TYPE-2 DIABETES

(Capita Selecta)

Putu Moda Arsana

FKUB, Malang 2016
EPIDEMIOLOGY
THE WORLDWIDE PANDEMIC OF
TYPE-2 DIABETES
prevalence (millions)
350
World wide diabetes

300
300

250 221

200
150
150

100

2000 2010 2025

International Diabetes Federation Diabetes Atlas 2000;

Amos et al. Diabet Med 1997;14 (Suppl 5):S1-S85.
 Top ten countries for estimated number of
adults with diabetes, 1995 and 2025
Country 1995 (millions) Country 2025 (millions)

Rank
1 India 19.4 India 57.2
2 China 16.0 China 37.6
3 U.S. 13.9 U.S. 21.9
4 Russian Fed. 8.9 Pakistan 14.5
5 Japan 6.3 Indonesia 12.4
6 Brazil 4.9 Russian Fed. 12.2
7 Indonesia 4.5 Mexico 11.7
8 Pakistan 4.3 Brazil 11.6
9 Mexico 3.8 Egypt 8.8
10 Ukraine 3.6 Japan 8.5
All other countries 49.7 103.6

Total 135.3 300.0

 REDUCTION IN LIFE EXPECTANCY
IN TYPE 2 DIABETES
Age at Marks & Krall Goodkin Panzram &
Diagnosis 1971 1975 Zabel-Langhennig
1981

10/15 (17) 27 -
15-19 16-17 23 -
20-29 12-14 16 -
30-39 10-11 11 -
40-49 8-9 10 7-8
50-59 6-7 6 5-6
60-69 4-5 5 3-4
70+ - - 3

Panzram G. Diabetologia 1987;30:123-31

THE ROLES OF RACE, CULTURE,
GENETICS, ENVIRONMENT, AND
BEHAVIOR
 Race /
Ethnicity

Culture Genetics

Diabetes
Risk
Prevalence
Outcomes

Lifestyle Health Care

Environment
 Genetics and DM
Both twin and population-based studies suggest
that T2DM has a strong genetic component

Complex interactions between a multitude of

genes.

Genes seem to be strongly influenced by

environmental and behavioral factors.

Are there specific genes that have been

identified?

Hawkes, Diabetic Medicine, 1997.

 Genetic Polymorphism and DM
Many candidates but little certainty
Genes Mechanism
Transcription factor 7-like 2 gene B-cell dysfunction (not insulin
(TCF7L2) resistance)
PPAR-gamma Insulin resistance
KCNJ11 B-cell dysfunction
CDKAL1 B-cell dysfunction
CDKN2A/B B-cell dysfunction
FTO Obesity
HHEX/IDE B-cell dysfunction
IGF2BP2 B-cell dysfunction or insulin resistance
SLC30A8 B-cell dysfunction
TCF2 B-cell dysfunction
Currently no commercially-available tests to help risk for developing T2DM
WFS1 B-cell dysfunction
Malecki, Diabetes Research and Clinical Practice, 2008.
Association of reported loci and risk for type 2
diabetes in pooled analysis of men and women

Cornelis, M. C. et. al. Ann Intern Med 2009;150:541-550

 “Obesogenic” and “Diabetogenic”
Environments
South LA has the highest
concentration of fast food
restaurants in the city

Getty Images – Los Angeles July 24th 2008

A high the ratio of fast-food and convenient stores to grocery

and produce stores is associated with higher prevalence of
both diabetes and obesity, even after controlling for
race/ethnicity, income, age, gender, and physical activity.

Auchincloss, Epidemiology. 2008.

California Center for Public Health Advocacy, April 2008, http://www.publichealthadvocacy.org/designedfordisease.html, last
accessed March 22, 2009
Does Environment affect Diabetes
Outcomes?
Diabetes patients with increased neighborhood
problems have more cardiovascular risk
In neighborhoods with
Higher rates of
more perceived problems
association smoking
•Crime
•Trash
•Lighting
Worse blood
•Traffic
pressure control

• Effect was seen even after adjusting for age, sex,

race/ethnicity, education, co-morbidities, and income
• Smoking and elevated blood pressure are strongly
associated with worse outcomes in DM
Gary, Diabetes Care, 2008.
Incidence of diabetes in men by
physical activity and BMI

BMI
Low
Middle
60 High
Case/10,000 p-yr

40

20 High
Middle
Low
0
Low Middle High
Physical activity
Helmrich. NEJM 325:147-152
THE LINK BETWEEN GENETICS
AND ENVIRONMENT
 Patho-mechanism of type-2 DM
Genetics Environment
Excess energy
intake
Insulin resistance Sedentary lifestyle

Obesity
 FFA
 Glucose

Impaired glucose tolerance

-cell failure -cell failure

Type 2 diabetes
EVOLUTION OF TYPE 2
DIABETES
 THE CONTINUUM OF GLUCOSE
INTOLERANCE

Type 2 Disability
Normal IGT Complications
Diabetes Death

Preclinical Clinical
state disease Complications

Primary Secondary Tertiary

prevention intervention intervention
IGT is driving the worldwide diabetes
pandemic
50
45
40
% of population

35 IGT
30 Undiagnosed
25 type 2 diabetes
20 Diagnosed
15 type 2 diabetes
10
5
0
20-44 45-54 55-64 65
Age (years)

Harris. Consultant. 1997;37 Suppl:S9

PATHO-MECHANISM OF
HYPERGLYCEMIA
 TYPICAL PATHOGENIC FEATURES OF
HYPERGLYCEMIA IN TYPE 2 DIABETES (2011)
Decreased incretin effect / increase
glucose absorption

Islet β cell
Increased lipolysis
and reduced
glucose uptake

Impaired
Islet  cell insulin
secretion

Increased hyperglycemia
glucagon
secretion
Increased glucose
reabsorption

Decrease glucose
uptake
Increased hepatic
glucose
production

Neurotransmitter
dysfunction
STRATEGIES TO PREVENT AND
MANAGING DYSGLYCEMIA IN
TYPE-2 DIABETES
 The continuum of glucose intolerance

Type 2 Disability
Normal IGT Complications
Diabetes Death

Preclinical Clinical
state disease Complications

Primary Secondary Tertiary

prevention intervention intervention
FACTS AROUND PREDIABETES

• Subjects with IFG or IGT are at increased risk of diabetes

and CV complications
• Landmark studies have demonstrated proof of concept that
intervention strategies can restore normoglycaemia or delay
the onset of diabetes with an acceptable risk benefit ratio
• A challenge for the future will be the transfer of intervention
strategies employed in trial design to routine medical
practice
 Diabetes prevention strategies and
outcomes
Intervention Risk
Therapy Study Reduction

Intensive lifestyle DPP, FDP 58% a

Metformin DPP 31% a
Acarbose STOP-NIDDM 25% a
Pravastatin WOSCOPS 30% a
Ramipril HOPE 34% a
Oestrogen/progesterone HERS 35% a
Intensive lifestyle XENDOS 37% b
+ Orlistat
a versus standard lifestyle advice b versus intensive lifestyle advice
 ANTIDIABETIC STRATEGIES
TO PREVENT COMPLICATIONS
Intervention to effect better control
means fewer complications
EVERY 1% Reduced Risk*
reduction in HBA1C

Deaths from diabetes

Heart attacks

Microvascular complications
1%
Peripheral vascular disorders
*p<0.0001
UKPDS 35 BMJ 2000;321:405-412
 AN INTEGRATED APPROACH IS NEEDED

To correct The glucotetrad:

FPG, ppPG, HbA1C, MAGE

Comorbidities of the metabolic

syndrome: obesity, hypertension,
hypercoagulation

To prevent Macrovascular disease

Microvascular disease
Diabetic nephropathy
Deterioration of β-cell function and
insulin sensitivity
 Glucose Tetrad Concept
Glucose fluctuations and activation of oxidative stress contribute to
progression of vascular complications

Monnier L et al. Diabetes Metab Res Rev 2009;25:393-402

 Targets for glycaemic control

HbA1C (%) FPG (mmol/L)

ADA (USA)1 <7 < 6.7 (120)*
IDF (Europe)2 < 6.5 < 6.0 (110)*
AACE (USA)3 < 6.5 < 6.0 (110)*
*mg/dL

1AmericanDiabetes Association. Diabetes Care 1999; 22(Suppl 1):S1-S114; 2European

Diabetes Policy Group. Diabetic Medicine 1999;16:716-30;
3American Association of Clinical Endocrinologists. Endocrine Pract (2002) 8(Suppl.

1):40-82
 Blocks
MECHANISM OF ACTION OF OAD Promotes

Liver Muscle
Adipose

Biguanide TZD
FFA release

GLP-1 AGONIS Circulation

DPP IV INHIBITOR Biguanide
⇓Glucose TZD
⇓FFA
FFA absorption

Glucose Intestinal lipase inhibitor

absorption

AGI Fat
Pancreas Insulin secretagogues
Carbohydrates Intestines
 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 SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
 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
Me ormin low

intolerance or 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):
contraindica on 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
HbA1c Weight gain gain neutral loss loss gain
≥9% 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

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

hyperglycemia or Insulin§ or Insulin§
(catabolic features,
BG ≥300-350 mg/dl,
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
HbA1c ≥10-12%) basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
36
Step-3 : Consider Individual
Approach
THE PROBLEM OF MANAGEMENT
TYPE-2 DM
Progressive hyperglycaemia in type 2
diabetes
9

Diet
Median HbA1C (%)

Insulin
Metformin
7
HbA1C 6.5%
(IDF & AACE goal value)
Sulphonylurea
6
0 2 4 6 8 10
Time from randomization (years)

UKPDS Group. Lancet 1998;352:854-65

LIMITED DURATION OF GLUCOSE-LOWERING
EFFICACY OF ANTIDIABETIC MONOTHERAPY

Data from overweight patients

60 Diet/exercise
% Patients attaining goal

Sulphonylurea
Metformin
Insulin
40

20

0
3 years 6 years 9 years

Duration of follow-up

Turner et al. JAMA 1999;281:2005-2

 TARGET-DRIVEN APPROACH FOR
SUSTAINED GLYCAEMIC CONTROL
+Monotherapy Insulin +/- oral agents
Diet +Combinations of
HbA1C oral agents
(%) Failure-based
9 treatment
of symptoms
approach
8
HbA1C < 7%
7 approach
ULN
6

Diagnosis +5 yrs +10 yrs + 15 years

Campbell. Br J Cardiol 2000;7:625-31

 Patients achieving glycaemic targets

Pre-UKPDS1 Post UKPDS2

UK Salford Study 1993-8 German IRIS Study 2000
60
100
Annual % of patients achieving target

n=6544 n=4575
50 90
80
40 70
61
60
30 48
50
40 32
20
30
18
20
10
10

0 0
< 7.0% < 9.0% <6.5% <7.0% <7.5% <8.0%
HbA1C HbA1C
1New et al. Diabetologia 2000;43:836-43 2IRIS study. German Diabetes Meeting 2001
Barriers
map

Patients barriers
Healthcare professional barriers
Healthcare/government barriers
Blue print for change program Perkeni 2013
 THE LANCET, 2010

Medicine might be
winning the battle of
glucose control, but is
losing the war against
diabetes
Thank You