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

1. Prevention Of Diabetes“A 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 1997;14 (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. Age at Diagnosis 10/15 15-19 20-29 30-39 40-49 50-59 60-69 70+ Marks & Krall 1971 (17) 16-17 12-14 10-11 8-9 6-7 4-5 - Goodkin 1975 27 23 16 11 10 6 5 - Panzram & Zabel-Langhennig 1981 - - - - 7-8 5-6 3-4 3 Reduction in life expectancy in type 2 diabetes Panzram G. Diabetologia 1987;30:123-31

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)

8. Progression to type 2 diabetes Annual rates of progression to moresevere forms of glucose intolerance Koehler et al. Diabetologia 2001;44 Suppl 1:A108

9. 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. 1997;37 Suppl:S9

10. OBESITY is the driving force behind IGT • Prevalence of OBESITYis 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 riskof 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 1999;22:1988-1992

12. IGT and risk of diabetes Impaired glucose tolerance Highest quartile 2-hour insulin Highest quartile fasting insulin Triglycerides >2.5 mmol/l (221 mg/dl) HDL <1 mmol/l (39 mg/dl) Waist-hip ratio >1.0 BMI >30 gm-2 Hypertension Family history of diabetes Relative risk of developingdiabetes ( 95% CI) Mykkanen et al (1993)

13. 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.

14. 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.

15. Primary Prevention in Diabetes ‘Risk Factors’ for Type 2 Diabetes GESTATIONAL DIABETES AND PARITY GENETIC FACTORS - Ethnicity - Family history (40%) CENTRAL OBESITY PHYSICAL INACTIVITY INCREASING AGE 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

17. 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)

18. Da Qing impaired glucose tolerance and Diabetes study • Number of patients: 577 with IGT • Mean 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

19. 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

20. 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 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

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 (p=0.0032) ,45% in IGT subjects (p=0.0024)

24. 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}

25. 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(p<0.001).

26. 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 (p=0.001)

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%(p=0.006) 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(p<0.0001). • 22% reduction in new-onset DM.

30. 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).

31. The Early Diabetes Intervention Trial (EDIT) • Number of patients: 631 with IGT • Intervention: Acarbose vs Metformin vs combination of A+M 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(p=0.12) and 37% for Metformin(p=0.17) • 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)

34. Diabetes Prevention Strategies And Outcomes INTERVENTION Intensive lifestyle Metformin Acarbose Pravastatin Ramipril Estrogen/progesterone ILSC + Orlistat Troglitazone Losartan Candesartan Rosiglitazone Natiglinide &Valsartan STUDY DPP, FDP DPP,EDIT STOP-NIDDM, EDIT WOSCOPS HOPE,DREAM HERS XENDOS TRIPOD LIFE CHARM 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 n=342 850 mg  1700 mg  2550 mg Metformin dosing protocol Follow up 6-20 years Median 10 years UKPDS 34. Lancet 1998;352:854-65

38. Benefits beyond blood glucose controlwith metformin in the UKPDS Metformin Intensive (n=342) Sulphonylurea / Insulin Intensive (n=951) 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 1998;352:854-65

39. Clinical outcomes for metforminin the UKPDS Myocardialinfarction Diabetes deaths Stroke  42%  39% 41% Median dose = 2550 mg/day UKPDS 34. Lancet 1998;352:854-65

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 n=1148 32 18 21 28 44 58 8.4 HOT Felodipine Aspirin n=1501 67 43 51 - 30 - 3.8 4S Simva-statin n=202 36 43 55 - 62 - 5.4 UKPDS Metformin n=753 42 36 39 50 41 25 10.7 UKPDS SU/Ins n=3867 10 6 16 6 (+)11 (+)17 10.7 HOPE Ramipril n=3577 37 24 22 - 33 - 4.5

41. Prevention of complications Optimising the dose of Metformin

42. Metformin dose in the UKPDS Metformin dose in clinical practice Metformin is frequently under-dosed Metformin dosage (mg/day) Scarpello. Br J Diabetes Vasc Dis 2001;1:28-36

43. 850 1700 2550 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)

45. 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.”

46. 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"

47. Thankyou very much