Management of type 2 diabetes

(capita selecta)

Putu Moda Arsana

Brawijaya University
 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
The worldwide pandemic of
type 2 diabetes

350
300
prevalence (millions)
World wide diabetes

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.
 Prevalence of type 2 diabetes in selected populations
aged 30-64 years (Age standardised)

China
Bantu
Polynesian
Polynesian Cook Islands
White US
Black US
Hispanic US
Chinese Mauritius
Asian Indian Fiji
Pima Indian

0 10 20 30 40 50
Prevalence (%)
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

 Trends in prevalence of obesity and
overweight

70 Women Men
70

60 60

50 50

Percent
Percent

40 40

30 30

20 20

10 10

0 0
1994 1995 1996 1997 1998 1999 2000 2001 1994 1995 1996 1997 1998 1999 2000 2001

Obese (BMI over 30 kg/m2) Overweight (BMI 25-30 kg/m2)

Health Surveys for England

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
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

 Type 2 diabetes:
pathophysiology, prevention
and intervention
Pre-diabetes IGT pathophysiology
Prevention and progression studies,
DECODE
Increased Insulin resistance: muscle and
adipose tissue
Metabolic syndrome
Clear abnormalities in insulin secretion,
kinetics
Step-up to double the risk of
cardiovascular disease
Obesity and prevalence of IGT

14 300

Total no. with IGT

12
10
200
IGT (%)

8
6
100
4
2
0 0
0 .4 .9 .9 .9 .9 5 0 .4 . 9 .9 .9 .9 35
<2 -22 -24 -26 -29 -34 >3 <2 -22 -24 -26 -29 -34 >
0 5 5 7 0
20 2.5 25 27 30 2
22
. 2 2 3
2
Body mass index (kg/m2)

Lindahl et al. Diabetes Care 1999;22:1988-1992

Effect of obesity per se on insulin
resistance

2.5
p=0.028
2.0 p=0.0001

1.5 Lean
GINF
mmol/m2/min Obese
p=0.016
1.0

0.5

Normal Diabetic
Ludvik et al. Diabetes 1995;44:1121
The continuum of glucose intolerance

Type 2 Disability
Normal IGT Complications
Diabetes Death

Preclinical Clinical
state disease Complications

Primary Secondary Tertiary

prevention intervention intervention
Evolution of type 2 diabetes

Birth Death

NGT IGT DM early late

Normal Pre- Diabetes Clinical Diabetes

Late/missed diagnosis
DYSGLYCEMIA Complication-based
Glucose, lipotoxicity

When does pre-diabetes start?

Evolution of type 2 diabetes
When do complications begin?

Birth Death

NGT IGT DM early late

Normal Pre- Diabetes Clinical Diabetes

Insulin resistance Insulin resistance Insulin resistance

Kinetic defects Kinetic defects

High basal insulin Progressive loss of

insulin secretion
Delayed insulin
secretion Increased HGP

GLUCOSE TOXICITY
LIPOTOXICITY
Dual defect of type 2 diabetes: treating a
moving target

Insulin Type 2 -cell

Resistance Diabetes Dysfunction
ia
aem
In
su lyc
lin erg
Ac yp
ti o
n -cell Failure H
Insulin
Concentration

Insulin
Resistance

Euglycaemia
Normal IGT Obesity Diagnosis of Progression of
type 2 diabetes type 2 diabetes
DeFronzo et al. Diabetes Care 1992;15:318-68
Typical pathogenic features of hyperglycemia
in type 2 diabetes (2011)
Decreased incretin effect / increase
glucose absorption

Islet 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
Kinetic defects in type 2 diabetes
Postprandial hyperglycaemia

Loss of first phase insulin secretion

Delayed post-challenge insulin response: too
little, too late
Marked delay in insulin action (glucose disposal)
Delayed suppression of hepatic glucose
production
Kinetics of whole body glucose disposal

12.5
5 mM
Glucose disposal rate

10 10 mM
(mg/kg/min)

7.5
5 mM

5 T50
(min)
Lean 33
2.5 Obese 74
DM 95
0
60 120 180 240 300
Time (min)

Nolan et al. Diabetes 1997;46:994-1000

Post-UKPDS target
Sustained near-normoglycaemia

9
Conventional

8 Intensive
HbA1C (%)

Treatment
gap
7

6
0
0 3 6 9 12 15
Years from randomisation
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

Diabetes prevention
strategies
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
Screening strategies: the Finland experience

Strong tradition of disease prevention in Finland

Questionnaire identifies high-risk individuals
Initial parameters evaluated:
Family history of diabetes
Gestational diabetes
Hypertension
Mildly elevated blood glucose
Overweight or abdominal obesity

Finnish Diabetes Association (www.diabetes.fi)

 Conclusions: diabetes prevention strategies
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
Clinical endpoint and health economic data are awaited
to determine the optimal choice of intervention
A challenge for the future will be the transfer of
intervention strategies employed in trial design to
routine medical practice
Key clinical trials in diabetes
prevention
 Principal intervention trials in subjects with
impaired glucose tolerance
Study N BMI Age FPG Follow Treatment
(kg/m2) (y) (mmol/L) -up (y)
DPP1 3234 34 51 5.9 2.8 Placebo
Metformin
Intensive lifestyle
DPS2 522 31 55 6.1 3.2 Diet / exercise
Intensive diet / exercise
STOP- 1429 31 54 6.2 3.3 Diet / exercise / placebo
NIDDM3 Diet / exercise / acarbose
Da Qing4 530 26 45 5.6 6.0 Control
Diet
Exercise
Diet / exercise

1
Diabetes Prevention Program Research Group, Diabetes Care 2000;23:1619-29;
2
Tuomilehto et al. N Engl J Med 2001;344:1343-50;
3
Chiasson et al. Lancet 2002;359:2072-7;
4
Pan et al. Diabetes Care 1997;20:537-44.
Overview of the Diabetes Prevention Program

Designed to evaluate interventions that may delay or

prevent the development of diabetes in people at
increased risk for type 2 diabetes
Conducted by US National Institutes of Health in
27 centres
Measured progression from IGT to established
type 2 diabetes
Intended follow-up 36 years with study end in 2002
Terminated early in August 2001 as the study had
answered its key research question

Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

Inclusion criteria in the DPP: a high-risk
population

IGT on 75 g oral glucose tolerance test

2-h plasma glucose 140 mg/dL (7.8 mmol/L) and
< 200 mg/dL (11.1 mmol/L)
FPG 5.3 and <7.0 mmol/L (95125 mg/dL)
(no lower limit for American Indian centres)
Age 25 years
Body mass index (BMI) 24 kg/m2
( 22 kg/m2 for Asian Americans)
Aimed for ~50% minorities, ~20% aged 65 years

Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

Treatments evaluated in the DPP

3234 subjects with IGT

Metformin Placebo Intensive

+ standard lifestyle + Standard lifestyle lifestyle
advice advice
intervention
Double-blind

Open

Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

Reduced risk of type 2 diabetes vs.
placebo/standard lifestyle advice

Metformin Intensive lifestyle

0

risk (%) of
diabetes vs. -20
placebo +
standard
lifestyle -31
-40
advice p<0.01

-60 -58

p<0.01
Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403
 Subgroup analyses in the DPP
Age (y) FPG (mmol/L) BMI (kg/m2)
44 59 60 6 .1 7.0 30 <35 35
< < >
25 45 >
5. 3 6.1 22 30
0 0 0
Reduction in diabetes risk
versus placebo (%)

-20 -20 -20

-40 -40 -40

-60 -60 -60

-80 -80 -80

Intensive lifestyle intervention Metformin

Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

 Diabetes prevention with metformin in
China (1)
Normal IGT Type 2 Diabetes
100
p=0.011 (unchanged)

Placebo
Metformin
% patients

50

p=0.011

0
N=70
Duration = 12 months

Li et al. Diabet Med;16:477-81

Diabetes prevention with metformin in
China (2)
Subject NGT IGT DM Annual DM Drop Outs
Nos % % % Incidence

Control 85 27.7 37.4 34.9 11.6 2

Group

Diet + 60 28.1 47.4 24.6 8.2 3

Exercise

Acarbose 88 71.1 22.9 6.0 2 5

50 mg tid

Metformin 88 44.4 43.2 12.4 4.1 7

250 mg tid
NGT, DM, IGT defined with 1985 WHO criteria using 75 g OGGT

Wenying et al. Chin J Endocrinol Metab 2001;17:131-134

Finnish Diabetes Prevention Study (DPS)

Probability of 1.0
not having
diabetes 0.9 Lifestyle
intervention
0.8

0.7
Control
0.6
Risk Reduction 58%
0.5
0 1 2 3 4 5 6
Year
Tuomilehto et al. N Engl J Med 2001;344:1343-1349
STOP NIDDM
1.00
Acarbose risk reduction 25%
Cumulative probability

0.90

0.80
Acarbose
0.70

0.60
Placebo
0.50

0.40
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300

Days after randomisation

Chiasson J-L et al. Lancet 2002;359:2072-2077

 2003 evidence base for intervention in
high-risk IGT subjects

Intervention Country Outcome

Lifestyle intervention United States1 positive

Finland2 positive
China3,4 positive

Metformin United States1 positive

China4 positive

Acarbose China3,4 positive

Canada5 positive
1
DPP Research Group. N Engl J Med 2002;346:393-403; 2Tuomilehto et al. N Engl J Med
2001;344:1343-50; 3Li et al. Diabet Med 1999;16:477-81; 4Wenying et al. Chin J Endocrinol
Metab 2001;17:131-4; 5Chiasson et al. Lancet 2002;359:2072-7
Antidiabetic strategies to
prevent complications
An integrated approach is needed
To correct The glucotriad:
FPG, ppPG increment peaks
HbA1C
Comorbidities of the metabolic
syndrome: obesity, hypertension,
hypercoagulation

To prevent Macrovascular disease

Microvascular disease
Diabetic nephropathy
Deterioration of -cell function
and insulin sensitivity
Managing the patient uncontrolled on diet
Lifestyle first
But has it failed irrevocably already?
Some patients find it very difficult to exercise and lose
weight
Several factors can impact on choice of new therapy
Level of hyperglycaemia, age, renal function, weight,
pre-existing CV disease
Individualised approach based on pathophysiology
Evidence-based medicine only on metformin,
glibenclamide, insulin (??? acarbose ???)
National & international guidelines
Metformin reduced complications in UKPDS
Intervention to effect better control means
fewer complications
EVERY 1% Reduced Risk*
reduction in HBA1C
Deaths from diabetes - 21%

Heart attacks - 14%

Microvascular complications - 37%

1%
Peripheral vascular disorders - 43%
*p<0.0001
UKPDS 35 BMJ 2000;321:405-412
Oral antidiabetic therapy for type 2
diabetes: clinical implications

Type 2 diabetes is a multi system

disorder that required multidisciplinary
care
There are a number of agents to choose
from
More choices translate into more
complex decision making
Treatment algorithm for type 2
diabetes
Aim Diet, exercise, health education

Sulphonylurea, metformin
Glucosidase Inhibitors
Glitinides
Thiazolidinediones
Oral combinations

Insulin

Improved control Insulin plus oral agents

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
1
American Diabetes Association. Diabetes Care 1999; 22(Suppl 1):S1-S114;
2
European Diabetes Policy Group. Diabetic Medicine 1999;16:716-30;
3
American Association of Clinical Endocrinologists. Endocrine Pract (2002)
8(Suppl. 1):40-82
Choice of agents in current use

Glipizide
Acarbose
Gliclazide
Miglitol
Glimepiride Sulphonylureas Voglibose
Glibenclamide

TZDs Metformin -glucosidase

inhibitors

Meglitinides
Rosiglitazone Repaglinide
Pioglitazone Nateglinide
Site and mode of action of oral
antidiabetic medications

Site of action MOA Agents

Insulin Sulphonylureas
secretion Other insulin
secretagogues

Glucose Biguanides
production Thiazolidinediones

Slow carbohydrate -glucosidase

-
digestion inhibitors

Peripheral insulin Thiazolidinediones

sensitivity (biguanides)

DeFronzo. Ann Intern Med 1999;131:281-303

Before intervention
Diagnosis & screening
Better definition of IFG required (threshold < 6 mmol/L)
HbA1C is of no value
Support for clinical risk scoring

Guidelines & willingness to intervene

Lack of advice on treating prediabetes
GPs are more conservative than hospital specialists
Burden of treating diabetes is already too heavy
Care is not optimal, why look for more problems?
Post-intervention
Lifestyle modification
Individualised exercise programmes
Need for motivational support (diary, friends, group support)
Complementary dietary advice

Pharmacological intervention
Adjust therapy to lifestyle (need info on benefits of dual aproach)
Need better definition of lifestyle failure to start drug therapy
Role of drug therapy in children should be evaluated
Need licensed indication for drug treatment in IGT
Metformin & acarbose are suitable candidates (AE overstated)
Type 2 diabetes: treating a
moving target
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

Hyperglycaemia and complications in
type 2 diabetes

60
% Incidence/1000 patient-years

50

40 Myocardial
infarction
30
Microvascular
disease
20

10

0
<6 6-<7 7-<8 8-<9 9-<10 10+
Updated HbA1C (%)

UKPDS 35. BMJ 2000;321:405-12

 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

Cumulative % of patients
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
New et al. Diabetologia 2000;43:836-43 2IRIS study. German Diabetes Meeting 2001
1
Strategy to normalise glucose:
Prediabetes and diabetes

Education, exercise and diet

Treating insulin resistance
TREAT TO PHENOTYPE
Treating insulin deficiency
Treating the kinetic defects (secretion and
action)
Combination therapies
Barriers to achieving good glycaemic
control

Progressive severity of hyperglycaemia

Limitations of current monotherapies
Fail to target dual endocrinopathies
Dose-limiting side-effects
Fail to arrest disease progression
Clinical practice
Sub-optimal compliance with therapy
Need for multiple therapies creating polypharmacy
and compliance problems
Conclusions
We face a global pandemic of type 2 diabetes
IGT and type 2 diabetes are stages in the progression of
dysglycaemia
Interventions at the IGT stage (pharmacological or
lifestyle) may delay or prevent type 2 diabetes
Lifestyle intervention or oral antidiabetic monotherapy
control blood glucose effectively for only a short time
once type 2 diabetes is established
Early application of combination therapy improves
glycaemic control
Design regimens to overcome the barriers to effective
glycaemic control