Diabetes management: Non-insulin medications

Kristi Kulasa, MD
Assistant Clinical Professor of Medicine
Director, Inpatient Glycemic Control
Department of Endocrinology, Diabetes and Metabolism
November 10, 2015

Learning Objectives
1. Describe the role of diet, exercise, and patient education
in the treatment of diabetes
2. Know the mechanism of action, dosing schedule,
indications, percent A1c reduction, and side effects for
common medications to treat type 2 diabetes including
biguanides, sulfonylureas, thiazolidinediones, alphaglucosidase inhibitors, incretins, and SGLT-2 inhibitors
3. Explain the clinical rationale for choosing a particular
medication to treat type 2 diabetes in terms of A1c
reduction, adverse effects, and co-morbidities
4. Differentiate key points in the treatment of type 1 and
type 2 diabetes

Outline

Mechanisms of Hyperglycemia
Available Treatment Options
Published algorithms for treatment of type 2 diabetes
Case Discussions

INSULIN
TZD

SU

DPP-4 INH

MEGLITINIDES

GLP-1 R
AGONISTS

GLP-1R AGONISTS

Increased Lipolytic Activity

Leading to Deleterious
Effects in Both Insulin
Secretion and Action

MET

Inappropriate
Hepatic
Glucose
Production

Reduced
Insulin
Secretion

Increased PostPrandial Secretion

of Glucagon

SGLT-2
RECEPTOR
BLOCKERS

HYPERGLYCEMIA

Decreased Incretin Action

Leads to Glucose
Stimulated Insulin Release
GLP-1R AGONISTS

Derangements at the Level of the

Hypothalamus Lead to Appetite
Dysregulation and Obesity

Gut
Glucose
Absorption

DPP-4 INHIBITORS

Reabsorb
Filtered
Glucose

Impaired Insulin Mediated

Glucose Disposal
TZD

COLESEVELAM
ACARBOSE

Lifestyle
Diet and Exercise

A1C reduction 1-2%

Weight loss
Improved utilization of insulin
Compliance difficult

Patient Education
Survival skills- meds, meter, hypoglycemia
Who to call

Biguanide
Generic: Metformin
US Brand: Fortamet, Glucophage, Glucophage
XR, Glumetza, Riomet
MOA: decreases hepatic gluconeogenesis and
improves insulin sensitivity in peripheral tissues
A1C lowering: 1.0-2.0%
Advantages: weight neutral, no hypoglycemia
Disadvantages: GI s/e (diarrhea, nausea, vomiting).
Contraindicated with serum creatinine 1.5 mg/dL in
males or 1.4 mg/dL in females. More recent studies
OK w/ Clcr down to 30 mL/minute w/ dose reduction <
45 mL/minute. Avoid use in patients with impaired liver
function due to potential for lactic acidosis.

Sulfonylurea
1st generation:
Acetohexamide
Chlorpropamide (Diabinese)
Tolbutamide (Orinase)

2nd generation:

Glipizide (Glucotrol) (Glucotrol XL)

Gliclazide (Diamicron R) (Diamicron MR)
Glyburide (Glibenclamide) (Diabeta) (Micronase) (Glynase)
Glimepiride (Amaryl)

Sulfonylurea

MOA: stimulates insulin secretion

A1C lowering: 1-2%
Advantages: rapid acting, low cost
Disadvantages: weight gain, hypoglycemia, effectiveness
decreases over time. Use with caution in elderly patients,
malnourished patients and in patients with impaired renal
or hepatic function

Thiazolidinediones
Pioglitazone - Actos
Rosiglitazone - Avandia
MOA: improves insulin sensitivity in
adipose tissue, skeletal muscle and liver
A1C lowering: 0.5-1.4%
Advantages: improved lipid profile (Pioglitazone), potential
decrease MI (Pioglitazone), no hypoglycemia
Disadvantages: fluid retention, CHF, weight gain, bone
fractures, bladder CA, potential to increase MI
(rosiglitazone)

SGLT-2 Inhibitors

Canagliflozin - Invokana
Dapagliflozin Farxiga
Empagliflozin Jardiance
MOA: blocks reabsorption of glucose by the kidney
A1C lowering: 0.7-1.0%
Advantages: weight loss and no hypoglycemia
Disadvantages: UTI, genital infections, increased urination,
intravascular volume contraction/symptomatic hypotension,
hyperkalemia, cannot use in renal impairment (contraindicated
GFR < 30 ml/min, not rec GFR <45-60 ml/min), euglycemic
DKA.

Incretins
Gut hormones that are secreted from enteroendocrine
cells into the blood within minutes of eating

Lipidsonline.org

DPP-IV inhibitors

Sitagliptin Januvia
Saxagliptin Onglyza
Linagliptin - Tradjenta
Alogliptin Nesina
MOA: glucose mediated insulin release, decreases
glucagon, slows gastric emptying
A1C lowering: 0.6-0.9%
Advantages: weight neutral, can use with renal
impairment, glucose dependent action, no hypoglycemia
Disadvantages: expensive (now covered on most plans)

Glucagon-like peptide 1 agonists

Exenatide - Byetta
Liraglutide - Victoza
Exenatide Once Weekly - Bydureon
Albiglutide Tanzeum
Dulaglutide Trulicity
MOA: glucose mediated insulin release, suppresses
glucagon secretion, slows gastric emptying, reduces food
intake
A1C lowering: 0.9-1.9%
Advantages: weight loss, glucose dependent action, no
hypoglycemia
Disadvantages: injections, GI s/e (nausea, vomiting),
expensive

Insulin

http://www.medicalcriteria.com/criteria/dbt_insulin.ht

Insulin
Category/Name of Insulin
Rapid-Acting
Insulin Lispro
Insulin Aspart
Insulin Glulisine
Short-Acting
Regular
Intermediate-Acting
NPH
Long-Acting
Insulin Detemir
Insulin Glargine

Brand Name
(manufacturer)

Onset, Peak, Duration

Appearance

Humalog (Lilly)
Novolog (Novo Nordisk)
Apidra (Sanofi-Aventis)

w/in 15 min, 1-3h, 3-5h

w/in 15 min, 1-3h, 3-5h
15-30 m, 30-60 m, 4h

Clear
Clear
Clear

Humulin R (Lilly)
Novolin R (Novo Nordisk)

30-60 min, 2-4h, 5-8h

Clear

Humulin N (Lilly)
Novolin N (Novo Nordisk)

1-2h, 4-10h, 14+ hrs

Cloudy

Levemir (Novo Nordisk)

Lantus (Sanofi-Aventis)

3-4h, 6-8h, 20-24h

1.5h, flat, 24h

Clear
Clear

Humulin 70/30 (Lilly)

Novolin 70/30 (Novo)
Humalog Mix 50/50 (Lilly)
Humalog Mix 75/25 (Lilly)
Novolog Mix 70/30 (Novo)

15-30m, 30m-3h, 14-24h

Cloudy
Cloudy
Cloudy
Cloudy
Cloudy

Insulin Mixtures
NPH/Reg (70%/30%)

LisproProtamine/Lispro (50%/50%)
LisproProtamine/Lispro (75%/25%)
AspartProtamine/Aspart (70%/30%)

5-10m, 1-4h, 18-24h

Insulin
A1C lowering: unlimited
Advantages: no dose limit, rapidly effective, improved lipid
profile
Disadvantages: weight gain, hypoglycemia, injections
(Qday-QID), monitoring

Type 1 vs Type 2
Type 1 Diabetes

Type 2 Diabetes

5-10% of patients with DM

90-95% of patients with DM

Autoimmune destruction of
pancreatic islets destroying
ability to make insulin

Metabolic disorder
characterized by insulin
resistance

Absolute insulin deficiency

Relative insulin deficiency

Treatment MUST include

insulin

Treatment CAN include insulin,

esp late in disease process

ADA/EASD Consensus Statement for Treatment of

Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 1
45 y/o male with newly diagnosed type 2 diabetes. He
Has been symptomatic with 2 months of polyuria,
polydipsia and unintentional weight loss of 20 lbs.
A1C 10.7%
Cr 0.8
Weight 85 kg (BMI 30)
What is the most appropriate initial treatment regimen?
A.
B.
C.
D.

Lifestyle change only, patient is very motivated

Lifestyle + metformin
Lifestyle + metformin + acarbose
Lifestyle + metformin + glipizide + basal insulin

ADA/EASD Consensus Statement for Treatment of

Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 2
56 y/o male with long-standing uncontrolled type 2 diabetes
x15yrs, CAD s/p MI 2003, class IV CHF and sleep apnea.
Home regimen: metformin 1000mg bid, glipizide 5mg bid
A1C 10%
Cr 0.6
Weight 95 kg (BMI 35)
Which of the following medication should be added next?
A.
B.
C.
D.

Lifestyle change only, patient is very motivated

Pioglitazone (Actos, TZD)
Liraglutide (Victoza, GLP-1 R agonist)
Sitagliptin (Januvia, DPP-IV inhibitor)

ADA/EASD Consensus Statement for Treatment of

Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 3
75 y/o female with long-standing type 2 diabetes and
osteoporosis recently admitted to the hospital with a hip
fracture s/p fall at home in the setting of hypoglycemia.
Home regimen: metformin 1000mg bid and glipizide 2.5mg bid
A1C 6.5%
Cr 0.4
Weight 40 kg (BMI 19)
Which of the following medication adjustment is most
appropriate?
A.
B.
C.
D.

No change necessary, A1C at goal

Stop glipizide and start sitagliptin (Januvia, DPP-IV inhibitor)
Stop metformin and start canagliflozin (Invokana, SGLT-2 inhibitor)
Stop glipizide and start pioglitazone (Actos, TZD)

ADA/EASD Consensus Statement for Treatment of

Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 4
45 y/o male with newly diagnosed DM2 w/ A1C 8.3%.
Denies polyuria, polydipsia or blurry vision.
Home regimen - none
A1C 8.3%
Cr 0.85
Weight 95 kg (BMI 30)
What is the most appropriate initial treatment regimen?
A.
B.
C.
D.

Lifestyle change only, patient is very motivated

Lifestyle + metformin (Glucophage, biguanide)
Lifestyle + sitagliptin (Januvia, DPP-IV inhibitor)
Lifestyle + canagliflozin (Invokana, SGLT-2 inhibitor)

ADA/EASD Consensus Statement for Treatment of

Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 5
45 y/o female with uncontrolled DM2 w/ A1C 10.2% as well as
heartburn, HTN and hyperlipidemia needs medication
escalation for DM, but is very concerned about weight gain and
will not take any medication that will cause weight gain.
Home regimen metformin 1000mg bid
A1C 10.2%
Cr 0.6
Weight 90 kg (BMI 34)
Which of the following medication(s) should be added next?
A. Lifestyle change only, patient is very motivated
B. Liraglutide (Victoza, GLP-1 R agonist) + glipizide (SU)
C. Sitagliptin (Januvia, DPP-IV inhibitor) + canagliflozin (Invokana,
SGLT-2 inhibitor)
D. Canagliflozin (Invokana, SGLT-2 inhibitor) + Liraglutide (Victoza,
GLP-1 R agonist)

ADA/EASD Consensus Statement for Treatment of

Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 6
65 y/o female with longstanding DM2 c/b retinopathy, neuropathy and
nephropathy w/ chronic kidney disease (Cr 1.7) as well as coronary
artery disease and congestive heart failure admitted to the hospital
with CHF exacerbation and acute kidney injury, noted to have
hypoglycemia at home 3x/week.
Home regimen: glipizide 5mg bid
A1C 7.2%
Cr 2.2 (GFR 24)
Weight 80 kg (BMI 28)
Which of the following medication adjustment is most appropriate?
A.
B.
C.
D.
E.

No change necessary, A1C at goal given age and co-morbidities

Stop glipizide and start pioglitazone (Actos, TZD)
Stop glipizide and start sitagliptin (Januvia, DPP-IV inhibitor)
Stop glipizide and start canagliflozin (Invokana, SGLT-2 inhibitor)
Stop glipizide and start metformin (Glucophage, biguanide)

ADA/EASD Consensus Statement for Treatment of

Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Questions?