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IMPLICATIONS OF UKPDS

IMPLICATIONS OF UKPDS. GSK Advisory Board 24 May 2003 Dr. J. R. Conway. Worldwide rates of diabetes mellitus: predictions. 80 70 60 50 40 30 20 10 0. Prevalence (millions). Year 1995 2000 2025. North America. Europe. Southeast Asia. World Health Organization. 1997.

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IMPLICATIONS OF UKPDS

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  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) Year 1995 2000 2025 North America Europe Southeast Asia World Health Organization.1997. Canadian Diabetes Association, 1998 website.

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

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

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

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

  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 gender male : female 59 : 41% ethnic group Caucasian 82% Asian 10% Afro-caribbean 8% Body Mass Index mean 28 kg/m2 fasting plasma glucose (fpg) median 11.5 mmol/L HbA1cmedian 9.1 % hypertensive 39%

  9. Main Randomisationn=4209 (82%) 342 allocated to metformin 3867 Conventional Policy30% (n=1138) Intensive Policy70% (n=2729) Insulinn=1156 Sulphonylurean=1573 Randomisation of Treatment Policies

  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. HbA1c cross-sectional, median values

  14. Beta cell function in the UKPDS 100 90 80 70 60 50 40 30 20 10 0 Beta cell function (%) –12 –10 –8 –6 –4 –2 0 2 4 6 Years from diagnosis 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. UKPDSTREATMENT FAILURE • On SU treatment: 5%/year • HbA1c increased 0.3%/year

  18. UKPDS monotherapy failureA1c<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 Time Insulin resistance Insulin production Glucose level Non- diabetes Pre- diabetes Type 2 diabetes Opara JU, Levine JH, South Med J. 1997;90:1162-1168.

  21. Pathophysiology Type 2 Diabetes: Underlying Defects Insulin resistance  Beta-cell function Type 2 diabetes 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.

  22. Pathophysiology Pathophysiology of Type 2 Diabetes Receptor + postreceptor defects Glucose Insulin resistance Liver Increased glucose production Peripheral Tissues (Muscle and Adipose) Pancreas Impaired insulin secretion Adapted from Saltiel et al. Diabetes1996; 45:1661-1669.

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

  24. THE ARGUMENT • Insulin insufficiency • Insulin resistance

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

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

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

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

  29. Thiazolidinediones: • Rosiglitazone -Avandia • Pioglitazone -Actos

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

  31. Long-term rosiglitazone monotherapy:Mean change in HbA1c Murphy K et al.Endocrine Society Meeting 2000; Poster 450.

  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. Glycemic parameters by body mass index (BMI):Rosiglitazone added to metformin Effect of BMI: Double-blind studies (26 weeks) BMI > 30 kg/m2: Extension study (18 months) 1 9.5 Patients completing 18 months on metformin + RSG therapy (N = 124) 9.0 0.5 8.5 0 Mean Change from Baseline in HbA1C (%) HbA1c (%) 8.0 -0.5 7.5 -1 7.0 0.0 -1.5 BMI < 25 BMI 25–30 BMI > 30 0 3 6 9 12 15 18 Months MET + placebo MET + RSG 4 mg/day MET + RSG 8 mg/day

  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 Montherapyon HbA1c 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 HbA1c 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 + SUon HbA1c 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.

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

  43. Beta cell function in the UKPDS 100 90 80 70 60 50 40 30 20 10 0 Beta cell function (%) –12 –10 –8 –6 –4 –2 0 2 4 6 Years from diagnosis 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

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