25), Sandy Lake, Ontario (26), and the Okanagan Valley, British Columbia (27), share the common values of incorporating traditions and local culture to promote empowerment, increased physical activity, balanced eating and healthy body weights. Other projects are targeting highrisk groups such as prenatal women (28). If successful, all
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of these programs will decrease the future incidence and projected prevalence of diabetes. Such programs also reinforce to individuals and families that they have some control over their risk for diabetes.This can impact positively on the approach to self-care and to the philosophy around family or community activities, all of which affect family members who already have the disease or are at risk for diabetes.
RECOMMENDATIONS
1.Treatment of diabetes in Aboriginal peoples should follow clinical practice guidelines [Grade D, Consensus]. 2.There must be recognition of, respect for and sensitivity regarding the unique language, culture and geographic issues as they relate to diabetes care and education in Aboriginal communities across Canada [Grade D, Consensus]. 3. Culturally appropriate primary prevention programs should be initiated by Aboriginal communities to increase awareness of diabetes, increase physical activity, improve eating habits and achieve healthy body weights, and to promote environments that are supportive of a healthy lifestyle [Grade D, Consensus]. 4. Community-based diabetes screening programs should be established in Aboriginal communities. Urban people of Aboriginal origin should be screened for diabetes in primary care settings [Grade D, Consensus].
OTHER RELEVANT GUIDELINES Screening and Prevention, p. S10 Organization and Delivery of Care, p. S14 Type 2 Diabetes in Children and Adolescents, p. S91 RELATED WEBSITES Aboriginal Diabetes Initiative, First Nations and Inuit Health Branch. Available at: http://www.hc-sc.gc.ca/fnihb/cp/ adi/index.htm. Accessed November 7, 2003. National Aboriginal Diabetes Association. Available at: http://www.nada.ca. Accessed November 7, 2003. REFERENCES
1. Young TK, Reading J, Elias B, et al.Type 2 diabetes mellitus in Canadas First Nations: status of an epidemic in progress. CMAJ. 2000;163:561-566. 2. Bobet E. Diabetes Among First Nations People: Information From the Statistics Canada 1991 Aboriginal Peoples Survey. Ottawa, ON: Minister of Public Works and Government Services Canada; 1998. Publication H34-88/1998E. 3. First Nations and Inuit Regional Health Survey: National Report 1999. St. Regis, QC: First Nations and Inuit Regional Health Survey National Steering Committee; 1999. 4. Harris SB, Gittelsohn J, Hanley A, et al. The prevalence of NIDDM and associated risk factors in Native Canadians. Diabetes Care. 1997;20:185-187.
5. Delisle HF, Rivard M, ko J-M. Prevalence estimates of diabetes and of other cardiovascular risk factors in the two largest Algonquin communities of Quebec. Diabetes Care. 1995; 18:1255-1259. 6. Harris SB, Zinman B, Hanley A, et al. The impact of diabetes on cardiovascular risk factors and outcomes in a native Canadian population. Diabetes Res Clin Pract. 2002;55:165-173. 7. Anand SS,Yusuf S, Jacobs R, et al. Risk factors, atherosclerosis, and cardiovascular disease among Aboriginal people in Canada: the Study of Health Assessment and Risk Evaluation in Aboriginal Peoples (SHARE-AP). Lancet. 2001;358:1147-1153. 8. Howard BV, Lee ET, Cowan LD, et al. Rising tide of cardiovascular disease in American Indians. The Strong Heart Study. Circulation. 1999;99:2389-2395. 9. Fabsitz RR, Sidawy AN, Go O, et al. Prevalence of peripheral arterial disease and associated risk factors in American Indians. The Strong Heart Study. Am J Epidemiol. 1999;149:330-338. 10. Mao Y, Moloughney BW, Semenciw RM, et al. Indian reserve and registered Indian mortality in Canada. Can J Public Health. 1992;83:350-353. 11. Diabetes in Canada. 2nd ed. Ottawa, ON: Centre for Chronic Disease Prevention and Control, Population and Public Health Branch, Health Canada; 2002. 12. Dean H. NIDDM-Y in First Nation children in Canada. Clin Pediatr (Phila). 1998;37:89-96. 13. Harris SB, Caulfield LE, Sugamori ME, et al.The epidemiology of diabetes in pregnant Native Canadians. A risk profile. Diabetes Care. 1997;20:1422-1425. 14. Dowse G, Zimmet P. The thrifty genotype in non-insulin dependent diabetes. BMJ. 1993;306:532-533. 15. Hegele RA, Cao H, Harris SB, et al. Hepatocyte nuclear factor-1 G319S. A private mutation in Oji-Cree associated with type 2 diabetes. Diabetes Care. 1999;22:524. 16. Young TK. Obesity among Aboriginal peoples in North America: epidemiological patterns, risk factors and metabolic consequences. In: Angel A, Anderson H, Bouchard C, et al, eds. Progress in Obesity Research. London, UK: John Libby; 1996:337-342. 17. Hanley AJG, Harris SB, Gittelsohn J, et al. Overweight among children and adolescents in a Native Canadian community: prevalence and associated factors. Am J Clin Nutr. 2000; 71:693-700. 18. Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49:2208-2211. 19. Young TK, Martens PJ,Taback SP, et al.Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among Native Canadians. Arch Pediatr Adolesc Med. 2002;156:651-655. 20. Maberley D, Cruess AF, Barile G, et al. Digital photographic screening for diabetic retinopathy in the James Bay Cree. Ophthalmic Epidemiol. 2002;9:169-178. 21. Maberley D,Walker H, Koushik A, et al. Screening for diabetic retinopathy in James Bay, Ontario: a cost-effectiveness analysis. CMAJ. 2003;168:160-164.
S112 22. Wolever T, Barbeau M-C, Charron S, et al. Guidelines for the nutritional management of diabetes mellitus in the new millennium: a position statement by the Canadian Diabetes Association. Can J Diabetes Care. 1999;23(3):56-69. 23. Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344:1343-1350. 24. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 25. Macaulay AC, Paradis G, Potvin L, et al. The Kahnawake Schools Diabetes Prevention Project: intervention, evaluation, and baseline results of a diabetes primary prevention program with a Native community in Canada. Prev Med. 1997;26:779-790. 26. Macaulay AC, Harris SB, Lvesque L, et al. Primary prevention of type 2 diabetes: experiences of 2 Aboriginal communities in Canada. Can J Diabetes. 2003;27:464-475. 27. Daniel M, Green LW, Marion SA, et al. Effectiveness of community-directed diabetes prevention and control in a rural Aboriginal population in British Columbia, Canada. Soc Sci Med. 1999;48:815-832. 28. Dyck RF, Sheppard MS, Cassidy H, et al. Preventing NIDDM among Aboriginal people: is exercise the answer? Description of a pilot project using exercise to prevent gestational diabetes. Int J Circumpolar Health. 1998;57(suppl 1):375-378.
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Perioperative Glycemic Control

INTRODUCTION Diabetes management at the time of surgery poses a number of challenges to the healthcare team.The physical stress associated with surgery typically results in acute hyperglycemia, which adversely affects immune function (1) and wound healing (2). Furthermore, hyperglycemia in the perioperative period may increase the risk of postoperative infections (3,4) and other adverse clinical outcomes, including renal allograft rejection (5). MAJOR SURGERY Improved postoperative glycemic control (plasma glucose [PG] levels of 4.5 to 6.0 mmol/L) using a continuous intravenous (IV) insulin infusion along with continuous feeding significantly decreases mortality and morbidity in patients who require postoperative intensive care and mechanical ventilation after major surgery (6). This benefit is observed even in those without a prior diagnosis of diabetes. Postoperative PG levels >6.1 mmol/L in patients with diabetes undergoing cardiac surgery are associated with an increased risk of in-hospital adverse outcomes (7). In this population, improved perioperative (both intraoperative and postoperative) glycemic control with a continuous IV insulin infusion also decreases the rate of deep sternal wound infectionsa major complication of cardiac surgery (8). However, the safe implementation of intensive glycemic control with a continuous IV insulin infusion requires an appropriate protocol and staff training to ensure effectiveness and to minimize hypoglycemia. MINOR AND MODERATE SURGERY The appropriate perioperative glycemic targets for minor or moderate surgeries are less clear. To date, no intervention studies have assessed the impact of different PG levels on morbidity or mortality in this setting. However, a number of small studies that compared different methods of achieving glycemic control during minor and moderate surgeries did not demonstrate any adverse effects of maintaining perioperative glycemic levels between 5.0 and 11.0 mmol/L (9-11). Given the data supporting tight perioperative glycemic The initial draft of this chapter was prepared by Alice Y.Y. Cheng MD FRCPC; Gillian L. Booth MD MSc FRCPC.
control during major surgeries and the compelling data showing the adverse effects of hyperglycemia, it is reasonable to target glycemic levels between 5.0 and 11.0 mmol/L for minor and moderate surgeries. RISK OF HYPOGLYCEMIA The benefits of improved perioperative glycemic control must be weighed against the risk of perioperative hypoglycemia, which may be masked by the actions of the anesthetic agents. This risk can be reduced by frequent capillary monitoring.
RECOMMENDATIONS
1. A continuous IV insulin infusion should be used to achieve glycemic levels of 4.5 to 6.0 mmol/L in postoperative patients who require intensive care and mechanical ventilation and demonstrate hyperglycemia (random PG >6.1 mmol/L) [Grade A, Level 1A (6)]. 2. A continuous IV insulin infusion should be used to maintain intraoperative glycemic levels between 5.0 and 11.0 mmol/L for patients with diabetes undergoing cardiac surgery [Grade C, Level 3 (8)]. 3. Perioperative glycemic levels should be maintained between 5.0 and 11.0 mmol/L for most other surgical situations [Grade D, Consensus].
REFERENCES
1. Kwoun MO, Ling PR, Lydon E, et al. Immunologic effects of acute hyperglycemia in nondiabetic rats. JPEN J Parenter Enteral Nutr. 1997;21:91-95. 2. Verhofstad MH, Hendriks T. Complete prevention of impaired anastomotic healing in diabetic rats requires preoperative blood glucose control. Br J Surg. 1996;83:1717-1721. 3. Golden SH, Peart-Vigilance C, Kao WHL, et al. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care. 1999;22:1408-1414. 4. Pomposelli JJ, Baxter JK III, Babineau TJ, et al. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. JPEN J Parenter Enteral Nutr. 1998;22:77-81. 5. Thomas MC, Mathew TH, Russ GR, et al. Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study. Transplantation. 2001;72: 1321-1324.
S114 6. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001; 345:1359-1367. 7. McAlister FA, Man J, Bistritz L, et al. Diabetes and coronary artery bypass surgery: an examination of perioperative glycemic control and outcomes. Diabetes Care. 2003;26:1518-1524. 8. Furnary AP, Zerr KJ, Grunkemeier GL, et al. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67:352-360, 360-362. 9. Raucoules-Aim M, Lugrin D, Boussofara M, et al. Intraoperative glycaemic control in non-insulin-dependent and insulin-dependent diabetes. Br J Anaesth. 1994;73:443-449. 10. Hemmerling TM, Schmid MC, Schmidt J, et al. Comparison of a continuous glucose-insulin-potassium infusion versus intermittent bolus application of insulin on perioperative glucose control and hormone status in insulin-treated type 2 diabetics. J Clin Anesth. 2001;13:293-300. 11. Christiansen CL, Schurizek BA, Malling B, et al. Insulin treatment of the insulin-dependent diabetic patient undergoing minor surgery. Continuous intravenous infusion compared with subcutaneous administration. Anaesthesia. 1988;43:533-537.
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Peri-acute Coronary Syndrome Glycemic Control

INTRODUCTION Patients with diabetes mellitus have greater short-term and long-term mortality after acute myocardial infarction (MI) than patients without diabetes, even in the era of thrombolytic therapy (1,2). Diabetes is also an independent predictor of mortality following other acute coronary syndromes (ACSs), such as unstable angina or non-Q-wave MI (3). Even in patients without a previous diagnosis of diabetes, hyperglycemia on admission for an acute MI is associated with higher mortality (4-6). These cases may represent previously unrecognized diabetes or glucose intolerance (7). GLYCEMIC CONTROL Biochemical abnormalities associated with relative (or absolute) insulin deficiency may be harmful during the acute phase of MI (8). Studies that have examined glucose-insulinpotassium (GIK) infusion therapy in patients presenting with an acute MI, regardless of their admission blood glucose (BG) level, have yielded variable results, and its routine use remains controversial (9). Insulin therapy in patients with diabetes presenting with an acute MI has been shown to be beneficial. The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study compared the use of conventional therapy to an insulin-glucose infusion to maintain BG levels between 7.0 and 10.0 mmol/L, followed by multidose subcutaneous (SC) insulin (intensive insulin therapy). Intensive insulin therapy resulted in a nearly 30% reduction in long-term mortality out to 3.4 years. One life was saved for every 9 patients treated with intensive insulin therapy. Particular benefit was observed in patients who had fewer cardiovascular risk factors and those who were not using insulin prior to randomization. An unresolved issue under investigation is whether the reduction in long-term mortality observed in the intensive insulin therapy group was due to the acute effect of insulin treatment on the myocardium, the use of SC insulin after the MI or improved glycemic control after the MI (10,11). Given the magnitude of benefit seen in the DIGAMI study and the knowledge that diabetes is a The initial draft of this chapter was prepared by AliceY.Y. Cheng MD FRCPC; Gillian L. Booth MD MSc FRCPC; Sarah E. Capes MD MSc FRCPC; David Thompson MD FRCPC.
predictor of mortality after an ACS (3), use of an insulinglucose infusion to improve glycemic control in the acute setting may be beneficial for all patients with diabetes presenting with an ACS. Patients who are treated with a multidose insulin regimen after an MI should be followed closely by a diabetes healthcare team with experience in managing intensified insulin therapy in order to safely maintain optimal glycemic control.
RECOMMENDATION
1. All patients with acute MI, regardless of whether or not they have a prior diagnosis of diabetes, should have their BG level measured on admission [Grade D, Consensus], and those with BG >12.0 mmol/L should receive insulinglucose infusion therapy to maintain BG between 7.0 and 10.0 mmol/L for at least 24 hours, followed by multidose SC insulin for at least 3 months [Grade A, Level 1A (10,11)]. An appropriate protocol should be developed and staff trained to ensure the safe and effective implementation of this therapy and to minimize the likelihood of hypoglycemia [Grade D, Consensus].
REFERENCES
1. Haffner SM, Lehto S, Rnnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234. 2. Mak K-H, Moliterno DJ, Granger CB, et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. J Am Coll Cardiol. 1997;30:171-179. 3. Malmberg K,Yusuf S, Gerstein HC, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation. 2000;102:1014-1019. 4. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet. 2000;355:773-778. 5. Bolk J, van der Ploeg T, Cornel JH, et al. Impaired glucose metabolism predicts mortality after a myocardial infarction. Int J Cardiol. 2001;79:207-214. 6. Wahab NN, Cowden EA, Pearce NJ, et al. Is blood glucose an independent predictor of mortality in acute myocardial infarction
S116 in the thrombolytic era? J Am Coll Cardiol. 2002;40:1748-1754. 7. Norhammar A,Tenerz , Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002;359:2140-2144. 8. Malmberg K, McGuire DK. Diabetes and acute myocardial infarction: the role of insulin therapy. Am Heart J. 1999; 138:S381-S386. 9. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation. 1997;96: 1152-1156. 10. Malmberg K, Rydn L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26:57-65. 11. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997; 314:1512-1515.
APPENDICES
Appendices
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Appendix 1
Etiologic Classification of Diabetes Mellitus

Type 1 diabetes mellitus Beta cell destruction, usually leading to absolute insulin deficiency Immune mediated Idiopathic Type 2 diabetes mellitus May range from predominant insulin resistance with relative insulin deficiency to predominant secretory defect with insulin resistance Gestational diabetes mellitus First onset or recognition of glucose intolerance during pregnancy Other specific types Genetic defects of beta cell function Chromosome 20, HNF-4alpha (formerly MODY1) Chromosome 7, glucokinase (formerly MODY2) Chromosome 12, HNF-1alpha (formerly MODY3) Mitochondrial DNA Others Genetic defects in insulin action Alstrom syndrome Leprechaunism Lipoatrophic diabetes Rabson-Mendenhall syndrome Type A insulin resistance Others Diseases of the pancreas Cystic fibrosis Fibrocalculous pancreatopathy Hemochromatosis Neoplasia Pancreatitis Trauma/pancreatectomy Others Endocrinopathies Acromegaly Aldosteronoma Cushing syndrome Glucagonoma Hyperthyroidism Pheochromocytoma Somatostatinoma Others Infections Congenital rubella Cytomegalovirus Others Uncommon forms of immune-mediated diabetes Anti-insulin receptor antibodies Stiff-man syndrome Others Drug or chemical induced Atypical antipsychotics Beta-adrenergic agonists Diazoxide Glucocorticoids Interferon alfa Nicotinic acid Pentamidine Phenytoin Protease inhibitors Thiazide diuretics Others Other genetic syndromes sometimes associated with diabetes Down syndrome Friedreichs ataxia Huntingtons chorea Klinefelter syndrome Laurence-Moon-Bardet-Biedl syndrome Myotonic dystrophy Porphyria Prader-Willi syndrome Turner syndrome Wolfram syndrome Others Adapted with permission from: The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(suppl 1):S5-S20.
HNF = hepatocyte nuclear factor MODY = maturity-onset diabetes of the young
S119
Appendix 2
History and Examination: Initial and Follow-up Visits

HISTORY TO BE TAKEN UPON DIAGNOSIS OF DIABETES Symptoms Onset and progression of hyperglycemia Symptoms of acute and long-term complications of diabetes (e.g. ophthalmologic, renal, cardiovascular, neurologic, skin and foot problems, sexual dysfunction)
APPENDICES
Medical history Endocrine disorders Infections Cardiovascular disease Surgery (e.g. pancreatic) Obstetric (if relevant) Medications (including alternative health products, herbs, traditional medicines) Abdominal obesity Gastrointestinal function (including symptoms of celiac disease in patients with type 1 diabetes) Sexual function Family history Diabetes Cardiovascular disease Dyslipidemia Hypertension Renal disease Infertility Hirsutism Autoimmune diseases Lifestyle assessment Nutritional habits Weight history Physical activity Tobacco use or exposure Drug or alcohol use Other Psychosocial/economic issues Contraception
Associated with the metabolic syndrome
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COMPONENTS OF INITIAL VISIT Physical examination General Height, weight, body mass index Waist circumference Blood pressure (lying and standing) Head and neck Eyes (pupillary reactions, extraocular movements, lens and fundi) Oral cavity (hygiene and caries, periodontal disease) Thyroid assessment Chest Metabolic control and risk factor evaluation Fasting plasma glucose A1C Fasting lipid profile (TC, HDL-C,TGs, calculated LDL-C) Microalbuminuria (random urine albumin to creatinine ratio and urine dipstick test) Serum creatinine Calculation of creatinine clearance Electrocardiogram Foot examination: monofilament or vibration at great toe Sexual function history in men Thyroid-stimulating hormone (in all patients with type 1 diabetes, in patients with type 2 diabetes if clinically indicated) Lifestyle Smoking cessation counselling Weight control counselling Physical activity counselling Nutrition counselling Other Signs of depression/anxiety Signs of eating disorders Assessment of nutritional habits/meal plans Assessment of patients understanding of diabetes and its management Assessment of patients use of alcohol and understanding of interactions between alcohol and diabetes medications Psychosocial/economic factors: family dynamics, education, employment, coping skills Contraception and family planning Referrals (as indicated) Cardiologist Diabetes educator Endocrinologist/internist Optometrist/ophthalmologist Nephrologist Podiatrist/foot specialist Psychiatrist/psychologist/social worker Registered dietitian Urologist
Respiration
Cardiovascular Signs of congestive heart failure (jugular venous pressure, edema) Heart sounds, pulses, bruits, murmurs Peripheral pulses Abdomen Organomegaly, masses, general examination Genitourinary Signs of fungal (e.g. yeast) infections Musculoskeletal system Foot inspection: monofilament or vibration at the great toe Joint mobility and arthropathy of hands, colour and temperature Pulses, reflexes, temperature, skin (appearance, signs of breakdown) Skin
Signs of cutaneous infections Signs of problems with injection sites Signs of dyslipidemias Acanthosis nigricans
Reproductive system Menstrual history (to screen for possible polycystic ovary syndrome) Sexual function history in men (screen for possible erectile dysfunction) Central nervous system Routine evaluation for dysesthesias Change in proprioception Evaluation for autonomic neuropathy
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COMPONENTS OF FOLLOW-UP VISITS Metabolic control and monitoring Patients monitoring records Determination of individual target goals Patients use of data Monitoring method used and technique Quality control of blood glucose meter (annual correlation with laboratory values) Antihyperglycemic medications Oral antihyperglycemic agents Type, dose, compliance, adjustments in response to monitoring Insulin Type, dose, injection sites, patients understanding of adjustments in response to food, activity, delivery method (pen, pen-like device, syringe, pump) Hypoglycemia Awareness, symptoms, frequency, time of occurrence, severity, precipitating causes, treatment and prevention Blood pressure and lipid medications Metabolic control and risk factor evaluation (as clinically indicated) Fasting plasma glucose A1C Fasting lipid profile (TC, HDL-C,TGs, calculated LDL-C) Microalbuminuria (random urine albumin to creatinine ratio and urine dipstick test) Serum creatinine Calculation of creatinine clearance Electrocardiogram Foot examination: monofilament or vibration at great toe Body mass index Blood pressure Thyroid-stimulating hormone (in all patients with type 1 diabetes, in patients with type 2 diabetes if clinically indicated) Referrals (as indicated) Cardiologist Diabetes educator Endocrinologist/internist Optometrist/ophthalmologist Nephrologist Podiatrist/foot specialist Psychiatrist/psychologist/social worker Registered dietitian Urologist Other MedicAlert Glucagon and/or glucose tablets Driving guidelines Hypoglycemia awareness training Sick-day planning and diabetic ketoacidosis prevention Foot care education Smoking prevention or cessation counselling Preconception or conception counselling Sexual function history in men Psychosocial issues
APPENDICES
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Appendix 3
Sample Diabetes Patient Care Plan
This Sample Diabetes Patient Care Plan is designed to assist you in recording appropriate information regarding the management of your patients with diabetes, and incorporates key concepts from the Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Other patient care plans may be available. It is important to use a care plan that best suits your practice needs.
S123
Name: __________________________________ Date of diagnosis: ____________________ Type of DM: ________________ Risk factors: Overweight Sedentary Family history Ethnicity IGT/IFG Smoker CVD Hypertension Dyslipidemia GDM/Macrosomia PCOS/Acanthosis nigricans Schizophrenia Medications Complications/Comorbidities (date of Dx): Retinopathy _________ Nephropathy _________ Neuropathy _________ Foot disorders _________ CVD _________ ED _________ Other _________ Referrals (date): Dietitian ________ DEC ________ Endo ________ Cardiol ________ Podiatrist ________ Ophthal/Optom _________ Nephrol _________ Psychol/Social worker _________ Other _________ Lifestyle: Smoking Exercise Diet Date Oral agents Insulin Drug plan: Formulary 3rd party Self Antihypertensives Lipid-lowering agents ASA Other
APPENDICES
Procedures/Tests/Targets Weight, BMI,WC BP 130/80 A1C 7% (6% if possible) Preprandial (47) (46) Postprandial (510) (58) Hypoglycemia SMBG Test/Exam Lipids: LDL-C <2.5 TC:HDL-C <4.0
Date
Date
Date
Date
Date
Date
Date
Date
Date
Date
Date
Date
Quarterly
Date
Date
Date
Date
Date
Date
Annually (or as clinically indicated)
Nephropathy: Random ACR Serum creatinine Creatinine clearance Foot care: Lower extremity exam Neuropathy: 10-g Left: + monofilament/vibration Right: + at great toe Retinopathy: Refer for dilated eye exam Left: + Right: + Left: + Right: + Left: + Right: + Left: + Right: + Left: + Right: + -
Refer Retinopathy: Present Absent Rx Yes No
Erectile dysfunction Psychosocial: Anxiety, depression, economic Immunization: Pneumococcal (lifetime)
Annual
influenza
Annual
influenza
Annual
influenza
Annual
influenza
Annual
influenza
Annual
influenza
S124 Management of hyperglycemia in type 2 diabetes

Clinical assessment and initiation of nutrition therapy and physical activity
Mild to moderate hyperglycemia (A1C <9.0%)
Marked hyperglycemia (A1C 9.0%)
Overweight (BMI 25 kg/m2)
Non-overweight (BMI <25 kg/m2)
Biguanide alone or in combination with 1 of: insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor
1 or 2 antihyperglycemic agents from different classes biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor If not at target
2 antihyperglycemic agents from different classes biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor
Basal and/or preprandial insulin
If not at target
If not at target
If not at target
Add a drug from a different class or Use insulin alone or in combination with: biguanide insulin secretagogue insulin sensitizer* alpha-glucosidase inhibitor
Add an oral antihyperglycemic agent from a different class or insulin*
Intensify insulin regimen or add: biguanide insulin secretagogue** insulin sensitizer* alpha-glucosidase inhibitor
Timely adjustments to and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A1C within 6 to 12 months *When used in combination with insulin, insulin sensitizers may increase the risk of edema or congestive heart failure.The combination of an insulin sensitizer and insulin is currently not an approved indication in Canada. **If using preprandial insulin, do not add an insulin secretagogue. May be given as a combined formulation: rosiglitazone and metformin.
Antihyperglycemic agents for use in type 2 diabetes

Drug class, generic name (trade name) Alpha-glucosidase inhibitor acarbose (Prandase ) Biguanide metformin (Glucophage, generic) Insulin Insulin secretagogues sulfonylureas: gliclazide (Diamicron, Diamicron MR, generic) glimepiride (Amaryl) glyburide (Diabeta, Euglucon, generic) (note: chlorpropamide and tolbutamide are still available in Canada, but rarely used) Insulin secretagogues (continued) nonsulfonylureas: nateglinide (Starlix ) repaglinide (GlucoNorm ) Insulin sensitizers (TZDs) pioglitazone (Actos ) rosiglitazone (Avandia ) Combined formulation of rosiglitazone and metformin (Avandamet)
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Appendix 4
Self-monitoring of Blood Glucose (SMBG) Records

SMBG values
Week Day ac Week 1 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Breakfast pc ac Lunch pc ac Dinner hs pc Daily average Weekly range (lowhigh) Weekly mean value
APPENDICES
Week 2
Week 3
Week 4
Week 5
Annual meter correlation testing with laboratory (date): _______________
SMBG: Average results

Recording period Blood glucose Breakfast Lunch Dinner Bedtime Average # of tests per: Day Week Average value
ac: pc: ac: pc: ac: pc: ac: pc:
Range (lowhigh)
ac: pc: ac: pc: ac: pc: ac: pc:
Annual meter correlation testing with laboratory (date): _______________
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Appendix 5
Basic Carbohydrate Counting for Diabetes Management
Basic Carbohydrate Counting

for Diabetes Management
Carbohydrate counting is a flexible way to plan your meals. It focuses on foods that contain carbohydrate as these raise your blood glucose the most. Follow these steps to count carbohydrates and help manage your blood glucose levels. Your dietitian will guide you along the way.
Step 1. Make healthy food choices Enjoy a variety of vegetables, fruits, whole grains, low fat milk products, and meat and alternatives at your meals. A variety of foods will help to keep you healthy. Use added fats in small amounts. This helps to control your weight and blood cholesterol. Choose portion sizes to help you to reach or maintain a healthy weight. Step 2. Focus on carbohydrate Your body breaks down carbohydrate into glucose.This raises your blood glucose levels. Carbohydrate is found in many foods, including starches, fruits, some vegetables, legumes, milk, sugary foods, and many prepared foods. Most protein and fat foods contain little carbohydrate. Moderate servings will not have a big effect on blood glucose levels. Step 3. Set carbohydrate goals Your dietitian will help you set a goal for grams of carbohydrate at each meal and snack.This may be the same from day to day or may be flexible, depending on your needs. Aim to meet your target within 5 grams per meal or snack. Step 4. Determine carbohydrate content Write down what you eat and drink throughout the day. Be sure to note the portion sizes.You may need to use measuring cups and food scales to be accurate. Record the grams of carbohydrate in these foods and drinks. For carbohydrate content of foods, check the Good Health Eating Guide Resource, food packages, food composition books, restaurant fact sheets and websites. Step 5. Monitor effect on blood glucose level Work with your health care team to correct blood glucose levels that are too high or too low.
vegetables starch protein
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Finding Carbohydrate Values using the Nutrition Facts table

Nutrition Facts
Per 90 g serving (2 slices)
Amount % Daily Value
Calories 170 Fat 2.7 g Saturated 0.5 g + Trans 0 g Cholesterol 0 mg Sodium 200 mg Carbohydrate 36 g Fibre 6 g Sugars 3 g Protein 8 g Vitamin A Calcium 1% 2% Vitamin C 0 % Iron 16 % 8% 13 % 24 % 1% 5%
The amount of carbohydrate in a food is listed on the Nutrition Facts table.

The amount listed is for the serving size given. Are you eating more, less, or the same? Compare your serving size to figure out the amount of carbohydrate you are eating. The total amount of carbohydrate in grams is listed first.This number includes starch, sugars and fibre. (Starch is not listed separately.)
APPENDICES
Fibre does not raise blood glucose and should be subtracted from the total carbohydrate.
Lets Carb Count! Sample Carbohydrate Counting

FOOD Example Sandwich Lunch Bread, whole wheat * Chicken breast Margarine Carrot sticks ** Green grapes ** Milk Tea/coffee PORTION SIZE 2 slices 2 oz/60 g 1 tsp/5 mL 1 /2 cup/125 mL 1 /2 cup/125 mL 1 cup/250 mL 1 cup/250 mL GRAMS OF CARBOHYDRATE 36g carb 6 g fibre= 0 0 10 g carb 10 g carb 12 g carb 0 Total carb: What did you eat and drink? 30 0 0 10 10 12 0
(CARB)
g carb
g carb g carb g carb
62 g carb
Total carb:
*taken
from actual label
**taken
from the Good Health Eating Guide Resource 2003
For more information on labelling, carbohydrate counting and fibre, please visit the Canadian Diabetes Association website, www.diabetes.ca.
2003 Canadian Diabetes Association
111019 02-151 08/03 Q-2M
S128
THE
Vegetables Starch Protein Foods
Appendix 6
G LY C E M I C I N D E X
If I eat foods with a low Glycemic Index can I eat as much as I want? No. Using the Glycemic Index to choose foods is only one part of
What is the Glycemic Index of food?
The Glycemic Index
The Glycemic Index (GI) is a scale that ranks carbohydrate-rich foods by how much they raise blood glucose levels compared to a standard food. The standard food is glucose or white bread. healthy eating.
Healthy eating also means:
Why should I eat foods with a low Glycemic Index?
Eating at regular times Choosing a variety of foods from all food groups Limiting sugars and sweets Reducing the amount of fat you eat Including foods high in fibre Limiting salt, alcohol and caffeine
Eating foods with a low Glycemic Index may help you to: Control your blood glucose level Control your cholesterol level Control your appetite Lower your risk of getting heart disease Lower your risk of getting type 2 diabetes
Use these meal planning ideas to include the Glycemic Index as part of healthy eating.
Enjoy vegetables, fruits, and low-fat milk products with your meals. These are carbohydrate-rich foods that, in general, have low glycemic index.
Remember that checking your blood glucose before and 1 or 2 hours after a meal is the best way to know how your body handles the meal.
Plan your meals with foods in the low and medium Glycemic Index starch choices on the list that follows. Try foods, such as barley, bulgar, couscous, or lentils, which have a low Glycemic Index.
Consult a registered dietitian for help with choosing low GI foods,
adapting recipes, and other ways to incorporate low GI foods in your meal plan.
Check out the Canadian Diabetes Association website, www.diabetes.ca, for more information.
A lot of starchy foods have a high Glycemic Index (GI). Choose medium and low GI foods more often.
Low GI (55 or less) *

choose more often
BREADS: BREADS:
Medium GI (56-69) *
choose less often
White bread Kaiser roll Bagel, white
CEREAL:
High GI (70 or more) *
choose most often

Whole wheat Rye Pita
CEREAL:
BREADS:
100% stone ground whole wheat Heavy mixed grain Pumpernickel Grapenuts Shredded Wheat Quick oats Bran flakes Corn flakes Rice Krispies Cheerios
GRAINS:
CEREAL:
All Bran Bran Buds with Psyllium Oatmeal Oat Bran

GRAINS:
GRAINS:
Parboiled or converted rice Barley Bulgar Pasta/Noodles

OTHER:
Basmati rice Brown rice Couscous
Short-grain rice
OTHER:
OTHER:
Sweet potato Yam Legumes Lentils Chickpeas Kidney beans Split peas Soy beans Baked beans
Potato, new/white Sweet corn Popcorn Stoned Wheat Thins Ryvita (rye crisps) Black bean soup Green pea soup
Potato, baking (Russet) French fries Pretzels Rice cakes Soda crackers
111018 02-134 08/02 Q-2.5M *Expressed as a percentage of the value for glucose Canadian values where available Adapted with permission from: Foster-Powell K, Holt SHA, Brand-Miller JC. International table of glycemic index and glycemic load values. Am J Clin Nutr. 2002;76:5-56.
One change I will make now is

S129
APPENDICES
S130
Appendix 7
Zimbabwe Hand Jive
Your hands can be very useful in estimating appropriate portions.Theyre always with you, and theyre always the same size! When planning a meal, use these portion sizes as a guide:
Carbohydrates (starch and fruit): Choose an amount the size of your 2 fists.
Protein: Choose an amount the size of the palm of your hand and the thickness of your little finger.
Vegetables: Choose as much as you can hold in both hands. Choose low-carbohydrate vegetables (e.g. green or yellow beans, broccoli, lettuce).
Fat: Limit fat to an amount the size of the tip of your thumb.
Drink no more than 250 mL (8 oz) of low-fat milk with a meal.
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Appendix 8
Just the Basics:Tips for Healthy Eating, Diabetes Management and Prevention
JUST THE BASICS

Tips for Healthy Eating, Diabetes Management and Prevention
Diabetes is a disease in which your body cannot properly store and use food for energy. The fuel that your body needs is called glucose, a form of sugar. Glucose comes from foods such as fruit, milk, some vegetables, starchy foods and sugar. To control your blood glucose you will need to eat healthy foods, be active and you may need to take pills and/or insulin.
APPENDICES
Here are some tips to help you until you see a registered dietitian.
TIPS REASONS
1. Eat three meals per day at regular times and space meals no more than six hours apart.You may benefit from a healthy snack. 2. Limit sugars and sweets such as sugar, regular pop, desserts, candies, jam and honey. 3. Limit the amount of high fat food you eat such as fried foods, chips, and pastries.
Eating at regular times helps your body control blood glucose levels.
The more sugar you eat, the higher your blood glucose will be. Artificial sweeteners can be useful. High fat foods may cause you to gain weight. A healthy weight helps with blood glucose control and is healthier for your heart. Foods high in fibre may help you feel full and may lower blood glucose and cholesterol levels.
4. Eat more high fibre foods (whole grain breads and cereals, lentils, dried beans and peas, brown rice, fruits and vegetables). 5. If you are thirsty, drink water.
Drinking regular pop and fruit juice will raise your blood glucose. Regular physical activity will improve your blood glucose control.
6. Add physical activity to your life.
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To help you plan for healthy eating

Milk
Vegetables
(at least 2 kinds)
Fruit Starch
(potato, rice, pasta)
Protein
(fish, lean meat, chicken, beans, lentils)
Eat more vegetables.These are very high in nutrients and low in calories. Choose starchy foods such as whole grain breads and cereals, rice, noodles, or potatoes at every meal. Starchy foods are broken down into glucose that your body needs for energy. Include fish, lean meats, low fat cheeses, eggs, or vegetarian protein choices as part of your meal. Have a glass of milk and a piece of fruit to complete your meal. Alcohol can affect blood glucose levels and cause you to gain weight.Talk to your healthcare professional about whether you can include alcohol in your meal plan and how much is safe. Its natural to have questions about what food to eat. A registered dietitian can help you include your favourite foods in a personalized meal plan.
CANADIAN DIABETES ASSOCIATION FOOD CHOICE VALUES AND SYMBOLS You may see these symbols on food packages or recipes.These symbols represent groupings of foods based mainly on their carbohydrate content.These symbols on food packages are not an endorsement by the Association.
STARCH FOODS (whole grain breads, cereals, pasta, corn, rice, potato etc.) FRUITS & VEGETABLES (oranges, bananas, carrots, peas, etc.) MILK (plain yogurt, milk, etc.) SUGARS (jam, sugar, popsicle, etc.) PROTEIN FOODS (lean meats, poultry, fish, eggs, low fat cheese etc.) FATS & OILS (oil, margarine, butter, salad dressing, bacon, etc.) EXTRAS (vegetables such as lettuce, celery, herbs and spices, diet beverages, etc.)
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JUST THE BASICS

Tips for Healthy Eating, Diabetes Management and Prevention
The Canadian Diabetes Association recommends that all people with diabetes should receive advice on nutrition from a registered dietitian. Good management of diabetes includes healthy eating, staying active and taking required medication. Be sure to eat breakfast. It provides a good start to the day.
SAMPLE MEAL PLANS
APPENDICES
To increase your physical activity. . .

build time for physical activity into your daily routine, try to be active most days of the week, walk whenever you can, instead of taking the car, start slowly and gradually increase the amount of effort; for instance progress from strolling to brisk walking, make family activities active; try swimming or skating instead of watching TV or a movie, try new activities; learn to dance, play basketball, or ride a bike, enjoy your improved sense of health and wellbeing.
You may find it helpful to use a measuring cup at first to be sure your serving sizes are correct.
FOR SMALLER APPETITES Breakfast: Cereal (12 cup, 125 ml) Toast (1 slice) 1 Orange Milk (1 cup, 250 ml) Peanut butter (1 tbsp, 15 ml) Tea or coffee
Lunch: 1 Sandwich - 2 slices of whole grain bread or 6" pita - meat, chicken or fish (2 oz, 60 g) - margarine or mayonnaise (1 tsp, 5 ml) Carrot sticks, 10 small Fruit yogurt (12 cup, 125 ml) Tea or coffee Dinner: Potato (1 medium) or rice (23 cup, 150 ml) Vegetables Margarine or butter (1 tsp, 5 ml) Lean meat, chicken, or fish (2 oz, 60 g) 1 4 Cantaloupe Milk (1 cup, 250 ml) Tea or coffee Evening Snack: Low fat cheese (1oz, 30 g) Soda crackers (6)
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To help you manage or prevent diabetes

To follow a healthy lifestyle . . .
have at least 3 out of the 4 key food groups at each meal: - starch foods - fruits & vegetables - protein foods - milk have portion sizes that will help you reach or maintain a healthy body weight; include high fibre foods such as whole grain breads and cereals, fresh fruits, vegetables and legumes, and grains (e.g. pasta, rice); make lower fat choices (e.g. use skim milk, lean ground beef, trim fat on meat, chicken etc., and use small amounts of added fat such as butter and salad dressings); healthy eating habits should be built around a healthy lifestyle keep active every day.
FOR BIGGER APPETITES Breakfast: Cereal (12 cup, 125 ml) Toast (2 slices) or 1 small bagel 1 Orange Milk (1 cup, 250 ml) Peanut butter (2 tbsp, 30 ml) Tea or coffee
Lunch: Soup (1 cup, 250 ml) Sandwich - 2 slices whole grain bread or 6" pita - lean meat, chicken or fish (3 oz, 90 g) - tomato slices - margarine or mayonnaise (1 tsp, 5 ml) Carrot sticks, 10 small Fruit yogurt (12 cup, 125 ml) Tea or coffee Afternoon Snack: 1 Medium apple or banana Dinner: 1 Large potato or cooked noodles (112 cup, 375 ml) . . . . Vegetables Margarine or butter (1 tsp, 5 ml) Green salad with lemon juice Lean meat, chicken or fish (4 oz, 120 g) 1 Pear Milk (1 cup, 250 ml) Tea or coffee Evening Snack: Low fat cheese (2 oz, 60 g) Melba toast (4) Milk (1 cup, 250 ml)
111015 02-148 01/03 Q-30M
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Appendix 9
Insulin Initiation Options in People With Type 2 Diabetes
The sample insulin regimens described here are examples only. Other options are possible. All people starting insulin should be counselled about the recognition and prevention of hypoglycemia.
Option A: Single bedtime injection of insulin added to oral antihyperglycemic agents (0.10.2 units/kg) 100% as basal insulin (e.g. NPH, N, glargine) at bedtime
APPENDICES
Option B: 2 insulin injections per day, premixed dose (e.g. 30/70, 50/50) (0.5 units/kg) 23 of total insulin dose in the morning 13 of total insulin dose with evening meal
Option C: Intensive insulin regimen (0.5 units/kg) 40% of total insulin dose as basal insulin (e.g. NPH, N, glargine) at bedtime 20% of total insulin dose as mealtime insulin, 3 times/day (e.g. rapid-acting insulin analogue, fast-acting insulin)
Insulin Dose Calculation

Regimen (units/kg) ______________________________________________ Weight (kg) ____________________________________________________ Total daily insulin dose (weight x units/kg) ____________________________ Dose Oral agent(s) Breakfast Lunch Dinner Bedtime
Insulin
Notes:
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Appendix 10
Level of Urinary Albumin by Various Test Methods and Stage of Diabetic Nephropathy
Normal
Stage of Nephropathy Microalbuminuria Negative Overt nephropathy (macroalbuminuria) Positive Urinary Albumin Level
Urine Test Urine dipstick 0
24-hour 30 mg/day ACR (male) 2.0 mg/mmol ACR (female) 2.8 mg/mmol
300 mg/day 20.0 mg/mmol 28.0 mg/mmol
1000 mg/day 66.7 mg/mmol 93.3 mg/mmol
ACR = albumin to creatinine ratio
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Appendix 11
Approach to Therapeutics in Diabetic Nephropathy
Already on an ACE inhibitor?
Yes
Choose second-line nephropathy therapy or refer
APPENDICES
No
On first-line nephropathy drug?
Yes
First-line drug at maximum dose?
Yes
No
No
No
Add first-line drug, then remeasure ACR between 2 weeks and 2 months after initiation of treatment
ACR normal?
Titrate dose of firstline drug upwards, then remeasure ACR between 2 weeks and 2 months after dose titration
Yes
Remeasure ACR in 1 year
Any time a medication is added or a dose of a medication is titrated, the patient must be monitored for side effects and toxicity. Physicians should refer to the most current Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, ON) and product monographs for detailed prescribing information. First-line drugs for diabetic nephropathy Type 1 diabetes: ACE inhibitor Type 2 diabetes: Creatinine clearance >60 mL/min: ACE inhibitor or ARB Creatinine clearance 60 mL/min: ARB Second-line drugs for diabetic nephropathy ACE inhibitor and ARB in combination or Add nondihydropyridine CCB ACE = angiotensin converting enzyme ACR = albumin to creatinine ratio ARB = angiotensin II receptor antagonist CCB = calcium channel blocker
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Appendix 12
Diabetes and Foot Care:A Patients Checklist
Many people with diabetes have problems with their feet. Ask your doctor to explain your own risk factors for foot problems.You can prevent serious foot problems by following these basic guidelines.
DO
check your feet every day for cuts, cracks, bruises, blisters, sores, infections or unusual markings. use a mirror to see the bottoms of your feet if you cant lift them up. check the colour of your legs and feet. If there is swelling, warmth or redness, or if you have pain, see your doctor or foot specialist right away. clean a cut or scratch with a mild soap and water and cover it with a dry dressing for sensitive skin. trim your toenails straight across. wash and dry your feet every day, especially between the toes. apply a good skin lotion every day on your heels and soles. Wipe off any excess lotion. change your socks every day. always wear a good supportive shoe. always wear professionally fit shoes from a reputable store. Professionally fit orthotics may help. choose shoes with low heels (under 5 cm high). buy shoes in the late afternoon (since your feet may have swollen slightly by then). avoid extreme cold and heat (including the sun). exercise regularly. see a foot care specialist for advice and education.
DONT
cut your own corns or calluses. treat your own in-growing toenails or slivers with a razor or scissors. See your doctor or foot care specialist. use over-the-counter medications to treat corns and warts. They are dangerous for people with diabetes. apply heat to your feet with a hot water bottle or electric blanket. You could burn your feet without realizing it. soak your feet for extended periods of time (i.e. no more than 20 minutes). take very hot baths. use lotion between your toes. walk barefoot inside or outside. wear tight socks, garters or elastics, or knee highs. wear over-the-counter insolesthey can cause blisters if they are not right for your feet. sit for long periods of time. smoke.
Adapted with permission from: Feeling WellDiabetes and Foot Care, A Patients Checklist Angelo Casella BSc DCh, 2002
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Appendix 13
Comorbid Conditions in Children With Type 1 Diabetes
AUTOIMMUNE THYROID DISEASE The prevalence of clinical autoimmune thyroid disease in children with type 1 diabetes is approximately 5% (1). The number of children with type 1 diabetes with a positive thyroid antibody level is higher and increases with age. Serum thyroid-stimulating hormone (TSH) level will identify children with compensated and frank hypothyroidism. Thyroiddirected antibodies will identify children with autoimmune thyroid disease, but measuring antibodies for screening purposes is not appropriate since treatment will be dictated by a rising serum TSH level when hypothyroidism occurs. Early detection and treatment of hypothyroidism will prevent growth failure and symptoms of hypothyroidism. Children with type 1 diabetes should be screened annually with serum TSH level to identify hypothyroidism (Table 1). ADDISONS DISEASE Addisons disease in children is rare, and screening is not justified in children with type 1 diabetes. However, measurement of serum adrenocorticotrophic hormone (ACTH) and/or morning serum cortisol level is indicated to rule out Addisons disease in a child with type 1 diabetes with recurrent severe hypoglycemia (Table 1).Treatment with hydrocortisone will prevent recurrent severe hypoglycemia in this situation and will prevent sudden death from adrenal insufficiency. CELIAC DISEASE Celiac disease (CD) occurs in 5 to 10% of children with type 1 diabetes (2-10), and 60 to 70% of cases of CD are asymptomatic. Asymptomatic CD may be present at diagnosis of diabetes or may occur during follow-up, usually during the
first 4 years after diagnosis of diabetes (2,3). While there is no controversy about the need for screening and treatment in a child with intestinal symptoms or with extraintestinal manifestations of CD (11,12), parents should be informed that the need for screening and treatment of asymptomatic CD is controversial. Screening for CD should be considered in any child with type 1 diabetes and poor linear growth, poor weight gain, fatigue, anemia, recurrent gastrointestinal symptoms, frequent hypoglycemia (13) and poor metabolic control (Table 1). REFERENCES
1. Kordonouri O, Klinghammer A, Lang EB, et al. Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey. Diabetes Care. 2002;25:1346-1350. 2. Barera G, Bonfanti R, Viscardi M, et al. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics. 2002;109:833-838. 3. Hansen D, Bennedbk FN, Hansen LK, et al. High prevalence of coeliac disease in Danish children with type I diabetes mellitus. Acta Paediatr. 2001;90:1238-1243. 4. Gillett PM, Gillett HR, Israel DM, et al. High prevalence of celiac disease in patients with type 1 diabetes detected by antibodies to endomysium and tissue transglutaminase. Can J Gastroenterol. 2001;15:297-301. 5. Aktay AN, Lee PC, Kumar V, et al.The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin. J Pediatr Gastroenterol Nutr. 2001;33:462-465. 6. Spiekerkoetter U, Seissler J,Wendel U. General screening for celiac disease is advisable in children with type 1 diabetes. Horm Metab Res. 2002;34:192-195. 7. Jaeger C, Hatziagelaki E, Petzoldt R, et al. Comparative
APPENDICES
Table 1. Screening for comorbid conditions in children with type 1 diabetes Condition Indications for screening Screening test Frequency
Hypothyroidism Addisons disease CD All children with type 1 diabetes Recurrent severe hypoglycemia Serum TSH level Serum ACTH level and/or morning serum cortisol Annually As clinically indicated As clinically indicated
Poor linear growth, poor weight gain, Tissue transglutaminase or endomysial fatigue, recurrent gastrointestinal antibodies plus IgA levels symptoms, anemia, frequent hypoglycemia and poor metabolic control
ACTH = adrenocorticotrophic hormone CD = celiac disease IgA = immunoglobulin A TSH = thyroid-stimulating hormone
S140 analysis of organ-specific autoantibodies and celiac diseaseassociated antibodies in type 1 diabetic patients, their firstdegree relatives, and healthy control subjects. Diabetes Care. 2001;24:27-32. Carlsson AK, Axelsson IEM, Borulf SK, et al. Prevalence of IgA-antiendomysium and IgA-antigliadin autoantibodies at diagnosis of insulin-dependent diabetes mellitus in Swedish children and adolescents. Pediatrics. 1999;103:1248-1252. Hill I, Fasano A, Schwartz R, et al.The prevalence of celiac disease in at-risk groups of children in the United States. J Pediatr. 2000;136:86-90. Fabiani E, Taccari LM, Rtsch I-M, et al. Compliance with gluten-free diet in adolescents with screening-detected celiac disease: a 5-year follow-up study. J Pediatr. 2000;136:841-843. Saukkonen T,Visnen S, kerblom HK, et al. Coeliac disease in children and adolescents with type 1 diabetes: a study of growth, glycaemic control, and experiences of families. Acta Paediatr. 2002;91:297-302. Amin R, Murphy N, Edge J, et al. A longitudinal study of the effects of a gluten-free diet on glycemic control and weight gain in subjects with type 1 diabetes and celiac disease. Diabetes Care. 2002;25:1117-1122. Mohn A, Cerruto M, Iafusco D, et al. Celiac disease in children and adolescents with type I diabetes: importance of hypoglycemia. J Pediatr Gastroenterol Nutr. 2001;32:37-40.
8.
9.
10.
11.
12.
13.
Index
INDEX
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Index
1998 Clinical Practice Guidelines for the Management of Diabetes in Canada, S1, S2, S4, S37, S99 1-hour plasma glucose (1hPG) following a 50-g glucose load. See Gestational diabetes mellitus (GDM), screening 24-hour split urine collection. See Nephropathy, screening, adolescents and Nephropathy, screening, children 24-hour urine collection for albumin. See Nephropathy, screening, adults 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. See Statins 7-standard field, stereoscopic-colour fundus photography. See Retinopathy, screening 75-g oral glucose tolerance test (OGTT), S7, S8, S10, S11, S12, S99, S100, S101, S102. See also Gestational diabetes mellitus (GDM), postpartum evaluation; Gestational diabetes mellitus (GDM), screening and Oral glucose tolerance test (OGTT) A1C, S8, S10, S33, S55, S60, S77, S120, S121, S123, S124. See also Glycemic, targets effect of lifestyle modification on, S25, S27, S29 measurement of, S21, S22 targets in adolescents, S84, S85 in adults, S18, S19 in children, S84, S85 in pregnancy, S94, S96 preconception, S94, S96 to inform treatment decisions, S37, S38, S39, S40, S92, S124 Abdominal obesity, S8, S10, S12, S46, S119 Aboriginal, S1, S10, S12, S54, S91, S92, S99, S110-S112 diabetes prevention, S110-S111 screening, S110, S111 treatment, S111 Acanthosis nigricans, S10, S12, S91, S99, S120, S123 Acarbose, S12, S38, S40, S44, S106, S124. See also Alphaglucosidase inhibitors and Oral antihyperglycemic agents Acesulfame potassium, S28. See also Sweeteners
Acetylsalicylic acid (ASA), S58, S59, S63, S68, S77, S123. See also Antiplatelet therapy Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, S62 Acute coronary syndromes (ACSs), S115-S116 management, S115 risk assessment, S115 Addisons disease, S88, S139 Adiposity. See Obesity Adjustment problems, S50 Adolescents, S33, S84-S90, S91-S93. See also Children counselling contraception and sexual health, S85 smoking prevention or cessation, S85 diabetes complications, S84, S85, S86-S87, S92 management, S84-S86, S92 prevention, S91-S92 screening, S91 dyslipidemia screening, S86, S87 treatment, S87, S92 eating disorders, S50, S85 glycemic targets, S19, S84, S85, S87, S92 hypertension, S86, S87, S92 insulin therapy, S84-S85, S92 metformin, S92 nephropathy screening, S86-S87, S92 treatment, S87 neuropathy, screening, S86, S87 retinopathy, screening, S86, S87, S92 Adrenocorticotrophic hormone (ACTH) level (serum), S139. See also Addisons disease Adult Treatment Panel III (ATP III), S8 African, S10, S12, S91, S99 Albumin to creatinine ratio (ACR). See Nephropathy, screening Albuminuria. See Nephropathy Alcohol, S28, S29, S62, S119, S120, S132
S143
Alpha-adrenergic blockers, S62, S63. See also Antihypertensive agents Alpha-glucosidase inhibitors, S12, S38, S39, S40, S44, S106, S107, S124. See also Acarbose and Oral antihyperglycemic agents Alternate site blood glucose (BG) testing, S22 Amputation, S72, S74, S110 Angiotensin II receptor antagonists (ARBs), S58, S62, S63, S68, S69, S87, S95, S96, S137. See also Antihypertensive agents Angiotensin converting enzyme (ACE) inhibitors, S58, S59, S62, S63, S68, S69, S87, S95, S96, S107, S137. See also Antihypertensive agents Antidepressant medications, S51, S72, S81 Antihyperglycemic agents, S27, S37, S38, S39, S40, S47, S121, S124. See also Insulin and Oral antihyperglycemic agents Antihypertensive agents, S62, S63, S69, S78, S81, S95, S96, S107, S121, S123. See also Alpha-adrenergic blockers; Angiotensin II receptor antagonists (ARBs); Angiotensin converting enzyme (ACE) inhibitors; Beta blockers; Calcium channel blockers (CCBs); Diltiazem; Diuretics and Verapamil Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), S62 Antiobesity agents, S38, S47, S48, S92. See also Diethylpropion; Gastrointestinal lipase inhibitors; Norepinephrine and serotonin reuptake inhibitors; Orlistat; Phentermine; Sibutramine and Sympathomimetic noradrenergic appetite suppressants Antiplatelet therapy, S58, S59, S63, S68. See also Acetylsalicylic acid (ASA) and Clopidogrel Antithrombotic Trialists Collaboration, S63 Anxiety disorders, S50, S51, S120, S123 Apolipoprotein B (apo B), S58, S59, S60, S61 Appropriate Blood Pressure Control in Diabetes (ABCD) trial, S62 Asian, S10, S12, S91, S99 Aspartame, S28. See also Sweeteners Atkins Diet , S47 Atorvastatin, S61. See also Statins Autoimmune thyroid disease, S88, S139 Autonomic symptoms. See Hypoglycemia, symptoms Bariatric surgery. See Obesity, treatment
Beck Depression Inventory, S50 Behaviour assessment, S50 change theory, S21 modification, S15, S21, S22, S27, S47, S92 therapy, S46, S47 Beta blockers, S62, S63, S81, S95, S107. See also Antihypertensive agents Beta cell defects, genetic, S91, S118 destruction, S7, S10, S32, S118 progressive failure, S37 Bezafibrate, S61. See also Fibrates Biguanides, S12, S37, S38, S39, S40, S124. See also Metformin and Oral antihyperglycemic agents Bile acid sequestrants, S60, S61. See also Cholestyramine resin and Colestipol HCl Binge episodes. See Eating disorders Blindness. See Retinopathy Blood glucose (BG), S7, S25, S27, S28, S29, S33, S37, S38, S43, S44, S66, S68, S72, S84, S126, S127, S128, S131, S132 capillary, S18, S21 control. See Glycemic, control fasting (FBG), S18, S21, S85, S101. See also Plasma glucose (PG), fasting (FPG) meter, S21-S22, S121, S125 monitoring. See Self-monitoring of blood glucose (SMBG) on admission for acute myocardial infarction (MI), S115 postprandial, S18, S21, S101. See also Plasma glucose (PG), postprandial preprandial, S18, S21, S22, S34. See also Plasma glucose (PG), preprandial targets. See Glycemic, targets Blood pressure (BP), S8, S66, S87, S120, S121, S123. See also Hypertension control, S46, S58, S59, S61, S62, S63, S68, S77, S78, S94-S95, S96 diastolic, S61, S62, S63, S78, S107 systolic, S61, S62, S63, S78, S107 targets, S61-S62, S63, S68, S78, S107 Body mass index (BMI), S39, S46, S47, S48, S59, S86, S87, S96, S99, S120, S121, S123, S124 Breastfeeding, S28, S92, S101, S102 Caffeine, S28 Calcium channel blockers (CCBs), S62, S63, S69, S95, S107, S137. See also Antihypertensive agents; Diltiazem and Verapamil
INDEX
S144
Canadas Guidelines for Healthy Eating, S27, S28, S29 Canadian Guidelines for Body Weight Classification in Adults, S46 Canadian Heart Health Survey, S58 Cancer, S46, S56 Capillary blood glucose (BG). See Blood glucose (BG) Capsaicin, S72 Carbamazepine, S72 Carbohydrate content, S27, S28, S29, S34, S44, S126, S128, S132 counting, S27, S29, S126-S127 for hypoglycemia, S43, S44. See also Hypoglycemia, prevention and Hypoglycemia, treatment intake, S21, S27, S28, S47, S95, S101 portion size, S126, S130 Cardiac surgery. See Surgery Cardiovascular (CV) disease (CVD), S2, S4, S8, S11, S12, S24, S25, S46, S63, S81, S95, S110, S119, S123 events, S18, S63, S66, S107 morbidity, S8, S60, S63, S107 mortality, S8, S12, S18, S24, S60, S61, S63, S107 risk factor modification, S8, S11, S12, S47, S58, S60, S62, S99 risk factors, S7, S8, S107, S110, S115 Cardiovascular Life Expectancy Model, S58 Care plan, sample, S122-S124 Carpal tunnel syndrome, S72. See also Neuropathy Cataracts, S76, S78 Celiac disease (CD), S88, S119, S139 Cerebral edema (CE), S86 Children, S12, S27, S32, S33, S84-S90, S91-S93, S110, S139-S140. See also Adolescents adjustment problems in, S50 diabetes complications, S84, S85, S86-S87, S92 management, S84-S86, S92 prevention, S91-S92 screening, S91 dyslipidemia screening, S86, S87 treatment, S87 glycemic targets, S19, S84, S85, S87, S92 hypertension, S86, S87 hypoglycemia, treatment, S44 insulin therapy, S84-S85, S92
nephropathy, screening, S86-S87, S92 neuropathy, screening, S86, S87 retinopathy, screening, S86, S87, S92 Chlorpropamide, S38, S124. See also Insulin secretagogues and Oral antihyperglycemic agents Cholesterol, S128. See also Dyslipidemia, screening and Lipid absorption inhibitors, S61. See also Ezetimibe high-density lipoprotein (HDL-C), S8, S58, S59, S60, S61, S120, S121 hypercholesterolemia, S107 low-density lipoprotein (LDL-C), S58, S59, S60, S61, S78, S120, S121, S123 total (TC), S59, S60, S61, S78, S120, S121 very low-density lipoprotein (VLDL-C), S27 Cholestyramine resin, S60, S61. See also Bile acid sequestrants Clopidogrel, S63. See also Antiplatelet therapy Cockcroft-Gault formula, S38, S66, S68, S70. See also Nephropathy, screening Cognitive function, S43 impairment, S84, S85 Cognitive-behaviour therapy, S50-S51 Colestipol HCl, S60, S61. See also Bile acid sequestrants Combination therapy glycemic control, S37, S38, S39, S40, S124, S135 hypertension, S62, S63 nephropathy, S69, S137 Complications. See Diabetes complications Congenital anomalies, S94, S96, S102 Contact lens fundus biomicroscopy. See Retinopathy, screening Continuous glucose monitoring, S22 Continuous intravenous (IV) insulin infusion, S113 Continuous subcutaneous insulin infusion (CSII). See Insulin Coping skills, S50, S51, S120 Coronary artery disease, S12, S62, S86, S87 heart disease, S62 Corticosteroids, S99 Cortisol, morning serum, S139. See also Addisons disease Counselling contraception and sexual health, in adolescents, S85 foot care, S74, S121 hypoglycemia, S34, S40, S135
S145
lifestyle, S27, S40, S91-S92, S102, S120 nutrition, S27, S29, S69, S96, S120 physical activity, S120 preconception or conception, S121 smoking prevention or cessation, S85, S120, S121 Counterregulatory hormone response, S33, S34, S95 Creatinine clearance, S38, S66, S68, S69, S70, S94, S95, S120, S121, S123, S137. See also Nephropathy, screening Cyclamates, S28. See also Sweeteners Daclizumab, S55 Depression, S50, S51, S84, S92, S120, S123 Dextrose tablets. See Hypoglycemia, treatment Diabetes complications, S1, S8, S14, S37, S50, S55, S56, S57-S82, S86-S87, S92, S94-S95, S96, S110, S119, S123. See also Macrovascular complications and Microvascular complications as risk factors, S10, S12, S59 prevention, S2, S18, S19, S27, S46, S58, S60, S61, S62, S63, S66, S68, S69, S72, S74, S77-S78, S81, S85, S107, S138 Diabetes Control and Complications Trial (DCCT), S18, S19, S21, S32, S34, S40, S77, S81 Diabetes Education Centre, S110, S123 Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE), S18 Diabetes healthcare (DHC) team. See Teams Diabetes Intervention Study, S18 Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, S115 Diabetes Prevention Program (DPP), S12 Diabetic ketoacidosis (DKA), S7, S22, S84, S86, S87, S91, S92, S95, S121 Dialysis, S22, S66, S69 Diastolic blood pressure (BP). See Blood pressure (BP) Dietary modification. See Nutrition therapy Diethylpropion, S47. See also Antiobesity agents and Sympathomimetic noradrenergic appetite suppressants Digital fundus photography. See Retinopathy, screening Diltiazem, S69. See also Antihypertensive agents and Calcium channel blockers (CCBs) Diuretics. See also Antihypertensive agents non-potassium-sparing, S69
thiazide, S81, S95, S107, S118 thiazide-like, S62, S63 Driving, S2, S34, S43, S44, S84, S121 Dysglycemia, S7-S9, S21, S101 Dyslipidemia, S8, S10, S12, S46, S58-S65, S81, S91, S119, S120, S123. See also Lipid screening, S120, S121, S123 adolescents, S86, S87 adults, S58-S59, S60 children, S86, S87 treatment adolescents, S87 adults, S59-S61 children, S87 elderly, S107 Early Treatment Diabetic Retinopathy Study (ETDRS), S76, S78
INDEX
Eating disorders, S50, S85, S120 Edmonton Protocol, S55 Education, S15, S22, S27, S29, S32, S34, S44, S50, S74, S84, S92, S106, S110, S111, S120, S121, S138 Ejaculatory disorders, S81 Elderly, S25, S38, S106-S109 diabetes management, S106-S107 prevention, S106, S107 glycemic targets, S106, S107 hypoglycemia, S106, S107 insulin therapy, S106-S107 End stage renal disease (ESRD), S66. See also Nephropathy Endomysial antibodies plus immunoglobulin A (IgA) levels, S139. See also Celiac disease (CD) Erectile dysfunction (ED), S4, S81-S82, S119, S123 management, S81, S107 screening, S81, S120, S121, S123 Ethanol. See Alcohol Examination, medical follow-up visits, S121 initial visit, S120 Exercise. See Physical activity Exercise electrocardiogram (ECG) stress test, S24, S25 Ezetimibe, S61. See also Cholesterol, absorption inhibitors Family behaviour therapy, S50, S51
S146
Fasting blood glucose (FBG). See Blood glucose (BG) lipid profile. See Dyslipidemia, screening and Lipid plasma glucose (FPG). See Plasma glucose (PG) Fat. See also Fatty acids abdominal. See Abdominal obesity body, S46 distribution, S47 intake, S12, S27, S28, S29, S47, S126, S128, S131-S134 monounsaturated, S27, S28, S29 plant oils, S28, S29 polyunsaturated, S28, S29 portion size, S130 saturated, S28, S29, S47 Fatty acids. See also Fat essential, S27 polyunsaturated omega-3, S28, S29 trans, S28, S29 Fenofibrate, S61. See also Fibrates Fetal hyperinsulinism, S101 Fibrates, S60, S61. See also Bezafibrate; Fenofibrate and Gemfibrozil Finnish Diabetes Prevention Study, S12 First morning albumin to creatinine ratio (ACR). See Nephropathy, screening, adolescents and Nephropathy, screening, children First Nations. See Aboriginal Fluvastatin, S61. See also Statins Focal/grid laser treatment. See Retinopathy, treatment Folic acid supplement, S94, S102 Foot care, S74-S75, S121, S123, S138 Foot ulcer, S72, S74, S119, S123 management, S74 prevention, S74, S138 screening, S74, S120, S121 Framingham Heart Study, S58 Fructose, S28 Gabapentin, S72 Gastric bypass procedure. See Obesity, treatment Gastric restrictive procedure. See Obesity, treatment Gastrointestinal lipase inhibitors, S47, S48. See also Antiobesity agents and Orlistat Gemfibrozil, S61. See also Fibrates
Generalized anxiety disorder. See Anxiety disorders Genetics, S7, S10, S91, S102, S110, S118 Gestational diabetes mellitus (GDM), S7, S10, S12, S99-S105, S110, S118, S123. See also Pregnancy glycemic targets, S100, S101 insulin therapy, S101 management, S100-S101 postpartum evaluation, S101-S102 screening, S99-S100 Glaucoma (primary, open-angle), S76 Gliclazide, S38, S39, S106, S107, S124. See also Insulin secretagogues and Oral antihyperglycemic agents Glimepiride, S38, S39, S106, S107, S124. See also Insulin secretagogues and Oral antihyperglycemic agents Glomerular filtration rate (GFR), S68 Glucagon. See Hypoglycemia, treatment Glucose disposal, S25, S106 gel. See Hypoglycemia, treatment intolerance, S7, S91, S92, S99, S115, S118 output, hepatic, S46 production, S25 solution. See Hypoglycemia, treatment tablets. See Hypoglycemia, treatment uptake, S46 Glucose-insulin-potassium (GIK) infusion therapy, S115 Glyburide, S38, S39, S96, S101, S106, S107, S124. See also Insulin secretagogues and Oral antihyperglycemic agents Glycated hemoglobin. See A1C Glycemic control, S6, S18, S19, S21, S22, S24, S27, S28, S29, S33, S37, S40, S46, S47, S48, S50, S55, S56, S58, S59, S61, S62, S68, S69, S72, S74, S77-S78, S92, S94, S95, S96, S101, S106, S107 perioperative, S113 postoperative, S113 goals, S21, S22, S33, S43 index, S27, S28, S29, S128-S129 targets, S33, S34, S37, S38, S40, S43, S62, S74, S87, S92, S121, S123, S124 in adolescents, S19, S84, S85 in adults, S19 in children, S19, S84, S85 in elderly, S106, S107 in gestational diabetes mellitus (GDM), S100, S101 in pregnancy, S19, S94, S95, S96 intra-, peri- and postoperative, S113 preconception, S94, S96
S147
Glycosylated hemoglobin. See A1C HbA1c. See A1C Healthcare team. See Teams Heart Protection Study (HPS), S60 High-density lipoprotein cholesterol (HDL-C). See Cholesterol Hirsutism, S99, S119 Hispanic, S10, S12, S91, S99 History, upon diagnosis of diabetes, S119 Home blood glucose (BG) monitoring. See Self-monitoring of blood glucose (SMBG) Honey. See Hypoglycemia, treatment Hydralazine, S95. See also Antihypertensive agents Hyperbilirubinemia, neonatal, S99 Hyperglycemia, S7, S8, S10, S29, S37, S38, S39, S40, S43, S77, S92, S95, S99, S102, S106, S113, S115, S119, S124 Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, S99 Hyperkalemia, S69 Hypertension, S8, S10, S12, S46, S55, S58-S65, S68, S69, S78, S81, S91, S94, S95, S107, S110, S119, S123. See also Blood pressure (BP) screening, S61, S62, S63, S86, S87 treatment, S62-S63, S92 Hypertension Optimal Treatment (HOT) trial, S61 Hypertriglyceridemia, S58, S59, S60 Hypocalcemia, neonatal, S99 Hypoglycemia, S19, S22, S32, S39, S43-S45, S55, S96, S113, S115, S123, S135 complications of, S43, S84, S85 delayed, S28, S29 drug-induced, S33, S34, S37, S40, S43, S106 fear of. See Anxiety disorders mild, S33, S34, S43, S44 moderate, S43, S44 neonatal, S99 nocturnal, S21, S33, S34, S40, S85, S95 prevention, S21, S27, S29, S33, S34, S37, S40, S44, S106, S107, S121 severe, S18, S33, S34, S40, S43, S44, S84, S85, S94, S95, S139 symptoms, S33, S43 treatment, S34, S38 adolescents, S43-S44
adults, S43-S44 children, S44 unawareness, S33, S34, S56, S95 Hypothyroidism, S139 Illness. See Sick-day management Immunization, S53-S54, S123 Impaired fasting glucose (IFG), S8, S99, S101, S102, S123 screening, S7, S10-S12 Impaired glucose tolerance (IGT), S8, S47, S91, S99, S100, S102, S123 of pregnancy, S100, S101 screening, S7, S10-S12 Impotence. See Erectile dysfunction (ED) In utero exposure to diabetes, S91, S102 Indirect slit-lamp fundoscopy. See Retinopathy, screening Infection, S56, S74, S113, S119 Insulin, S22, S28, S32-S36, S44, S76, S86, S100, S123, S131 action, S7, S21, S84, S101, S118 analogues, extended long-acting, S32, S33, S37, S38, S85, S95. See also Insulin, glargine analogues, rapid-acting, S32, S34, S85, S95, S107, S135. See also Insulin, aspart and Insulin, lispro animal, S32, S34 aspart, S32, S33, S40, S95, S101. See also Insulin, analogues, rapid-acting basal, S32, S33, S39, S124, S135 bolus, S32 continuous subcutaneous insulin infusion (CSII), S21, S32, S33, S85, S95, S96 deficiency, S7, S115, S118 delivery systems, S32, S55, S106-S107, S121 fast-acting, S32, S85, S135. See also Insulin, regular glargine, S32, S33, S37, S40, S85, S95, S101, S135. See also Insulin, analogues, extended long-acting human, S32, S34 intensive therapy, S18, S21, S27, S29, S32, S33-S34, S37, S40, S43, S46, S55, S77, S85, S95-S96, S115, S135 intermediate-acting, S32, S37, S38, S85. See also Insulin, NPH lispro, S32, S33, S34, S40, S95, S101. See also Insulin, analogues, rapid-acting long-acting, S32, S37, S38 mealtime, S40, S135 multiple daily injections, S21, S32, S33, S34, S85, S95, S96, S101, S115, S135 NPH, S32, S33, S37, S40, S135. See also Insulin, intermediate-acting omission for weight control. See Eating disorders premixed, S32, S106, S107, S135
INDEX
S148
preprandial, S39, S124 pump therapy. See Insulin, continuous subcutaneous insulin infusion (CSII) regular, S32, S33, S34, S40. See also Insulin, fast-acting resistance, S7, S8, S24, S37, S61, S91, S92, S95, S102, S106, S118 resistance syndrome. See Metabolic syndrome sensitivity, S25, S27, S46, S47 therapy in adolescents, S84-S85, S92 in children, S84-S85, S92 in combination with oral antihyperglycemic agents, S37, S38, S39, S40, S124, S135 in elderly, S106-S107 in gestational diabetes mellitus (GDM), S101 in pregnancy, S94, S95-S96 in type 1 diabetes, S32-S36, S84-S85 in type 2 diabetes, S37, S38, S39, S40, S92, S124, S135 Insulin secretagogues, S28, S37, S38, S39, S40, S43, S124. See also Chlorpropamide; Gliclazide; Glimepiride; Glyburide; Nateglinide; Nonsulfonylurea insulin secretagogues; Oral antihyperglycemic agents; Repaglinide; Sulfonylureas and Tolbutamide Insulin sensitizers, S38, S39, S40, S106, S107, S124. See also Oral antihyperglycemic agents; Pioglitazone; Rosiglitazone and Troglitazone Insulin-glucose infusion, S115 Intensive care, S113 Intensive insulin therapy. See Insulin, intensive therapy Interdisciplinary approach, S46-S47, S48, S74 team. See Teams Interstitial glucose, S22 Intracorporal injection therapy with prostaglandin E1 (PGE1), S81 Intraurethral therapy using prostaglandin E1 (PGE1), S81 Inuit. See Aboriginal Islet autoantibodies, S10, S91, S102 Islet transplantation, S55-S56 Isomalt, S28. See also Sugar alcohols Isosorbide dinitrate spray, S72 Ketoacidosis. See Diabetic ketoacidosis (DKA) Ketone testing, S22, S34, S95, S101 Ketosis, S47, S95, S96, S101
Kidney function. See Nephropathy Kidney transplant. See Renal, transplantation Kumamoto study, S18 Lactation. See Breastfeeding Laser therapy. See Retinopathy, treatment Latent autoimmune diabetes in adults (LADA), S7 Lifestyle interventions counselling, S27, S40, S91-S92, S102, S120 diabetes and complications prevention, S8, S12, S102, S106, S107, S110, S111 treatment, S25, S37, S39, S40, S46, S47, S48, S58, S59, S60, S62, S68, S92, S95, S101, S124 Lipid. See also Dyslipidemia control, S28, S29, S47, S59, S60, S68, S77, S78 hyperlipidemia, S55, S68, S86, S87 medications, S60, S61, S87, S121, S123 profile, S24, S58, S59, S60, S86, S123 targets, S59, S60, S62, S107 Lipid Research Clinics Follow-up Cohort, S58 Lovastatin, S61. See also Statins Low-density lipoprotein cholesterol (LDL-C). See Cholesterol Macroalbuminuria. See Nephropathy Macrosomia, S10, S12, S95, S99, S101, S123 Macrovascular complications, S10, S18, S19, S37, S58-S65, S87. See also Diabetes complications prevention, S58, S60, S61, S63, S85 Macular edema, S76, S78 Major surgery. See Surgery Maltitol, S28. See also Sugar alcohols Mannitol, S28. See also Sugar alcohols Maturity-onset diabetes of the young (MODY), S118 Mechanical ventilation, S113 Meglitinides. See Nonsulfonylurea insulin secretagogues Metabolic decompensation, S7, S11, S92 Metabolic syndrome, S8, S10, S12, S47, S92, S119 Metformin, S12, S37, S38, S39, S40, S91, S92, S96, S124. See also Biguanides and Oral antihyperglycemic agents Methyldopa, S95. See also Antihypertensive agents Mtis. See Aboriginal
S149
Mexiletine, S72 Microalbuminuria. See Nephropathy Microvascular complications, S6, S8, S18, S19, S32, S37, S61, S62, S66-S71, S72-S73, S74-S75, S76-S80, S81-S82, S92. See also Diabetes complications Minor surgery. See Surgery Moderate surgery. See Surgery Modification of Diet in Renal Disease (MDRD) study, S68, S70 Monitoring. See Self-monitoring of blood glucose (SMBG) Monofilament, 10-g Semmes-Weinstein. See Neuropathy, screening Multidisciplinary team. See Teams Multiple daily insulin injections. See Insulin Mycophenolate mofetil, S55 Mydriatic retinal photography. See Retinopathy, screening Myocardial infarction (MI), S18, S62, S63, S95, S115 Nateglinide, S38, S39, S106, S124. See also Insulin secretagogues and Oral antihyperglycemic agents National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), S8 National Diabetes Surveillance Strategy (NDSS), S1, S2 National Population Health Survey, S1 Needle phobia. See Anxiety disorders Nephropathy, S4, S12, S59, S61, S62, S63, S66-S71, S77, S110, S119, S136 prevention, S58, S68, S69, S107 in pregnancy, S94-S95 screening adolescents, S86-S87, S92 adults, S38, S66-S68, S69, S120, S121, S123 children, S86-S87, S92 in pregnancy, S94-S95, S96 preconception, S94-S95, S96 treatment, S137 adolescents, S87 adults, S55, S68-S70 Neural tube defects, S94 Neurogenic symptoms. See Hypoglycemia, symptoms Neuroglycopenic symptoms. See Hypoglycemia, symptoms Neuropathic pain, S72. See also Neuropathy
Neuropathy, S55, S68, S72-S73, S74, S119 autonomic, S24, S33, S55, S72, S81, S87, S120 carpal tunnel syndrome, S72 management, S72 mononeuropathy, S72 peripheral, S24, S72 polyneuropathy, S72 prevention, S72 screening, S120, S123 adolescents, S86, S87 adults, S72 children, S86, S87 somatic, S72 Nicotinic acid (niacin), S61, S118 Nonalcoholic fatty liver disease, S92 Nondiabetic renal disease, S66, S67, S68 Nonmydriatic retinal photography. See Retinopathy, screening Nonproliferative retinopathy. See Retinopathy Non-Q-wave myocardial infarction (MI). See Acute coronary syndromes (ACSs) Nonsulfonylurea insulin secretagogues, S38, S106, S124. See also Insulin secretagogues; Nateglinide; Oral antihyperglycemic agents and Repaglinide Norepinephrine and serotonin reuptake inhibitors, S47, S48. See also Antiobesity agents and Sibutramine Nutrition therapy, S27-S31 assessment, S39, S119, S120, S123, S124 counselling, S27, S29, S69, S96, S120 diabetes complications, prevention, S27 prevention, S12, S107, S110, S111 treatment, S15, S27, S37, S39, S40, S47, S59, S60, S84, S95, S96, S101, S106, S124 strategies, S28, S126-S127, S128-S129, S130, S131-S134 Obesity, S2, S12, S46-S49, S99, S102, S110 assessment, S46 classification, S46 in adolescents, S87, S91, S92 in children, S1, S46, S87, S91, S92 treatment, S46-S48 Ophthalmoscopy. See Retinopathy, screening Opioid analgesics, S72
INDEX
S150
Oral antihyperglycemic agents, S21, S22, S37, S38, S39, S40, S47, S92, S94, S96, S101, S106, S107, S121, S123, S124, S135. See also Acarbose; Alpha-glucosidase inhibitors; Biguanides; Chlorpropamide; Gliclazide; Glimepiride; Glyburide; Insulin secretagogues; Insulin sensitizers; Nateglinide; Nonsulfonylurea insulin secretagogues; Pioglitazone; Repaglinide; Rosiglitazone; Sulfonylureas; Tolbutamide and Troglitazone Oral glucose tolerance test (OGTT), S7, S8, S10, S11, S12, S18, S91, S99, S100, S101, S102. See also 75-g oral glucose tolerance test (OGTT) Orlistat, S38, S47, S48. See also Antiobesity agents and Gastrointestinal lipase inhibitors Orthotics, S138 Overweight, S1, S10, S12, S25, S39, S40, S46, S47, S59, S68, S91, S123, S124 Pancreas after kidney (PAK) transplantation, S55 Pancreas transplant alone (PTA), S55 Pancreas transplantation, S55 Papaverine, S81 Penile prosthesis, S81 Perioperative glycemic control, S113-S114 Peripheral vascular disease, S74, S110 Phentermine, S47. See also Antiobesity agents and Sympathomimetic noradrenergic appetite suppressants Phentolamine, S81 Phobic disorders. See Anxiety disorders Photocoagulation, S56, S76, S77, S78. See also Retinopathy, treatment Physical activity, S1, S2, S15, S21, S24-S26, S28, S32, S46, S95, S101, S131, S138 aerobic, S24, S25, S59, S106, S107 assessment, S24, S39, S119, S123, S124 counselling, S120 diabetes and complications prevention, S12, S107, S110, S111 treatment, S24, S25, S37, S39, S40, S47, S48, S59, S60, S84, S106, S124 effect on screening test results, S66, S86 resistance, S24, S25, S106, S107 strategies, S24, S25, S133 Pioglitazone, S38. See also Insulin sensitizers and Oral antihyperglycemic agents
Plasma glucose (PG), S43, S113 casual, S7, S10, S11 control. See Glycemic, control fasting (FPG), S7, S8, S10, S11, S12, S18, S19, S21, S22, S33, S91, S92, S94, S102, S120, S121. See also Blood glucose (BG), fasting (FBG) postprandial, S18, S19, S21, S94, S95, S100, S101. See also Blood glucose (BG), postprandial preprandial, S19, S85, S94, S100, S101. See also Blood glucose (BG), preprandial targets. See Glycemic, targets Polycystic ovary syndrome (PCOS), S10, S12, S91, S92, S99, S120, S123 Postoperative glycemic control, S113 Pravastatin, S61. See also Statins Preconception care, S94, S102, S121 Prediabetes. See Impaired fasting glucose (IFG) and Impaired glucose tolerance (IGT) Pre-eclampsia, S94, S95, S96 Pregnancy, S28, S37, S77, S94-S98. See also Gestational diabetes mellitus (GDM) avoidance of, in adolescents, S85 complications diabetes, S94-S95, S96 fetal, S94, S95, S96 maternal, S94, S95, S96 conception counselling, S121 glycemic control, S94, S95, S96 targets, S94, S95, S96 hypertension, treatment, S95, S96 insulin therapy, S95-S96 management of diabetes during pregnancy, S95-S96 nephropathy, screening, S94-S95, S96 retinopathy, screening, S94, S96 Prevention, S10-S13 diabetes, S12, S15, S91, S92, S102, S106, S107, S110, S111, S131-S134 diabetes complications, S2, S18, S19, S27, S46, S58, S60, S61, S62, S63, S66, S68, S69, S72, S74, S77-S78, S81, S85, S107, S138 Problem Areas in Diabetes scale, S50 Proliferative retinopathy. See Retinopathy Protein content of bedtime snack, S34, S44 intake, S27, S28, S29, S47 portion size, S130 Psychosocial support and reinforcement, S51
S151
Pumps, insulin. See Insulin, continuous subcutaneous insulin infusion (CSII) Random urine albumin to creatinine ratio (ACR). See Nephropathy, screening Renal function. See Nephropathy protection, S58, S59, S68, S69 transplantation, S55, S66 Repaglinide, S38, S39, S106, S124. See also Insulin secretagogues and Oral antihyperglycemic agents Respiratory distress syndrome, S99 Retinal photography. See Retinopathy, screening Retinopathy, S12, S63, S68, S76-S80, S81, S94, S110, S119, S123 nonproliferative, S76, S78 preproliferative, S24 prevention, S18, S55, S77-S78 proliferative, S24, S62, S76, S78 screening, S123 adolescents, S86, S87, S92 adults, S76-S77 children, S86, S87, S92 in pregnancy, S94, S96 in remote communities, S110 preconception, S94, S96 transient early worsening, S56, S77, S78 treatment, S78 vitreous hemorrhage, S63, S77, S78 Rosiglitazone, S38, S39, S124. See also Insulin sensitizers and Oral antihyperglycemic agents Rosuvastatin, S61. See also Statins Roux-en-Y gastric bypass. See Obesity, treatment Saccharin, S28. See also Sweeteners Salt. See Sodium Scatter laser treatment. See Retinopathy, treatment Schizophrenia, S10, S12, S123 Self-care. See Self-management Self-management, S14, S15, S22, S27, S32, S34, S50, S94, S111 Self-monitoring of blood glucose (SMBG), S32, S84, S85, S100, S101, S121, S123 frequency, S21, S22 overnight, S33, S34, S95 postprandial, S22, S95, S96 preprandial, S22, S95, S96 record, sample, S125
Serum creatinine. See Nephropathy, screening, adults Sexual function history. See Erectile dysfunction (ED), screening Sibutramine, S47, S48. See also Antiobesity agents and Norepinephrine and serotonin reuptake inhibitors Sick-day management, S22, S32, S37, S84, S86, S121 Simultaneous pancreas and kidney (SPK) transplantation, S55 Simvastatin, S60, S61. See also Statins Smoking, S1, S81, S119, S120, S121, S123, S138 cessation, S15, S58, S59, S60, S68, S74, S85, S92 prevention, S15, S85 Snacks, S27, S34, S44, S95, S101, S126 Sodium, S28, S62 Sorbitol, S28. See also Sugar alcohols
INDEX
South Asian, S10, S12, S91, S99 Spontaneous abortion, S94, S96 Starvation ketosis, S95, S101 Statins, S5, S59, S60, S61, S107. See also Atorvastatin; Fluvastatin; Lovastatin; Pravastatin; Rosuvastatin and Simvastatin Stereoscopic digital photography. See Retinopathy, screening Study to Prevent Non Insulin Dependent Diabetes Mellitus (STOP-NIDDM), S12 Sucralose, S28. See also Sweeteners Sucrose, S27, S28, S29, S44. See also Hypoglycemia, treatment Sugar alcohols, S28. See also Isomalt; Maltitol; Mannitol; Sorbitol and Xylitol Sulfonylureas, S37, S38, S39, S40, S106, S107, S124. See also Chlorpropamide; Gliclazide; Glimepiride; Glyburide; Insulin secretagogues; Oral antihyperglycemic agents and Tolbutamide Supplement folic acid, S94, S102 vitamin, S28, S29 Surgery, S119 cardiac, S113 insulin use during, S37, S113 major, S113 minor, S113 moderate, S113 vascular, S74
S152
Sweeteners, S28. See also Acesulfame potassium; Aspartame; Cyclamates; Saccharin and Sucralose Sympathomimetic noradrenergic appetite suppressants, S47. See also Antiobesity agents; Diethylpropion and Phentermine Syndrome X. See Metabolic syndrome Systolic blood pressure (BP). See Blood pressure (BP) Tacrolimus, S55, S56 Teams diabetes healthcare (DHC), S14, S15, S29, S33, S44, S50, S84, S87, S94, S106, S107, S115 healthcare, S22, S47, S113 interdisciplinary, S14, S94 interdisciplinary pediatric diabetes healthcare (DHC), S84, S92 interdisciplinary pregnancy, S96 multidisciplinary, S14, S110 Thiazide diuretics. See Diuretics Thiazolidinediones (TZDs), S38, S40, S106, S107, S124. See also Insulin sensitizers; Oral antihyperglycemic agents; Pioglitazone; Rosiglitazone and Troglitazone Third National Health and Nutrition Survey (NHANES III), S8 Thyroid-stimulating hormone (TSH) level (serum), S120, S121, S139. See also Autoimmune thyroid disease Timed overnight urine collection. See Nephropathy, screening Tissue transglutaminase, S139. See also Celiac disease Tolbutamide, S38, S124. See also Insulin secretagogues and Oral antihyperglycemic agents Total cholesterol to high-density lipoprotein cholesterol ratio (TC:HDL-C), S58-S59, S60, S61, S123. See also Dyslipidemia, screening and Lipid Transplantation islet, S55-S56 pancreas, S55 renal, S55, S66 Tricyclic antidepressants, S72 Triglycerides (TGs), S8, S27, S28, S47, S58, S59, S60, S61, S78, S120, S121 Troglitazone, S106. See also Insulin sensitizers and Oral antihyperglycemic agents Tuning fork, 128-Hz. See Neuropathy, screening Type 5 phosphodiesterase (PDE5) inhibitors, S81, S107. See also Erectile dysfunction (ED)
United Kingdom Prospective Diabetes Study (UKPDS), S6, S18, S21, S37, S40, S61, S62, S76, S81 United Kingdom Prospective Diabetes Study (UKPDS) risk engine, S58, S63 United States (US) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]), S8 Unstable angina. See Acute coronary syndromes (ACSs) Urinary albumin, S66, S67, S69, S136. See also Nephropathy, screening, adults protein. See Nephropathy, screening, adults Urine dipstick test, S66, S67, S136. See also Nephropathy, screening, adults Vaccine. See Immunization Vacuum constriction devices, S81 Vascular disease, S10, S12, S58, S59, S60, S74 protection, S55, S58, S59, S61, S68, S74 risk, S58, S59, S60, S63 Verapamil, S69. See also Antihypertensive agents and Calcium channel blockers (CCBs) Very low-density lipoprotein cholesterol (VLDL-C). See Cholesterol Vitrectomy. See Retinopathy, treatment Vitreous hemorrhage. See Retinopathy Waist circumference, S8, S46, S47, S120, S123 Warfarin, S77 Wisconsin Epidemiologic Study of Diabetic Retinopathy, S76 World Health Organization (WHO), S8 Xylitol, S28. See also Sugar alcohols
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December 2003 Volume 27 Supplement 2

Canadian Journal of Diabetes

A Publication of the Professional Sections of the Canadian Diabetes Association

December 2003 Volume 27 Supplement 2

Canadian Journal of Diabetes

A Publication of the Professional Sections of the Canadian Diabetes Association

2003 CLINICAL PRACTICE GUIDELINES

2003 CLINICAL PRACTICE GUIDELINES

Clinical Practice Guidelines Committees

Jean-Franois Yale MD CSPQ Professor of Medicine, McGill University, Montreal, Quebec

2003 CLINICAL PRACTICE GUIDELINES

2003 CLINICAL PRACTICE GUIDELINES

Canadian Journal of Diabetes

2003 CLINICAL PRACTICE GUIDELINES

25. 26. 27. 28.

2003 CLINICAL PRACTICE GUIDELINES

Level 2 Level 3 Level 4 Level 1A

Studies of treatment and prevention

Level 1B Level 2 Level 3 Level 4 Studies of prognosis Level 1

Level 2 Level 3 Level 4

2003 CLINICAL PRACTICE GUIDELINES

Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories

2hPG in a 75-g OGTT (mmol/L)

The initial draft of this chapter was prepared by Ehud Ur MB FRCP.

2003 CLINICAL PRACTICE GUIDELINES

2003 CLINICAL PRACTICE GUIDELINES

Screening and Prevention

S11 Figure 1. Screening for type 2 diabetes, IFG and IGT

5.76.9 mmol/L plus risk factor(s) for diabetes/IGT* (see Table 1)

6.16.9 mmol/L and no risk factors for diabetes/IGT (see Table 1)

SCREENING AND PREVENTION

2hPG in a 75-g OGTT

Isolated IFG Isolated IGT IFG and IGT

Rescreen as clinically indicated

2003 CLINICAL PRACTICE GUIDELINES

SCREENING AND PREVENTION

2003 CLINICAL PRACTICE GUIDELINES

Organization and Delivery of Care

2003 CLINICAL PRACTICE GUIDELINES

CANADIAN DIABETES ASSOCIATION

2003 CLINICAL PRACTICE GUIDELINES

Targets for Glycemic Control

2-hour postprandial PG (mmol/L)

2003 CLINICAL PRACTICE GUIDELINES

Monitoring Glycemic Control

2003 CLINICAL PRACTICE GUIDELINES

2003 CLINICAL PRACTICE GUIDELINES

Physical Activity and Diabetes

Vigorous effort: >70% of persons maximum heart rate

Table 2. Resistance exercise Definition Examples

*Initial instruction and periodic supervision recommended

2003 CLINICAL PRACTICE GUIDELINES

2003 CLINICAL PRACTICE GUIDELINES

Acceptable daily intake (mg/kg body weight)

Table 2. Examples of standard alcoholic drinks Drink

Ethanol content (%)

2003 CLINICAL PRACTICE GUIDELINES

2003 CLINICAL PRACTICE GUIDELINES

Insulin Therapy in Type 1 Diabetes

Humulin-R Novolinge Toronto

Humulin-L Humulin-N Novolinge NPH Humulin-U

*Approved, but not yet available, in Canada

2003 CLINICAL PRACTICE GUIDELINES

2003 CLINICAL PRACTICE GUIDELINES