1. IMPLICATIONS OF UKPDS GSK Advisory Board 24 May 2003 Dr. J. R. Conway

2. Worldwide rates of diabetes mellitus: predictions 80 70 60 50 40 30 20 10 0 Prevalence (millions) North America EuropeSoutheas t Asia Year 1995 2000 2025 World Health Organization. 1997. Canadian Diabetes Association, 1998 website.

3. Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris) 2.2 Million Canadians Have Diabetes Mellitus Harris. Diabetes Care 1993;16:642-52.

4. Haffner Am J Cardiol 1999;84:11J-4J. Framingham study: diabetes and CAD mortality at 20-year follow-up Cardiovascular Disease Risk is Increased 2 to 4 Times

5. UK Prospective Diabetes Study multi-centre randomised controlled trial of different therapies of Type 2 diabetes

6. Does an intensive glucose control policy reduce the risk of complications of diabetes? UK Prospective Diabetes Study

7. Blood Glucose Control Study : Aims to determine whether improved glucose control of Type 2 diabetes will prevent clinical complications therapy with –sulphonylurea - first or second generation –insulin –metformin – has any specific advantage or disadvantage

8. Patient Characteristics 5102 newly diagnosed Type 2 diabetic patients age 25 - 65 years mean 53 y gendermale : female59 : 41% ethnic group Caucasian82% Asian 10% Afro-caribbean8% Body Mass Index mean 28 kg/m 2 fasting plasma glucose (fpg) median 11.5 mmol/L HbA 1c median 9.1 % hypertensive39%

9. Randomisation of Treatment Policies 342 allocated to metformin Conventional Policy 30% (n=1138) Intensive Policy 70% (n=2729) Sulphonylurea n=1573 Insulin n=1156 Main Randomisation n=4209 (82%) 3867

10. Actual Therapy

11. Any Diabetes Related Endpoint 1401 of 3867 patients (36%) First occurrence of any one of: diabetes related death non fatal myocardial infarction, heart failure or angina non fatal stroke amputation renal failure retinal photocoagulation or vitreous haemorrhage cataract extraction or blind in one eye

12. Microvascular Endpoints (cumulative) renal failure or death, vitreous haemorrhage or photocoagulation 346 of 3867 patients (9%)

13. HbA 1c cross-sectional, median values

14. Beta cell function in the UKPDS Years from diagnosis Beta cell function (%) 100 90 80 70 60 50 40 30 20 10 0 –12–10–8–6–4–20246 Holman RR et al. Diabetes Res Clin Pract 1998;40(suppl):S21–S25

15. WHAT’S THE PROBLEM It used to be easy diet+DiaBeta/glyburide metformin do as you’re told We must reach glucose targets -CDA guidelines; UKPDS; Kumamoto see you later It doesn’t work poor control vascular complications

16. A BIG ISSUE glyburide works-then fails metformin works-then fails insulin, using standard regimens, works-then fails

17. UKPDS TREATMENT FAILURE On SU treatment: 5%/year HbA1c increased 0.3%/year

18. UKPDS monotherapy failure A1c<0.07 at 9 years % UKPDS JAMA 1999 281 2005

19. COMBINATION THERAPY Achieves better blood glucose levels Less side-effects than high dose monotherapy Delays use of insulin Patients more prepared for aggressive therapies ? Protects beta-cell function M. Riddle Am J Med 2000;108(6A) 15S-22S

20. Insulin resistance: an underlying problem Insulin resistance Insulin production Glucose level Time Non- diabetes Pre- diabetes Type 2 diabetes Opara JU, Levine JH, South Med J. 1997;90:1162-1168.

21. Type 2 Diabetes: Underlying Defects Type 2 diabetes  Beta-cell function Insulin resistance Other defects:  lipolysis release of NEFA  hepatic glucose production Adapted from Matthaei et al. Endocrine Reviews 2000;21:585-618. Adapted from Frayn. Br J Nutr 2000;83(suppl 1): S71-S77. Pathophysiology

22. Pathophysiology of Type 2 Diabetes Adapted from Saltiel et al. Diabetes 1996; 45:1661-1669. Liver Pancreas Peripheral Tissues (Muscle and Adipose) Increased glucose production Glucose Impaired insulin secretion Receptor + postreceptor defects Insulin resistance Pathophysiology

23. Metabolic syndrome Obesity Atherosclerosis risk Insulin resistance Diabetes Dyslipidaemia Hyper- tension

24. THE ARGUMENT Insulin insufficiency Insulin resistance

25. Insulin resistance: an underlying problem Insulin resistance Insulin production Glucose level Time Non- diabetes Pre- diabetes Type 2 diabetes Opara JU, Levine JH, South Med J. 1997;90:1162-1168.

26. Treatment: stepwise approach 1 2 3 4 5 Combination of oral medicines Oral plus insulin Insulin One oral medicine Diet & exercise + + +

27. % of Patients Uncontrolled (HbA1c  115% N) Diet Only (n=506) Oral Monotherapy (n=740) Dual Oral Therapy(n=98)Insulin(n=903) 0 50% 100% General Population (non-Aboriginal; n=2015) Aboriginal (n=232) NS p = 0.017 p < 0.05 NS 60.9% 54.5% 44.1% 59.2% 56.9% 68.2% 24.8% 20.0% Prevalence of Uncontrolled Glucose Levels in an Alberta Aboriginal and Non-Aboriginal Population (N=2,247)

28. Table 3: UNCONTROLLED DIABETES DURATION on THERAPY years * * p<0.001 MONO DUAL INSULIN ** ** p=0.009 age

29. Thiazolidinediones: Rosiglitazone-Avandia Pioglitazone-Actos

30. Peroxisome Proliferator Activated Receptors (PPAR) are Ligand-Activated Nuclear Receptors Thyroid Hormones Steroid Hormones ThyroidSteroid RAR RXR Receptors Orphans retinoic acid  PPAR  PPAR  PPAR  peroxisome proliferator activated receptors (PPAR)

31. Murphy K et al. Endocrine Society Meeting 2000; Poster 450. Long-term rosiglitazone monotherapy: Mean change in HbA 1c

32. Fasting Plasma Glucose Conway,R; Rosiglitazone in Family Practice, CDA Oct 2002

33. HbA1c over 40 months Conway,R; Rosiglitazone in Family Practice, CDA, Oct 2002

34. -1.5 -0.5 0 0.5 1 Mean Change from Baseline in HbA 1C (%) BMI < 25BMI 25–30BMI > 30 Months BMI > 30 kg/m 2 : Extension study (18 months) Glycemic parameters by body mass index (BMI): Rosiglitazone added to metformin MET + placebo MET + RSG 4 mg/day MET + RSG 8 mg/day HbA 1c (%) Effect of BMI: Double-blind studies (26 weeks) 0369121518 0.0 7.0 7.5 8.0 8.5 9.0 9.5 Patients completing 18 months on metformin + RSG therapy (N = 124)

35. Long-Term Durability of Rosiglitazone as Monotherapy or in Combination Therapy in Patients with Type 2 Diabetes Gould E, Cobitz, A. Presented at 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19-22, 2002 #P1-60

36. Results Effect Avandia Montherapy on HbA 1c Open-label 42-month Completer Analysis* *Patients who received Avandia 8 mg qd and 4 mg bid for at least 42 months during 2 double-blind, 26-week, placebo-controlled trials and their open label extensions. Completer analysis limited by potential bias towards responders to treatment, and small numbers of patients at various time points. 1. Gould E,et al. Presented at 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19-22, 2002 #P1-60

37. Results Effect of Avandia+ Metformin on HbA 1c Open-label 30-month Completer Analysis* *Patients who received Avandia 4 mg bid plus 2.5 g/day of metformin for at least 30 months during 1 double-blind, 26-week, placebo-controlled trial and its open label extension. Completer analysis limited by potential bias towards responders to treatment, and small numbers of patients at various time points. 1. Gould E,et al. Presented at 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19-22, 2002 #P1-60

38. Results Effect of Avandia + SU on HbA 1c Open-label 30-month Completer Analysis* *Patients who received Avandia 2 mg bid plus glyburide for at least 30 months during 1 double-blind, 26-week, placebo-controlled trial and its open label extension. Completer analysis limited by potential bias towards responders to treatment, and small numbers of patients at various time points. 1. Gould E,et al. Presented at 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19-22, 2002 #P1-60

39. WHAT HAS CHANGED We must treat the Metabolic Syndrome (insulin resistance) -glucose levels -blood pressure -lipids

40. ORAL AGENTS Dose Response

41. Riddle M. Combining sulfonylureas and other oral agents. Am J of Med. 2000; 106(6A):16S-22S.

43. Beta cell function in the UKPDS Years from diagnosis Beta cell function (%) 100 90 80 70 60 50 40 30 20 10 0 –12–10–8–6–4–20246 Holman RR et al. Diabetes Res Clin Pract 1998;40(suppl):S21–S25

44. NON-EVIDENCE-BASED THOUGHTS Use two agents early-on in treatment Consider a ‘glitazone’ + metformin, or fast-acting insulin secretor

45. A Peek at the Future Fast-acting insulin secretors: gliclazide MR/repaglinide/nateglinide Metformin TZD rosiglitazone/pioglitazone Statin ACE/ARB Insulin

46. Insulin Secretion Evidence Impaired beta-cell function in 1 st degree relatives Type 2 diabetes can occur without insulin resistance but not without impaired insulin secretion Reduction of obesity normalizes insulin resistance but not not impaired insulin secretion

47. Insulin Resistance Evidence Population-based study (N=888) Prevalence of insulin resistance in subjects with: – Impaired glucose tolerance65.9% – Type 2 diabetes83.9% – Plurimetabolic syndrome95.2% – Subjects with no metabolic disorder 9.6% Bonora E et al, Diabetes 1998;47:1643-1649