Surabaya

Diabetes & Nutrition Centre

PERKIRAAN JUMLAH PENDERITA DM TAHUN 2035

WESTERN
PACIFIC
INCREASE
46%
In
YEAR 2035

POSISI INDONESIA DALAM JUMLAH

PENDERITA DM di DUNIA

KOMPLIKASI KRONIS DM

ADA-EASD Position Statement Update:

Management of Hyperglycemia in T2DM, 2015

GLYCEMIC TARGETS

- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])

- Pre-prandial PG <130 mg/dl (7.2 mmol/l)
- Post-prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is the key:

Tighter targets (6.0 - 6.5%) - younger, healthier

Looser targets (7.5 - 8.0%+) - older, comorbidities,

hypoglycemia prone, etc.

- Avoidance of hypoglycemia
PG = plasma glucose

Diabetes Care 2012;35:13641379; Diabetologia 2012;55:15771596

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Lowering HbA1c reduces the risk of

complications

21%

Deaths related
to diabetes

37%

Microvascular
complications

14%

Myocardial
infarction

HbA1c
1%

Stratton IM, et al. BMJ . 2000; 321:405

Stratton IM, e t a l. B MJ 2000; 3 21:405412.

Impact of Intensive Therapy for Diabetes:

Summary of Major Clinical Trials
Study

Microvasc

UKPDS

DCCT /
EDIC*

ACCORD

ADVANCE
VADT

CVD

Kendall DM, Bergenstal RM. International Diabetes Center 2009

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.
Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358:2560. DuckworthW et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024)

Mortality

Initial Trial
Long Term Follow-up

ADA-EASD Position Statement Update:

Management of Hyperglycemia in T2DM, 2015

BACKGROUND

Overview of the pathogenesis of T2DM

Insulin secretory dysfunction

Insulin resistance (muscle, fat, liver)
Increased endogenous glucose production
Decreased incretin effect
Deranged adipocyte biology

Diabetes Care 2012;35:13641379; Diabetologia 2012;55:15771596

Multiple, Complex Pathophysiological

Abnormalities in T2DM
pancreatic
insulin
secretion

incretin
effect

_
gut
carbohydrate
delivery &
absorption

pancreatic
glucagon
secretion

HYPERGLYCEMIA
_

+
hepatic
glucose
production

renal
glucose
excretion

peripheral
glucose
uptake

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple, Complex Pathophysiological

Abnormalities in T2DM
GLP-1R
agonists

Insulin
Glinides S U s

incretin
effect
DPP-4
inhibitors

Amylin
mimetics

A G I s

gut
carbohydrate
delivery &
absorption

pancreatic
insulin
secretion

pancreatic
glucagon
secretion DA

agonists

HYPERGLYCEMIA

Metformin

Bile acid
sequestrants

+
hepatic
glucose
production

renal
glucose
excretion

T Z D s

peripheral
glucose
uptake

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Natural Progression of Type 2 Diabetes May

Result in the Need for Combination Therapy
Maintaining glycemic control in patients with type 2
diabetes can be challenging due to the natural progression
of the disease1
The natural progression of type 2 diabetes may require
multiple agents with comprehensive mechanisms of
actions1
An agent of one therapeutic category may be added to an
agent of a different therapeutic category, with the
following exception2:
Agents with similar mechanisms of action may not be
effective in combination
1. Campbell IW. Diabetes. 2 000;7(10):625-6 31.
2. Kuritzky L e t al. Diabetes Ther. 2 011; 2(3):162-1 77.

Limits to getting patients to target

Limited efficacy on glycaemic control

Hypoglycaemia
Weight gain
Side effects other than weight gain or
hypoglycaemia

Sulfonylureas (glibenclamide,
gliclazide, glipizide, glimepiride)
The mechanism of action involves a direct
secretory effect on the pancreatic islet beta-
cells.
Sulphonylureas enhance insulin secretion
Hypoglycaemia can occur because these drugs
potentiate the release of insulin even when
glucose concentrations are below the normal
threshold

Biguanides (metformin)
Metformin has a variety of clinical actions that
extend beyond just the glucoselowering effects
such as weight reduction, improving lipid
profiles and vascular effects, which includes
improving endothelial function, as well as
decreasing PAI-1 levels
insulin sensitivity is improved and mediated via
modification of post-receptor signalling in the
insulin pathway.

 Metformin is quickly absorbed and fully

eliminated in the urine via tubular secretion.
Therefore it is prudent to avoid this drug in
patients with impaired renal function
Contraindications : Impairment of renal
function, conditions predisposing to hypoxia or
reduced perfusion lactic acidosis, liver
disease, alcohol abuse and a history of a
previous episode of lactic acidosis.
Drop in HbA1C levels of 1 - 2%.

Thiazolidinediones (pioglitazone,
rosiglitazone)
stimulation of a nuclear PPAR- increase in
insulin sensitivity
pioglitazone especially has a more favourable
effect on major cardiovascular outcomes
decrease in intima media thickness, an
improvement of endothelial function
Decrease in inflammatory and procoagulant
biomarkers
Effectively lower the HbA1C by 0.5 - 1.5%.

Glucosidase inhibitors
(acarbose)
The -glucosidase inhibitors inhibit the
activity of the glucosidase enzymes
Should be taken with the first bite of food
during a meal and not more than 15 minutes
after the start of the meal.
Decrease in intestinal carbohydrate
absorption
An average decrease in HbA1C of 0.5 -1.0%
can be expected

Oral Class
Biguanides

Mechanism
Activates AMP-
kinase (?other)
Hepatic glucose
production

Advantages
Extensive experience
No hypoglycemia
Weight neutral
? CVD

Disadvantages

Cost

Gastrointestinal
Low
Lactic acidosis (rare)
Contraindications

Sulfonylureas Closes KATP channels Extensive experience

Insulin secretion
Microvascular risk

Hypoglycemia
Weight
Low durability

Low

Meglitinides

Closes KATP channels Postprandial glucose

Insulin secretion
Dosing flexibility

Hypoglycemia
Weight
? Blunts ischemic
preconditioning
Dosing frequency

Mod.

TZDs

PPAR- activator
Insulin sensitivity

Weight
Edema/heart
failure
Bone fractures

Low

No hypoglycemia
Durability
TGs (pio)
HDL-C
CVD events (pio)

Table 1. Properties of anti-hyperglycemic agents

Diabetes Care 2015;38:140-149;

Diabetologia 2015;58:429-442

Oral Class

Mechanism

Advantages

Disadvantages

Cost

-Glucosidase Inhibits -glucosidase

inhibitors
Slows carbohydrate
digestion / absorption

No hypoglycemia
Nonsystemic
Postprandial glucose
CVD events

Gastrointestinal
Dosing frequency
Modest A1c

Mod.

DPP-4
inhibitors

Inhibits DPP-4
Increases incretin
(GLP-1, GIP) levels

No hypoglycemia
Well tolerated

Angioedema /
urticaria
? Pancreatitis
? Heart failure

High

Bile acid
sequestrants

Bind bile acids

? Hepatic glucose
production

No hypoglycemia
LDL-C

Gastrointestinal
Modest A1c
Dosing frequency

High

Dopamine-2
agonists

Activates DA receptor
Alters hypothalamic
control of metabolism
insulin sensitivity

No hypoglyemia
? CVD events

Modest A1c
Dizziness, fatigue
Nausea
Rhinitis

High

SGLT2
inhibitors

Inhibits SGLT2 in
proximal nephron
Increases glucosuria

Weight
No hypoglycemia
BP
Effective at all stages

GU infections
Polyuria
Volume depletion
LDL-C
Cr (transient)

High

Table 1. Properties of anti-hyperglycemic agents

Diabetes Care 2015;38:140-149;

Diabetologia 2015;58:429-442

Injectabl
e
Class

Mechanism

Advantages

Disadvantages

Cost

Amylin
mimetics

Activates amylin
receptor
glucagon
gastric emptying
satiety

Weight
Gastrointestinal
Postprandial glucose Modest A1c
Injectable
Hypo if insulin dose
not reduced
Dosing frequency
Training requirements

GLP-1
receptor
agonists

Activates GLP-1 R
Insulin, glucagon
gastric emptying
satiety

Weight
No hypoglycemia
Postprandial glucose
Some CV risk factors

Gastrointestinal
High
? Pancreatitis
Heart rate
Medullary ca (rodents)
Injectable
Training requirements

Insulin

Activates insulin
receptor
Myriad

Universally effective
Unlimited efficacy
Microvascular risk

Hypoglycemia
Weight gain
? Mitogenicity
Injectable
Patient reluctance
Training requirements

Table 1. Properties of anti-hyperglycemic agents

High

Variable

Diabetes Care 2015;38:140-149;

Diabetologia 2015;58:429-442

Conservative management of glycaemia: Traditional stepwise

approach

OAD
OAD
OAD
Diet and
monotherapy
dual
exercise monotherapy up-titration therapy

HbA1c (%)

10

OAD
triple
therapy

OAD +
OAD +
multiple daily
basal insulininsulin injections

9
8

Majority of patients (47.8%) remain

above glycaemic targets3

7
6
Duration of diabetes
OAD = oral antihyperglycaemia drug
Adapted from Campbell IW. Br J Cardiol. 2 000;7:625631.
1. ADA/EASD Position Statement, Diabetes Care 2 012
2. AACE/ACE. Endocr Prac. 2 009;15:540559. 3 . Dodd AH et al, Curr Med Res Opin; 2 000; 291:1605-1613

HbA1c 7% ADA1
HbA1c 6.5% AACE2

Healthy eating, weight control, increased physical activity & diabetes education

Monotherapy

Metformin

Efficacy*
Hypo risk
Weight
Side effects
Costs

high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Dual
therapy!
Efficacy*
Hypo risk
Weight
Side effects
Costs

Metformin

Metformin

Sulfonylurea

Thiazolidinedione

DPP-4
inhibitor

SGLT2
inhibitor

GLP-1 receptor
agonist

Insulin (basal)

high
moderate risk
gain
hypoglycemia
low

high
low risk
gain
edema, HF, fxs
low

intermediate
low risk
neutral
rare
high

intermediate
low risk
loss
GU, dehydration
high

high
low risk
loss
GI
high

highest
high risk
gain
hypoglycemia
variable

Metformin

Metformin

Metformin

Metformin

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Metformin

Triple
therapy

Sulfonylurea

+
TZD

Metformin

Thiazolidinedione

Metformin

Metformin

DPP-4
Inhibitor

+
SU

SGLT-2
Inhibitor

SU

SU

Metformin

GLP-1 receptor
agonist

Metformin

Insulin (basal)

+
TZD

SU

or

DPP-4-i

or

DPP-4-i

or

TZD

or

TZD

or

TZD

or

DPP-4-i

or

SGLT2-i

or

SGLT2-i

or

SGLT2-i

or

DPP-4-i

or

Insulin

or

SGLT2-i

or

Insulin

or

Insulin

or GLP-1-RA

or GLP-1-RA

or

or

Insulin

or GLP-1-RA

Insulin

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin

Combination
Figure
2. Anti-hyperglycemic therapy
Insulin +
Basal
injectable
!
therapy
in T2DM:
General recommendations

Mealtime Insulin or

GLP-1-RA

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Healthy eating, weight control, increased physical activity & diabetes education

Monotherapy

Metformin

Efficacy*
Hypo risk
Weight
Side effects
Costs

high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Dual
therapy!
Efficacy*
Hypo risk
Weight
Side effects
Costs

Metformin

Metformin

Sulfonylurea

Thiazolidinedione

DPP-4
inhibitor

SGLT2
inhibitor

GLP-1 receptor
agonist

Insulin (basal)

high
moderate risk
gain
hypoglycemia
low

high
low risk
gain
edema, HF, fxs
low

intermediate
low risk
neutral
rare
high

intermediate
low risk
loss
GU, dehydration
high

high
low risk
loss
GI
high

highest
high risk
gain
hypoglycemia
variable

Metformin

Metformin

Metformin

Metformin

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Metformin

Triple
therapy

Sulfonylurea

+
TZD

Metformin

Thiazolidinedione

Metformin

Metformin

DPP-4
Inhibitor

+
SU

SGLT-2
Inhibitor

SU

SU

Metformin

GLP-1 receptor
agonist

Metformin

Insulin (basal)

+
TZD

SU

or

DPP-4-i

or

DPP-4-i

or

TZD

or

TZD

or

TZD

or

DPP-4-i

or

SGLT2-i

or

SGLT2-i

or

SGLT2-i

or

DPP-4-i

or

Insulin

or

SGLT2-i

or

Insulin

or

Insulin

or GLP-1-RA

or GLP-1-RA

or

or

Insulin

or GLP-1-RA

Insulin

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin

Combination
Figure
2. Anti-hyperglycemic therapy
Insulin +
Basal
injectable
!
therapy
in T2DM:
General recommendations

Mealtime Insulin or

GLP-1-RA

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Healthy eating, weight control, increased physical activity & diabetes education

Monotherapy

Metformin

Efficacy*
Hypo risk
Weight
Side effects
Costs

high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Dual
therapy!
Efficacy*
Hypo risk
Weight
Side effects
Costs

Metformin

Metformin

Sulfonylurea

Thiazolidinedione

DPP-4
inhibitor

SGLT2
inhibitor

GLP-1 receptor
agonist

Insulin (basal)

high
moderate risk
gain
hypoglycemia
low

high
low risk
gain
edema, HF, fxs
low

intermediate
low risk
neutral
rare
high

intermediate
low risk
loss
GU, dehydration
high

high
low risk
loss
GI
high

highest
high risk
gain
hypoglycemia
variable

Metformin

Metformin

Metformin

Metformin

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Metformin

Triple
therapy

Sulfonylurea

+
TZD

Metformin

Thiazolidinedione

Metformin

Metformin

DPP-4
Inhibitor

+
SU

SGLT-2
Inhibitor

SU

SU

Metformin

GLP-1 receptor
agonist

Metformin

Insulin (basal)

+
TZD

SU

or

DPP-4-i

or

DPP-4-i

or

TZD

or

TZD

or

TZD

or

DPP-4-i

or

SGLT2-i

or

SGLT2-i

or

SGLT2-i

or

DPP-4-i

or

Insulin

or

SGLT2-i

or

Insulin

or

Insulin

or GLP-1-RA

or GLP-1-RA

or

or

Insulin

or GLP-1-RA

Insulin

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin

Combination
Figure
2. Anti-hyperglycemic therapy
Insulin +
Basal
injectable
!
therapy
in T2DM:
General recommendations

Mealtime Insulin or

GLP-1-RA

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Healthy eating, weight control, increased physical activity & diabetes education

Monotherapy

Metformin

Efficacy*
Hypo risk
Weight
Side effects
Costs

high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Dual
therapy!
Efficacy*
Hypo risk
Weight
Side effects
Costs

Metformin

Metformin

Sulfonylurea

Thiazolidinedione

DPP-4
inhibitor

SGLT2
inhibitor

GLP-1 receptor
agonist

Insulin (basal)

high
moderate risk
gain
hypoglycemia
low

high
low risk
gain
edema, HF, fxs
low

intermediate
low risk
neutral
rare
high

intermediate
low risk
loss
GU, dehydration
high

high
low risk
loss
GI
high

highest
high risk
gain
hypoglycemia
variable

Metformin

Metformin

Metformin

Metformin

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference choice dependent on a variety of patient- & disease-specific factors):

Metformin

Triple
therapy

Sulfonylurea

+
TZD

Metformin

Thiazolidinedione

Metformin

Metformin

DPP-4
Inhibitor

+
SU

SGLT-2
Inhibitor

SU

SU

Metformin

GLP-1 receptor
agonist

Metformin

Insulin (basal)

+
TZD

SU

or

DPP-4-i

or

DPP-4-i

or

TZD

or

TZD

or

TZD

or

DPP-4-i

or

SGLT2-i

or

SGLT2-i

or

SGLT2-i

or

DPP-4-i

or

Insulin

or

SGLT2-i

or

Insulin

or

Insulin

or GLP-1-RA

or GLP-1-RA

or

or

Insulin

or GLP-1-RA

Insulin

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin

Combination
injectable
therapy!

Basal Insulin +

Mealtime Insulin or

GLP-1-RA

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442