Prevention Of Diabetes

1
Prevention Of DiabetesA Dream Or A Reality

• By
• Professor
• Dr Intekhab Alam
• Department of Medicine
• Postgraduate Medical Institute,
• Lady Reading Hospital, Peshawar

2
The worldwide pandemic oftype 2 diabetes
World wide diabetesprevalence (millions)
2000
2010
2025
International Diabetes Federation Diabetes Atlas
2000 Amos et al. Diabet Med 199714 (Suppl
5)S1-S85.
3
Estimated Growth in the Prevalence of Diabetes
1994-2010
McCarty, Zimmet 1994
4
Association of Age Diabetes
Age distribution Caucasians
S.Asian

• 25-34 0 2.3
• 35-44 0.7 4.9
• 45-54 3.0 6.3
• 55-64 4.0 12.5
• 65-74 6.1 10.7
• Newcastle Unwin et al

WPR-IDF, Beijing May 2002
5
Reduction in life expectancy in type 2 diabetes
Panzram G. Diabetologia 198730123-31
6
The continuum of glucose intolerance
Type 2 Diabetes
Disability Death
Complications
Normal
IGT
Preclinical state
Clinical disease
Complications
Secondary intervention
Tertiary intervention
Primary prevention
7
Classification of glucose intolerance
2-h plasma glucose (mmol/L)
11.1
7.8
NGT
IGT
6.1
IFG
IGT/IFG
FPG (mmol/L)
7.0
Type 2 Diabetes
approximately 1 in 7 people aged over 40 years
have impaired glucose tolerance (IGT)
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Progression to type 2 diabetes
Annual rates of progression to moresevere forms
of glucose intolerance
IFG IGT IFG IGT Type 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
Koehler et al. Diabetologia 200144 Suppl 1A108
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IGT is driving the worldwide diabetes pandemic
50 45 40 35 30 25 20 15 10 5 0
IGT
Undiagnosedtype 2 diabetes
of population
Diagnosedtype 2 diabetes
20-44
45-54
55-64
?65
Age (years)
Harris. Consultant. 199737 SupplS9
10

• 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.

11
Obesity and prevalence of IGT
Body mass index (kg/m2)
Lindahl et al. Diabetes Care 1999221988-1992
12
IGT and risk of diabetes
Impaired glucose tolerance
Highest quartile 2-hour insulin
Highest quartile fasting insulin
Triglycerides gt2.5 mmol/l (221 mg/dl)
HDL lt1 mmol/l (39 mg/dl)
Waist-hip ratio gt1.0
BMI gt30 gm-2
Hypertension
Family history of diabetes
Relative risk of developingdiabetes (? 95 CI)
Mykkanen et al (1993)
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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.

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Whom and when to screen for IGT

• Individuals gt45 yrs of age especially who have
  BMI of gt25 kg/m2.
• Individuals lt45 with BMI gt30 or who have one or
  more of the following risk factors
• ive family history,LowHDL, high TG, HTN, h/o
  GDM, Infant birth wt gt9lbs, belonging to
  noncaucasian group.

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Primary Prevention in Diabetes
Risk Factors for Type 2 Diabetes
GENETIC FACTORS - Ethnicity - Family history
(40)
GESTATIONAL DIABETES AND PARITY
CENTRAL OBESITY
INCREASING AGE
PHYSICAL INACTIVITY
Williams G, Pickup JC. Handbook of Diabetes. 2nd
Edition, Blackwell Science. 1999.
16
Strategies In Prevention Of Diabetes

• Intensive lifestyle counseling
• Pharmacotherapy
• Established antidiabetic agents
• Metformin, Acarbose, Glitazones
• ACE inhibitors and ARBs
• Ramipril, Losartan, Valsartan, Candesarttan

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• 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)

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Da Qing impaired glucose tolerance and Diabetes
study

• Number of patients 577 with IGT
• Mean BMI lt25 vs gt25 kg/m2
• Major intervention control vs diet only vs
  exercise only vs both
• Average follow up 6 yrs.
• ConclusionIncidence of diabetes control group
  67.7, Diet only 43.8, Exercise only 41.1 and
  46 in both intervention (plt0.05)
• 26.3 in lt25 and 51.1 in gt25 BMI subjects

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The Finnish study(DPS)

• Number of patients 522 with IGT
• Mean age 55
• Mean 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

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The Diabetes Prevention Program(DPP)

• Number of patients 3,234 with IGT
• Mean age 51
• Mean BMI 34 kg/m2
• Major intervention Intensive LSC vs Metformin
  standard LSC vs Placebostandard 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

21
Troglitazone in Prevention of Diabetes(TRIPOD
study)

• Number of patients 235 with GDM
• Major intervention Troglitazone vs Placebo
• Average follow up 2.6 yrs.
• Relative risk reduction 56 with Troglitazone
• Study was dropped following withdrawal of the
  drug from the market in 1998

22
Study to Prevent- NIDDM(STOP-NIDDM trial)

• Number of patients 1429 with IGT
• Mean age 55
• Mean BMI 31 kg/m2
• Major intervention Acarbose vs Placebo
• Average follow up 3.3 yrs.
• Relative risk reduction 32 for DM and
• 34 for HTN
• NNT 11 cases for 3.3yrs

23
Xenical in Prevention of Diabetes in Obese
Subjects(XENDOS)

• Number of patients 3305 with obesity
• 79 with normal and 21 with IGT
• Mean BMI 30 kg/m2
• Major intervention Orlistat 120mg TDS
• Objective To see the effect of Orlistat on
  the progression of diabetes
• Average follow up 4 yrs.
• Relative risk reduction 37 in all (p0.0032)
  ,45 in IGT subjects (p0.0024)

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• TRIALS SHOWING A REDUCTION IN THE DEVELOPMENT OF
  DIABETES
• The Heart Outcomes Prevention Evaluation(HOPE).
• Losartan Intervention for Endpoint(LIFE)
  Reduction in Hypertension Study
• West of Scotland Coronary Prevention
  Study(WOSCOPS).
• The Heart and Estrogen/Progestin Replacement
  Study(HERS).
• Candesartan in Heart Failure-Assessment of
  Reduction in Mortality and Morbidity(CHARM

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The Heart Outcomes Prevention Evaluation (HOPE)

• Number of patients 9297 with high risk of
  vascular disease
• Mean age 55 or older
• Major intervention Ramipril 10mg
• Primary 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(plt0.001).

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Losartan Intervention for Endpoint (LIFE)
Reduction in Hypertension Study

• Number of patients 9193 with HTN LVH.
• Mean age 55-80
• Objectives 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 (p0.001)

27
West of Scotland Coronary Prevention
Study(WOSCOPS)

• Number of patients 5974 with h/o MI
• Mean age 45-65
• Objective to assess cardiovascular events
• Intervention Pravastatin vs Placebo
• 30 reduction in the development of diabetes with
  Pravastatin compared to placebo

28
The Heart and Estrogen/Progestron Replacement
Study (HERS)

• Number of patients 2763 postmeno-
• pausal women
• Intervention 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(p0.006) risk reduction
  for the development of DM was noted with an NNT
  of 30 for 4 yrs.

29
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(plt0.0001).
• 22 reduction in new-onset DM.

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• TRIALS IN PROGRESS
• The Early Diabetes Prevention Trial (EDIT).
• Diabetes Reduction Assessment with Ramipril and
  Rosiglitazone Medication(DREAM).
• Nateglinide and Valsartan in Impaired Glucose
  Tolerance Outcomes Research (NAVIGATOR).

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The Early Diabetes Intervention Trial (EDIT)

• Number of patients 631 with IGT
• Intervention Acarbose vs Metformin vs
  combination of AM vs Placebo
• Primary endpoint Occurrence of DM
• Average follow up 6 yrs.
• Interim results at 3 yrs 522 subjects have
  remained in the trial showing an 8 risk
  reduction with Acarbose(p0.12) and 37 for
  Metformin(p0.17)
• Expected follow up for 6 yrs.

32
Diabetes Reduction Assessment with Ramipril and
Rosiglitazone Medication(DREAM)

• Number of patients 4000 with IGT
• Intervention Combination of Ramipril and
  Rosiglitazone vs placebo
• Primary endpoint new onset DM or
• all-cause mortality
• Average follow up 3 yrs.
• Ongoing trial, results expected in April 2007.

33
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 mortality
• Ages 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)

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Diabetes Prevention Strategies And Outcomes
INTERVENTION Intensive lifestyle Metformin Acarbo
se Pravastatin Ramipril Estrogen/progesterone ILS
C Orlistat Troglitazone Losartan Candesartan Ros
iglitazone Natiglinide Valsartan
STUDY DPP, FDP DPP,EDIT STOP-NIDDM,
EDIT WOSCOPS HOPE,DREAM HERS XENDOS TRIPOD LIFE CH
ARM DREAM NAVIGATOR
RR 58 a 31 a 25 a ongoing 30 a 34 a 35
a 37 56 25 22 ongoing ongoing
a versus standard lifestyle advice b versus
intensive lifestyle advice
35
Metformin the foundation oral therapy that
offers prevention of type 2 diabetes and its
complications
36
Prevention of complications

• Clinical outcome benefits with Metformin

37
Patients randomised to Metformin in theUK
Prospective Diabetes Study
Patients allocated to metformin n342
850 mg ? 1700 mg ? 2550 mg
Metformin dosing protocol
Follow up 6-20 years Median 10 years
UKPDS 34. Lancet 1998352854-65
38
Benefits beyond blood glucose controlwith
metformin in the UKPDS
Metformin Intensive (n342)
Sulphonylurea / Insulin Intensive (n951)
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
UKPDS 34. Lancet 1998352854-65
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Clinical outcomes for metforminin the UKPDS
Myocardialinfarction
Stroke
Diabetes deaths
? 42
? 39
? 41
Median dose 2550 mg/day
UKPDS 34. Lancet 1998352854-65
40
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)
UKPDS Captopril Atenolol n1148 32 18 21 28 44 58
8.4
HOT Felodipine Aspirin n1501 67 43 51 - 30 - 3.8
4S Simva-statin n202 36 43 55 - 62 - 5.4
UKPDS SU/Ins n3867 10 6 16
6 ()11 ()17 10.7
HOPE Ramipril n3577 37 24 22 - 33 - 4.5
UKPDS Metformin n753 42 36 39 50 41 25 10.7
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Prevention of complications

• Optimising the dose of Metformin

42

Metformin is frequently under-dosed
Metformin dosage (mg/day)
Scarpello. Br J Diabetes Vasc Dis 2001128-36
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Optimising metformin dosage evidence-based
conclusions
Metformin daily dosage (mg)
500 1000 1500 2000 2500 3000
Glycaemic benefits Clinical benefits Tolerance
and safety
44
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)

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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.

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Conclusion
Benefits of diabetes prevention for patients

• "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"

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Thankyou very much