Initiating

diabetes & its

comorbidities
treatment

Maya Kusumawati
Maya Kusumawati Endocrinology & Metabolism,
FK UNPAD/RSHS FK UNPAD- RSHS
 2

Pria, 30 tahun, Pria, 50 tahun

Wanita, 70 tahun
Eksekutif Muda DMT2 sejak 5 Tahun
DMT2 sejak 25 Tahun
Baru Diketahui DMT2 Laboratorium : Kreatinin 1,8
Laboratorium : Kreatinin 1,2
Laboratorium : Normal LDL 180
Tekanan Darah : 150/90
Tekanan Darah : Normal Tekanan Darah : 160/90
Overweight
Overweight Obesitas, Sedentary

Berapa Target HbA1C dan Pilihan Terapi ?

Initiating Diabetes Treatment
and its Comorbidities

Main Learning Points

Understand the different classes of antihyperglycaemic agents (AHA) and

when to use which AHAs either as monotherapy or in combination with
other AHAs

Understand to manage dyslipidemia and hypertension in DM patients

Natural History of Type II Diabetes Mellitus
Years from -10 -5 0 5 10 15
diagnosis
Onset Diagnosis

Insulin resistance
Insulin secretion

Postprandial
glucose
Fasting glucose Microvascular complications
Macrovascular complications
Pre-diabetes Type II diabetes

Sources:!
Ramlo-Halsted BA et al. Prim Care. 1999;26:771-789
Nathan DM et al. NEJM 2002;347:1342-1349
 Normoglycemia
Beta cell Muscle and fat
produces
Islet insulin

NORMAL
Glucose Homeostasis

Liver
Alpha cell
produces FASTING INPUT NUTRISI
glucagon

5
 6
TYPE 2 DM
Diminished
insulin Normoglycemia
Hyperglycemia
Beta
cell Muscle and fat
produces
insulin
Insulin resistance
(decreased glucose uptake)
Glucose Homeostasis

Liver
Alpha
cell
produces Excess glucose output
glucagon INPUT NUTRISI
Pathogenesis T2DM - The Ominous Octet
GLP1
TZDs Islet -cell TZDs
GLP1
SU
Decreased
Incretin Effect
Increased
Impaired Lipolysis
Insulin Secretion

Islet -cell
GLP1
SGLT2
DPP4

Increased Increased Glucose

Glucagon Secretion Reabsorption

TZDs
Increased
HGP
GLP1
Neurotransmitter MET
Decreased Glucose
TZDs Dysfunction Uptake
MET GLP1
DeFronzo RA. Banting Lecture 2008. From the triumvirate to the ominous octet: a
GLP1 Bromocriptine new paradigm for the treatment of type 2 diabetes mellitus.
 Antihyperglycemic Agents
Class Primary Mechanism of Action Agent(s) Available as

Acarbose Precose or generic

-Glucosidase inhibitors Delay carbohydrate absorption from intestine
Miglitol Glyset

Decrease glucagon secretion!

Amylin analogue Slow gastric emptying! Pramlintide Symlin
Increase satiety
Decrease HGP!
Biguanide Metformin Glucophage or generic
Increase glucose uptake in muscle
Decrease HGP?!
Bile acid sequestrant Colesevelam WelChol
Increase incretin levels?

Alogliptin Nesina
Increase glucose-dependent insulin secretion! Linagliptin Tradjenta
DPP-4 inhibitors
Decrease glucagon secretion Saxagliptin Onglyza
Sitagliptin Januvia

Dopamine-2 agonist Activates dopaminergic receptors Bromocriptine Cycloset

Nateglinide! Starlix or generic!

Glinides Increase insulin secretion
Repaglinide Prandin
DPP-4 = dipeptidyl peptidase; HGP = hepatic glucose production.
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
 9

Class Primary Mechanism of Action Agent(s) Available as

Increase glucose-dependent insulin secretion! Albiglutide! Tanzeum!

Decrease glucagon secretion! Dulaglutide! Trulicity!
GLP-1 receptor
Exenatide! Byetta!
agonists Slow gastric emptying!
Exenatide XR! Bydureon!
Increase satiety Liraglutide Victoza

Canagliflozin! Invokana!
SGLT2 inhibitors Increase urinary excretion of glucose Dapagliflozin! Farxiga!
Empagliflozin Jardiance
! !
Glimepiride! Amaryl or generic!
Glipizide! Glucotrol or generic!
Sulfonylureas Increase insulin secretion
Glyburide Diaeta, Glynase,
Micronase, or generic

Increase glucose uptake in muscle and fat! Pioglitazone! Actos!

Thiazolidinediones
Decrease HGP Rosiglitazone Avandia

GLP-1 = glucagon-like peptide; HGP = hepatic glucose production; SGLT2 = sodium glucose cotransporter 2.
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Effects of AHA
Met GLP1RA SGLT2I DPP4I TZD AGI Coles BCR-QR SU/ Glinide Insulin Pram

Mod to
SU: mod! marked
FPG Mild to
Mod Mod Mild Mod Neutral Mild Neutral Glinide: (basal Mild
lowering mod*
mild insulin or
premixed)

Mod to
marked
PPG Mod to (short/ Mod to
Mild Mild Mod Mild Mod Mild Mild Mod
lowering marked rapid-acting marked
insulin or
premixed)

AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; FPG =
fasting plasma glucose; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; Mod = moderate; PPG = postprandial glucose;
SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones.
*Mild: albiglutide and exenatide; moderate: dulaglutide, exenatide extended release, and liraglutide.
 BCR- SU/
Met GLP1RA SGLT2I DPP4I TZD AGI Coles Insulin Pram
QR Glinide

NAFLD benefit Mild Mild Neutral Neutral Mod Neutral Neutral Neutral Neutral Neutral Neutral

SU: mod
to severe!
Mod to
Hypo-glycemia Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral Glinide: Neutral
severe*
mild to
mod

Slight
Weight Loss Loss Neutral Gain Neutral Neutral Neutral Gain Gain Loss
loss

AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; GLP1RA =
glucagon-like peptide 1 receptor agonists; Met = metformin; Mod = moderate; NAFLD, nonalcoholic fatty liver disease; SGLT2I = sodium-glucose
cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones.
*Especially with short/ rapid-acting or premixed.
Continued from previous slide
 Met GLP1RA SGLT2I DPP4I TZD AGI Coles BCR-QR SU/ Glinide Insulin Pram

Dose Increased
Contrain Exenatid
adjust- May Increased risks of
Renal dicated e contra- GU
ment worsen hypo- hypo-
impairment/ in stage indicated infection Neutral Neutral Neutral Neutral
(except fluid glycemia glycemia
GU 3B, 4, 5 CrCl <30 risk
lina- retention risk and fluid
CKD mg/mL
gliptin) retention

GI adverse
Mod Mod* Neutral Neutral* Neutral Mod Mild Mod Neutral Neutral Mod
effects

CHF Neutral Neutral Neutral Neutral Mod Neutral Neutral Neutral Neutral Neutral Neutral

Possible
CVD Neutral Neutral Neutral Neutral Neutral Neutral Safe ? Neutral Neutral
benefit

Mod bone
Bone Neutral Neutral Bone loss Neutral Neutral Neutral Neutral Neutral Neutral Neutral
loss

AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; CHF = congestive heart failure; CVD = cardiovascular
disease; DPP4I = dipeptidyl peptidase 4 inhibitors; GI = gastrointestinal; GLP1RA = glucagon-like peptide 1 receptor agonists; GU = genitourinary;
Met = metformin; Mod = moderate; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones.
*Caution in labeling about pancreatitis.
Caution: possibly increased CHF hospitalization risk seen in CV safety trial.
Profiles of AHA
 Factors to consider when choosing an antihyperglycaemic
agent

Effectiveness in lowering glucose

Safety profile

Tolerability

Cost

Effect on body weight

Other effects (e.g. reduced cardiovascular outcomes with

metformin, empagliflozin)

Nathan DM et al. Management of Hyperglycemia in type 2 Diabetes, a consensus algorithm for the initiation and adjustment of
therapy, a consensus statement from ADA/EASD. Diabetes Care 2006;29(8):1963-72.
 ADA/EASD treatment algorithm

American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes
Care 2015;38(Suppl. 1):S41S48
ABCDHH
COST &
EFFECTIVENESS
Danish treatment guidelines for type 2
diabetes
HbA1c target value is individual
!
HbA1c <48 mmol/mol (6.5%) in the first years, where hypos
are of little concern. Aims to reduce complications
!
HbA1c <53 mmol/mol (7.0%) in later phases, balancing
between hypos and the risk for microvascular complications
!
HbA1c <58 mmol/mol (7.5%) in long-term patients with
hypos and macrovascular complications (ischaemic heart disease,
peripheral arterial disease, and stroke)
!
HbA1c 58-75 mmol/mol (7.5 - 9.0%) in elderly patients in
Antihyperglycaemic agents that are
currently available in Indonesia
Metformin

Sulfonylureas (SUs) and glinides

-glucosidase inhibitors (AGIs)

Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)

Glucagon-like peptide-1 (GLP-1) agonists

Thiazolidinediones (TZDs)
Diabetes and the elderly
of any AHA
Always start with the lowest dose
Increase gradually
Hypoglycaemia may increase the
risk of falls and heart attack in
elderly
Use shorter-acting AHA to reduce
the risk of hypoglycaemia
Remember the possibility of
Forgetfulness
Poor motivation
Depression
Cognitive deficits
Polypharmacy
Reduced manual dexterity
These factors affect the ability to
maintain self-care and achieve maximum
benefits from AHAs
 Initiating diabetes treatment

Summary Main Learning Points

Metformin is usually the first drug of Understand the different classes of

choice antihyperglycaemic agents (AHA) and
Personalized initiation and when to use which AHAs either as
intensification of AHAs depending on monotherapy or in combination with
the needs of the individual patient other AHAs
Diabetes, hypertension and dyslipidaemia
Triangular Focus Treatment Implications

40-60% of type 2 diabetes

patients will also have either
hypertension, dyslipidaemia or
Diabetes both
Hypertension and dyslipidaemia
are both well established risk
factors for diabetes-related
complications like CVD and
Dyslipidaemia Hypertension nephropathy
Early and correct treatment of
hypertension and dyslipidaemia
can delay the onset of diabetes
complications
UKPDS 38. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 Diabetes. BMJ.
1998;317:703-713.
 Recommendations by the Eight Joint National Committee
(JNC 8)

Patient Subgroup Target systolic BP Target diastolicBP

(mmHg) (mmHg)
60 years < 150 < 90
< 60 years < 140 < 90
> 18 years with CKD < 140 < 90
> 18 years with Diabetes < 140 < 90

CKD = Chronic Kidney Disease, BP = Blood Pressure

James PA et al. 2014 Guideline for Management of High Blood Pressure. JAMA. 2014: 311(5): 507-520
Diabetes increases cardiovascular risk in patients with hypertension
Systolic BP and cardiovascular mortality

Stamler J, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor
Intervention Trial. Diabetes Care. 1993;16(2):434444.
Lowering blood pressure is beneficial for diabetes patients with hypertension
Hypertension Optimal Treatment (HOT) Trial

Hansson L, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertnsion, HOT
Randomised Trial. Lancet. 1998;351: 1755-1762.
 ADA Recommendations on hypertension 2016
Systolic Blood Pressure <140 mmHg, depending on
patient characteristics and response to therapy.
Lower SBP targets, such as <130 mmHg may be
appropriate for certain individual such as younger
patients and those with albuminuria if they can be
achieved without undue treatment burden.

SBP >120 mmHg SBP > 140 mmHg

or DBP >80 mmHg or DBP > 90 mmHg

Advise on lifestyle Pharmacological

changes therapy in addition
to lifestyle therapy
Years
ADA - Standards of Medical Care in Diabetes 2016. Diabetes Care, Vol. 39, Supplement 1, January 2016.
Most relevant drugs that are indicated for hypertension
patients with diabetes

Source: JNC 7 Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004
Dyslipidaemia in diabetes
Total cholesterol

LDL cholesterol

HDL cholesterol

Triglyceride
 Meta-analysis of statin treatment in
diabetes
Risk reduction of clinical outcomes per 40 mg/dL
(1.0 mmol/L) reduction in LDL cholesterol:
!
All-cause mortality 9%
CVD mortality 13 %
Major vascular events 21 %
Stroke 21 %
Coronary revascularisation 25 %
No difference in non-vascular mortality
Independent of baseline LDL or prior CVD
Lancet. Efficacy of cholesterol-lowering therapy in 19.686 people with diabetes in 14 randomised trials of statins (meta-analysis).
371, 117-25, 2008.
 Statin treatment in diabetes
ADA 2016 recommendations

ADA - Standards of Medical Care in Diabetes 2016. Diabetes Care, Vol. 39, Supplement 1, January 2016.
Panduan Pengelolaan Dislipidemia di Indonesia (PERKENI) - 2015
 Diabetes and its comorbidities Hypertension and dyslipidaemia
Lecture
Summary
Hypertension should be treated to
prevent diabetes-associated
complications
Control lipid profile to prevent
cardiovascular event in diabetes
Target of LDL-cholesterol in diabetes:
No CVD : < 100 mg/dL
Prior CVD or high risk : < 70 mg/
dL
Main learning points
Understand the relationship between
diabetes and hypertension
Know how to treat hypertension in
diabetes patients
Understand the relationship between
diabetes and dyslipidaemia
Know how to treat dyslipidaemia in
diabetes patients
 34

Pria, 30 tahun, Pria, 50 tahun

Wanita, 70 tahun
Eksekutif Muda DMT2 sejak 5 Tahun
DMT2 sejak 25 Tahun
Baru Diketahui DMT2 Laboratorium : Kreatinin 1,8
Laboratorium : Kreatinin 1,2
Laboratorium : Normal LDL 180
Tekanan Darah : 150/90
Tekanan Darah : Normal Tekanan Darah : 160/90
Overweight
Overweight Obesitas, Sedentary

Berapa Target HbA1C dan Pilihan Terapi ?

Don`t Forget To..
Do your part
!
Protect their heart

Multifaceted approach
+
Individualize therapy
 36

THANK YOU