Prevention Of Diabetes “A Dream” Or “A Reality”

Prevention Of Diabetes

“A Dream” Or “A Reality”By

Professor

Dr Intekhab AlamDepartment of Medicine

Postgraduate Medical Institute,Lady Reading Hospital, Peshawar

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The worldwide pandemic oftype 2 diabetes

International Diabetes Federation Diabetes Atlas 2000; Amos et al. Diabet Med 1997;14 (Suppl 5):S1-S85.

Estimated Growth in the Prevalence of Diabetes 1994-2010

Estimated Growth in the Prevalence of Diabetes 1994-2010

0

50

100

150

200

250

300

Africa Asia Russia L. Amer. Europe Pacific N.Amer.

Per

cen

t In

crea

se

McCarty, Zimmet 1994

25-34 0 2.3

35-44 0.7 4.9

45-54 3.0 6.3

55-64 4.012.5

65-74 6.110.7

» Newcastle Unwin et al

Association of Age & Diabetes

Age distribution Caucasians S.Asian

WPR-IDF, Beijing May 2002

Reduction in life expectancy in type 2 diabetes

Age atDiagnosis

10/1515-1920-2930-3940-4950-5960-6970+

Marks & Krall1971

(17)16-1712-1410-11

8-96-74-5-

Goodkin1975

272316111065-

Panzram &Zabel-Langhennig

1981

----

7-85-63-43

Panzram G. Diabetologia 1987;30:123-31

Preclinical state

Normal IGT

Clinical disease

Type 2Diabetes

Disability Death

Complications

Complications

Primaryprevention

Secondaryintervention

Tertiaryintervention

The continuum of glucose intolerance

2-h plasma glucose (mmol/L)

FP

G (

mm

ol/L

)

7.8 11.1

6.1

7.0

NGT

IFG

IGT

IGT/IFG

Type 2 Diabetes

Classification of glucose intolerance

approximately 1 in 7 people aged over 40 years have impaired glucose tolerance (IGT)

IFG IGT IFG + IGTType 2

diabetes

Normal glucose tolerance

1.3 3.9 0.5 0.6

IFG - 3.7 6.5 2.4

IGT - - 0.9 2.7

IFG + IGT - - - 9.9

Progression to type 2 diabetes

Annual rates of progression to moresevere forms of glucose intolerance

Koehler et al. Diabetologia 2001;44 Suppl 1:A108

Harris. Consultant. 1997;37 Suppl:S9

IGT

Undiagnosedtype 2 diabetes

Diagnosedtype 2 diabetes

504540353025201510

5020-44 45-54 55-64 65

Age (years)

% o

f p

op

ula

tio

n

IGT is driving the worldwide diabetes pandemic

OBESITY is the driving force behind IGT

Prevalence of OBESITY is reaching epidemic proportions worldwide. In USA 50% of the population is overweight while 20-22% is obese.

A person with a BMI of 30 carries 5 times higher risk of developing diabetes than a person with a normal BMI.

0

2

4

6

8

10

12

14

<20

20-2

2.4

22.5

-24.

9

25-2

6.9

27-2

9.9

30-3

4.9>3

5

IGT

(%

)

0

100

200

300

<20

20-2

2.4

22.5

-24.

9

25-2

6.9

27-2

9.9

30-3

4.9

>35

To

tal

no

. w

ith

IG

T

Body mass index (kg/m2)

Obesity and prevalence of IGT

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

IGT and risk of diabetes

0 1 2 3 4 5 6 7 8 9 10

Triglycerides >2.5 mmol/l (221 mg/dl)

Impaired glucose tolerance

Highest quartile 2-hour insulinHighest quartile fasting insulin

HDL <1 mmol/l (39 mg/dl)

Waist-hip ratio >1.0BMI >30 gm-2

HypertensionFamily history of diabetes

Mykkanen et al (1993)

Relative risk of developingdiabetes ( 95% CI)

Consequences of IGT

All cause mortality is 1.96 times higher than in people with normal glucose tolerance

Mortality per 1000 person-years is 20.8 for IGT as compared to 40.9 with DM.

40-50% of adults with IGT will develop type 2 diabetes within ten years.

IGT clusters with other and is itself a CV risk factor.

Whom and when to screen for IGT

Individuals >45 yrs of age especially who have BMI of >25 kg/m2.

Individuals <45 with BMI >30 or who have one or more of the following risk factors:+ive family history,LowHDL, high TG, HTN, h/o GDM, Infant birth wt >9lbs, belonging to noncaucasian group.

‘Risk Factors’ for Type 2 Diabetes

CENTRAL CENTRAL OBESITYOBESITY

GENETIC FACTORSGENETIC FACTORS- Ethnicity- Ethnicity- Family history - Family history (40%)(40%)

INCREASING INCREASING AGEAGE

GESTATIONAL GESTATIONAL DIABETES DIABETES

AND PARITYAND PARITY

PHYSICAL PHYSICAL INACTIVITYINACTIVITY

Primary Prevention in Diabetes

Williams G, Pickup JC. Handbook of Diabetes. 2nd Edition, Blackwell Science. 1999.

Strategies In Prevention Of Diabetes

Intensive lifestyle counseling

Pharmacotherapy:Established antidiabetic agents:

Metformin, Acarbose, GlitazonesACE inhibitors and ARBs

Ramipril, Losartan, Valsartan, Candesarttan

PROSPECTIVE TRIALS OF DIABETES PREVEENTION

1. Da Qing Impaired Glucose Tolerance and Diabetes Study

2. The Finnish Study(DPS)

3. The Diabetes Prevention Program(DPP)

4. Troglitazone in Prevention of Diabetes(TRIPOD)

5. Study to prevent NIDDM (STOP-NIDDM)

6. Xenical in the Prevention of Diabetes in Obese Subjects(XENDOS)

Da Qing impaired glucose tolerance and Diabetes study

Number of patients: 577 with IGTMean BMI: <25 vs >25 kg/m2

Major intervention: control vs diet only vs exercise only vs both

Average follow up: 6 yrs.Conclusion:Incidence of diabetes:

control group 67.7%, Diet only 43.8%, Exercise only 41.1% and 46% in both intervention (p<0.05)26.3% in <25 and 51.1% in >25 BMI subjects

The Finnish study(DPS)

Number of patients: 522 with IGTMean age: 55Mean BMI: 31 kg/m2

Major intervention: Intensive lifestyle counseling.

Average follow up: 3.2 yrs.Relative risk reduction: 58% with

ILSC (incidence of DM in control group 23% vs 11% in Intensive Group)

NNT: 22 for one yr and 5 for 5yrs

The Diabetes Prevention Program(DPP)

Number of patients: 3,234 with IGTMean age: 51Mean BMI: 34 kg/m2

Major intervention: Intensive LSC vs Metformin+ standard LSC vs Placebo+standard LSC

Average follow up: 2.8 yrs.Relative risk reduction: 58% with ILSC

31% with Metformin

NNT: 7 for ILSC and 14 for Metformin for 3yrs

Troglitazone in Prevention of Diabetes(TRIPOD study)

Number of patients: 235 with GDMMajor intervention: Troglitazone vs PlaceboAverage follow up: 2.6 yrs.

Relative risk reduction: 56% with Troglitazone

Study was dropped following withdrawal of the drug from the market in 1998

Study to Prevent- NIDDM(STOP-NIDDM trial)

Number of patients: 1429 with IGTMean age: 55Mean BMI: 31 kg/m2

Major intervention: Acarbose vs Placebo

Average follow up: 3.3 yrs.Relative risk reduction: 32% for DM and

34% for HTNNNT: 11 cases for 3.3yrs

Xenical in Prevention of Diabetes in Obese Subjects(XENDOS)

Number of patients: 3305 with obesity79% with normal and 21% with IGT

Mean BMI:30 kg/m2

Major intervention: Orlistat 120mg TDSObjective: To see the effect of Orlistat on

the progression of diabetesAverage follow up: 4 yrs.

Relative risk reduction: 37% in all (p=0.0032) ,45% in IGT subjects (p=0.0024)

TRIALS SHOWING A REDUCTION IN THE DEVELOPMENT OF DIABETES

1. The Heart Outcomes Prevention Evaluation(HOPE).

2. Losartan Intervention for Endpoint(LIFE) Reduction in Hypertension Study

3. West of Scotland Coronary Prevention Study(WOSCOPS).

4. The Heart and Estrogen/Progestin Replacement Study(HERS).

5. Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity(CHARM}

The Heart Outcomes Prevention Evaluation (HOPE)

Number of patients: 9297 with high risk of vascular disease

Mean age: 55 or olderMajor intervention: Ramipril 10mgPrimary endpoint: composite outcome of

Stroke, MI or cardiovascular death.Average follow up: 4.5 yrs.Post hoc analysis of 5270 nondiabetic

subjects revealed a 34% lower rate of newer diabetes in treated group(p<0.001).

Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study

Number of patients: 9193 with HTN & LVH.Mean age: 55-80Objectives: to assess the ability of

Losartan to reduce cardiovascular morbidity and mortality.

Intervention: Losartan vs Atenolol

In 7998 nondiabetic subjects Losartan reduced the new onset of diabetes by 25% as compared to Atenolol (p=0.001)

West of Scotland Coronary Prevention Study(WOSCOPS)

Number of patients: 5974 with h/o MIMean age: 45-65Objective: to assess cardiovascular

eventsIntervention: Pravastatin vs Placebo

30% reduction in the development of diabetes with Pravastatin compared to placebo

The Heart and Estrogen/Progestron

Replacement Study (HERS)

Number of patients: 2763 postmeno-

pausal womenIntervention: Combination of conjugated

estrogen and progesteron vs placebo.Primary endpoint: Occurrence of CHD

Average follow up: 4.1 yrs.Conclusion: no reduction in CHD. Out of

2029 nondiabetic women a 35%(p=0.006) risk reduction for the development of DM was noted with an NNT of 30 for 4 yrs.

Cadesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity

(CHARM)

Number of patients: 7601 with CHF Intervention: Candesartan Primary endpoint: CHF hospitalization

or CV death Average follow up: 3.2 yrs Conclusion: Significant reduction in

CHF hospitalization(p<0.0001). 22% reduction in new-onset DM.

TRIALS IN PROGRESS

1. The Early Diabetes Prevention Trial (EDIT).

2. Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication(DREAM).

3. Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR).

The Early Diabetes Intervention Trial (EDIT)

Number of patients: 631 with IGTIntervention: Acarbose vs Metformin vs

combination of A+M vs Placebo Primary endpoint: Occurrence of DMAverage follow up: 6 yrs.

Interim results: at 3 yrs 522 subjects have remained in the trial showing an 8% risk reduction with Acarbose(p=0.12) and 37% for Metformin(p=0.17)

Expected follow up for 6 yrs.

Diabetes Reduction Assessment with Ramipril

and Rosiglitazone Medication(DREAM)

Number of patients: 4000 with IGTIntervention: Combination of Ramipril and

Rosiglitazone vs placeboPrimary endpoint: new onset DM or

all-cause mortalityAverage follow up: 3 yrs.

Ongoing trial, results expected in April 2007.

Nateglinide and Valsartan in Impared

Glucose Tolerance Outcomes Research (NAVIGATOR)

Number of patients: 7500 with IGT Intervention: Valsartan vs Nateglinide Primary endpoint: new onset DM or CV events

and all-cause mortalityAges of the participants: 50 yrs or older with CVD

55 yrs or older with risk factors for CVD

Average follow up: 5-6 yrs.

Ongoing trial (results in 2006-7)

Diabetes Prevention Strategies And Outcomes

INTERVENTION

Intensive lifestyleMetforminAcarbose

PravastatinRamiprilEstrogen/progesteroneILSC + OrlistatTroglitazoneLosartanCandesartanRosiglitazoneNatiglinide &Valsartan

STUDY

DPP, FDPDPP,EDITSTOP-NIDDM, EDITWOSCOPSHOPE,DREAMHERSXENDOSTRIPODLIFECHARMDREAMNAVIGATOR

RR

58% a

31% a

25% a

ongoing30% a

34% a

35% a

37%56% 25%22%

ongoingongoing

a versus standard lifestyle advice b versus intensive lifestyle advice

Metformin: the foundation oral therapy that offers prevention

of type 2 diabetes and its complications

Clinical outcome benefits with Metformin

Prevention of complications

Patients allocated to metforminn=342

Metformin

dosing

protocol

850 mg

1700 mg

2550 mg

Follow up 6-20 yearsMedian 10 years

UKPDS 34. Lancet 1998;352:854-65

Patients randomised to Metformin in theUK Prospective Diabetes Study

Diabetes-related deaths

All-cause mortality

Any diabetes-related

endpoint

Myocardial infarction

Stroke

*Compared with conventional therapy (overweight group)

Change in risk*

42%

36%

32%

39%

41%

P value

0.017

0.011

0.0023

0.01

0.13

Change in risk*

20%

8%

7%

21%

14%

P value

0.19

0.49

0.46

0.11

0.60

MetforminIntensive (n=342)

Sulphonylurea / InsulinIntensive (n=951)

UKPDS 34. Lancet 1998;352:854-65

Benefits beyond blood glucose controlwith metformin in the UKPDS

Clinical outcomes for metforminin the UKPDS

Myocardialinfarction StrokeDiabetes deaths

42% 39% 41%

Median dose = 2550 mg/day

UKPDS 34. Lancet 1998;352:854-65

Risk reductions from intervention studies in type 2 diabetes

Clinical Outcomes

Diabetes-related deaths (%)

All-cause mortality (%)

All MI (%)

Fatal MI (%)

All stroke (%)

Fatal stroke (%)

Follow-up (years)

UKPDSSU/Ins

n=3867

10

6

16

6

(+)11

(+)17

10.7

UKPDSCaptoprilAtenololn=1148

32

18

21

28

44

58

8.4

HOPERamipril

n=3577

37

24

22

-

33

-

4.5

HOTFelodipine

Aspirinn=1501

67

43

51

-

30

-

3.8

4SSimva-statinn=202

36

43

55

-

62

-

5.4

UKPDSMetformin

n=753

42

36

39

50

41

25

10.7

Optimising the dose of Metformin

Prevention of complications

0

1000

2000

3000

Austria Ita

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Belgiu

mUSA

Germ

any

Switzer

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Portugal UK

Spain

France

Metformin is frequently under-dosedM

etfo

rmin

do

sag

e (m

g/d

ay) Metformin dose in the UKPDS

Metformin dose in clinical practice

Scarpello. Br J Diabetes Vasc Dis 2001;1:28-36

Optimising metformin dosage: evidence-based conclusions

Glycaemic benefits

Clinical benefits

Tolerance and safety

Metformin daily dosage (mg)

500

1000

1500

2000

2500

3000

850

1700

2550

Metformin: foundation therapy for prevention of type 2 diabetes and its complications

Reduced morbidity and mortality in the UKPDS

Unique reduction of cardiovascular complications beyond that expected from blood glucose control

IDF and ADA guidelines favour the use of metformin as foundation therapy for type 2 diabetes where possible

The antihyperglycaemic efficacy of metformin is dose-related with an optimal daily dose of 2000 mg/day

Metformin is well tolerated across its dosage range

Gastrointestinal side-effects are usually transient

Minimised by slow dosage titration

Only about 5% of patients cannot tolerate metformin

Proven to prevent or delay type 2 diabetes (DPP)

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.

Failure to identify IGT meant that there was a “missed opportunity to prevent diabetes.”

Conclusion

"Every year a person can live free of diabetes means an added year of life free of the pain, disability, and

medical costs incurred by this disease"

Benefits of diabetes prevention for patients