Surabaya

 Diabetes  &  Nutrition  Centre

 PERKIRAAN JUMLAH PENDERITA DM  TAHUN 2035

WESTERN  
PACIFIC
INCREASE
46%
In  
YEAR  2035

2
 POSISI INDONESIA DALAM JUMLAH
PENDERITA DM di DUNIA

3
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:
Ø Tighter  targets  (6.0  -­‐ 6.5%)  -­‐ younger,  healthier
Ø Looser  targets  (7.5  -­‐ 8.0%+)  -­‐ older,  comorbidities,  
hypoglycemia  prone,  etc.
- Avoidance  of  hypoglycemia

PG  =  plasma  glucose Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
 Lowering  HbA1c reduces  the  risk  of  
complications

Deaths  related  
21% to  diabetes

HbA1c
Microvascular  
37% complications
1%

Myocardial  
14% infarction

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

Stratton  IM,  e t  a l.  B MJ 2000;;  3 21:405–412.
 Impact  of  Intensive  Therapy  for  Diabetes:    
Summary  of  Major  Clinical   Trials
Study Microvasc CVD Mortality
UKPDS ê ê çè ê çè ê
DCCT  /  
EDIC*   ê ê çè ê çè çè

ACCORD ê çè é
ADVANCE ê çè çè
VADT ê çè çè
Kendall DM, Bergenstal RM. © International Diabetes Center 2009
Initial  Trial  
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. Long  Term  Follow-­‐up  
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)
 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;35:1364–1379; Diabetologia 2012;55:1577–1596

Multiple,  Complex   Pathophysiological  
Abnormalities  in  T2DM
pancreatic  
incretin insulin
effect   secretion
pancreatic  
glucagon
_ secretion
gut
carbohydrate
?
delivery  & HYPERGLYCEMIA
absorption  

+ peripheral
hepatic   renal   glucose  
glucose   glucose   uptake  
production excretion
Adapted  from:  Inzucchi SE,  Sherwin  RS  in:  Cecil  Medicine  2011  
Multiple,  Complex   Pathophysiological  
Abnormalities  in  T2DM
GLP-­1R Insulin
agonists pancreatic  
Glinides S  U  s insulin
incretin
effect   secretion
DPP-­4   Amylin pancreatic  
inhibitors mimetics glucagon
_ secretion DA  
gutA  G  I  s
carbohydrate
agonists
?
delivery  & HYPERGLYCEMIA
absorption  
Metformin T  Z  D  s
_
Bile  acid
sequestrants

+ peripheral
hepatic   renal   glucose  
glucose   glucose   uptake  
production excretion
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  à 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-­‐γ  à increase  in  
insulin  sensitivity
• pioglitazone especially  has  a  more  favourable
effect  on  major  cardiovascular  outcomes    à
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  α-­‐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 Mechanism Advantages Disadvantages Cost
Biguanides • Activates  AMP-­‐ • Extensive  experience • Gastrointestinal Low
kinase   (?other) • No  hypoglycemia • Lactic  acidosis  (rare)
• ↓ Hepatic  glucose   • Weight  neutral • Contraindications
production • ?   ↓ CVD
Sulfonylureas • Closes   KATP channels • Extensive  experience • Hypoglycemia Low
• ↑ Insulin   secretion • ↓ Microvascular risk • ↑ Weight
• Low  durability

Meglitinides • Closes   KATP channels • ↓ Postprandial   glucose • Hypoglycemia Mod.

• ↑ Insulin   secretion • Dosing   flexibility • ↑ Weight
• ?   Blunts   ischemic  
preconditioning
• Dosing   frequency

TZDs • PPAR-­‐γ activator • No  hypoglycemia • ↑ Weight   Low

• ↑ Insulin   sensitivity • Durability • Edema/heart
• ↓ TGs   (pio) failure
• ↑ HDL-­‐C   • Bone  fractures
• ↓ CVD   events (pio)
Diabetes Care 2015;38:140-149;
Table  1.  Properties   of  anti-­‐hyperglycemic  agents Diabetologia 2015;58:429-442
 Oral  Class Mechanism Advantages Disadvantages Cost
α-­‐Glucosidase • Inhibits  α-­‐glucosidase • No   hypoglycemia • Gastrointestinal Mod.
inhibitors • Slows   carbohydrate   • Nonsystemic • Dosing   frequency
digestion  /   absorption • ↓ Postprandial   glucose • Modest ↓ A1c
• ↓ CVD  events
DPP-­‐4 • Inhibits  DPP-­‐4 • No   hypoglycemia • Angioedema  /   High
inhibitors • Increases  incretin • Well  tolerated urticaria
(GLP-­‐1,  GIP)  levels • ?   Pancreatitis
• ?   ↑ Heart failure
Bile  acid • Bind   bile  acids • No   hypoglycemia • Gastrointestinal High
sequestrants • ?   ↓ Hepatic  glucose   • ↓ LDL-­‐C • Modest ↓ A1c
production • Dosing   frequency
Dopamine-­‐2 • Activates  DA receptor • No   hypoglyemia • Modest ↓ A1c High
agonists • Alters   hypothalamic   • ?   ↓ CVD  events • Dizziness,   fatigue
control  of  metabolism • Nausea
• ↑ insulin  sensitivity • Rhinitis
SGLT2 • Inhibits SGLT2  in   •↓ Weight • GU infections High
inhibitors proximal   nephron • No   hypoglycemia • Polyuria
• Increases  glucosuria • ↓ BP • Volume  depletion
• Effective at   all   stages • ↑ LDL-­‐C
• ↑Cr   (transient)
Diabetes Care 2015;38:140-149;
Table  1.  Properties   of  anti-­‐hyperglycemic  agents Diabetologia 2015;58:429-442
Injectabl Mechanism Advantages Disadvantages Cost
e
Class
Amylin • Activates  amylin • ↓ Weight • Gastrointestinal High
mimetics receptor • ↓ Postprandial   glucose • Modest ↓ A1c
• ↓ glucagon • Injectable
• ↓ gastric   emptying • Hypo  if   insulin  dose  
• ↑ satiety not   reduced
• Dosing   frequency
• Training requirements
GLP-­‐1   • Activates  GLP-­‐1  R • ↓ Weight • Gastrointestinal High
receptor   • ↑ Insulin, ↓ glucagon • No   hypoglycemia • ?   Pancreatitis
agonists • ↓ gastric   emptying • ↓ Postprandial   glucose • ↑ Heart   rate
• ↑ satiety • ↓ Some   CV  risk   factors • Medullary ca (rodents)
• Injectable
• Training   requirements
Insulin • Activates insulin   • Universally effective • Hypoglycemia Variable
receptor • Unlimited efficacy • Weight gain
• Myriad • ↓ Microvascular risk • ?   Mitogenicity
• Injectable
• Patient   reluctance
• Training   requirements
Diabetes Care 2015;38:140-149;
Table  1.  Properties   of  anti-­‐hyperglycemic  agents Diabetologia 2015;58:429-442
 Conservative  management  of  glycaemia:  Traditional  stepwise  
approach

OAD   OAD   OAD   OAD  +  

Diet   and OAD   monotherapy dual triple OAD  +   multiple  daily
exercise monotherapy up-­‐titration therapy therapy basal   insulininsulin  injections
10

9
HbA1c (%)

Majority  of  patients  (47.8%)  remain  

8
above  glycaemic targets3
HbA1c ≤  7%  ADA1
7

HbA1c ≤  6.5%  AACE2

6
OAD  =  oral  antihyperglycaemia  drug Duration  of  diabetes
Adapted  from  Campbell  IW.  Br  J  Cardiol.  2 000;7:625–631.
1.  ADA/EASD  Position  Statement,    Diabetes  Care  2 012
2.  AACE/ACE.  Endocr  Prac.  2 009;15:540–559.  3 .  Dodd  AH  et  al,  Curr  Med  Res  Opin;  2 000;  291:1605-­‐1613  
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†! dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high variable

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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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  
injectable           Insulin +
Basal Mealtime Insulin or GLP-1-RA
in  T2DM:  
therapy General  recommendations
‡!
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†! dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high variable

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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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  
injectable           Insulin +
Basal Mealtime Insulin or GLP-1-RA
in  T2DM:  
therapy General  recommendations
‡!
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†! dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high variable

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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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  
injectable           Insulin +
Basal Mealtime Insulin or GLP-1-RA
in  T2DM:  
therapy General  recommendations
‡!
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†! dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high variable

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 Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

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 GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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 Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡! Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442