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Issues in Diabetes Care

Issues in Diabetes Care. Academic Half-day February 2002 D. Hunt. Outline. 1. Significance of diabetes mellitus 2. Glycemic control: - evidence - oral agents - insulin 3. Blood pressure control 4. Nephropathy and microalbuminuria 5. Cases. Significance of diabetes mellitus.

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Issues in Diabetes Care

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  1. Issues in Diabetes Care Academic Half-day February 2002 D. Hunt

  2. Outline 1. Significance of diabetes mellitus 2. Glycemic control: - evidence - oral agents - insulin 3. Blood pressure control 4. Nephropathy and microalbuminuria 5. Cases

  3. Significance of diabetes mellitus • 5% of the population has diagnosed diabetes • 10% Type 1; 90% Type 2 • prevalence increases with age: 20 - 44: 1% 45 - 65: 5% > 65: 10% • the true prevalence of diabetes is estimated to be twice the prevalence of diagnosed diabetes

  4. 1.5 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.

  5. Proliferative retinopathy Type 1: 25% after 15 years Type 2: 4% - 12% after 15 years Blindness: 10% - 15% of patients with proliferative retinopathy have severe visual loss within 2 years Diabetes is the leading cause of adult-onset blindness

  6. Nephropathy Type 1: 30% after 15 years Type 2: 20% after 15 years Follow-up from the Multiple Risk Factor Intervention Trial: RR for end-stage renal disease: 9.0 (7.4 - 11.0) Diabetes is the leading cause of end-stage renal disease

  7. Neuropathy Loss of foot sensation > foot ulcers and infections > foot amputations Amputation rate: 2 - 30/1000 patient-years Diabetes is the leading cause of non-traumatic amputation

  8. 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.

  9. Macrovascular disease Multiple Risk Factor Intervention Trial: Follow-up of 350,000 screened patients RR for cardiovascular death: 3.0 Swedish cohort study: Baseline age: 51 - 59 Follow-up: 16 years RR for cardiovascular death: 2.9 (2.3 - 5.6)

  10. Glycemic control - Type 1 diabetes The Diabetes Control and Complications Trial: • 1441 patients with Type 1 diabetes • intensive insulin therapy vs conventional therapy • follow-up 6.5 years Early retinopathy: 24% vs 7% Microalbuminuria: 20% vs 13% Neuropathy: 10% vs 3%

  11. Glycemic control Can these results be applied to people with Type 2 diabetes? Potential benefits: Decreased microvascular disease Potential adverse effects: Increased cardiovascular mortality with oral hypoglycemic agents and insulin

  12. UK Prospective Diabetes Study Does an intensive glucose control policy reduce the risk of complications for people with Type 2 diabetes?

  13. 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

  14. Treatment Policies in 3867 patients Conventional Policy n = 1138 • initially with diet alone • aim for near normal weight best fasting plasma glucose < 15 mmol/L asymptomatic • when marked hyperglycaemia developsallocate to non-intensive pharmacological therapy

  15. Treatment Policies in 3867 patients Intensive Policy with sulphonylurea or insulin n = 2729 • aim for fasting plasma glucose < 6 mmol/L asymptomatic • when marked hyperglycaemia developson sulphonylurea add metformin move to insulin therapyon insulin, transfer to complex regimens

  16. Actual Therapy

  17. HbA1c cross-sectional, median values

  18. 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

  19. Any Diabetes Related Endpoint (cumulative ) 1401 of 3867 patients (36%)

  20. Diabetes Related Deaths • 414 of 3867 patients (11%) • Any of: • fatal myocardial infarction or sudden death • fatal stroke • death from peripheral vascular disease • death from renal disease • death from hyper/hypoglycaemia

  21. Diabetes Related Deaths (cumulative) 414 of 3867 patients (11%)

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

  23. Myocardial Infarction (cumulative) fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%)

  24. Aggregate Clinical Endpoints

  25. Progression of Retinopathy Two step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale

  26. Microalbuminuria Urine albumin >50 mg/L

  27. Glycemic control - UKPDS Intensive blood glucose control reduces the risk of diabetic complications, the greatest effect being on microvascular complications

  28. UK Prospective Diabetes Study Does metformin in overweight diabetic patients have any advantages or disadvantages?

  29. Randomisation Main Randomisation4209 Non overweight2505 Overweight1704 Conventional Policy411 Intensive Policy1293 Insulin or Sulphonylurea951 Metformin342

  30. Any diabetes related endpoint overweight patients M v Cp=0.0023 M v Ip=0.0034

  31. Diabetes related deaths overweight patients Mv C p=0.017 M v Ip=0.11

  32. Myocardial Infarction overweight patients M v Cp=0.010 M v Ip=0.12

  33. Microvascular endpoints overweight patients M v Cp=0.19 M v Ip=0.39

  34. Metformin Comparisons overweight patients RR (95% CI) favours metformin favours conventional

  35. Metformin in Overweight Patients • compared with conventional policy 32% risk reduction in diabetes-related endpoints p=0.002342% risk reduction in diabetes-related deaths p=0.01736% risk reduction in all cause mortality p=0.01139% risk reduction in myocardial infarction p=0.01

  36. Natural History of Type 2 Diabetes Henry. Am J Med 1998;105(1A):20S-6S.

  37. Oral Antihyperglycemic Agents: Biguanides (metformin) LIVER MUSCLE • Decreases hepatic glucose production • Enhances peripheral glucose uptake • Increased insulin sensitivity in the periphery • HbA1c: 7.1% vs. 8.6% (US Metformin Study) 7.4% vs. 8.0% (UKPDS) • Not associated with hypoglycemia • May promote weight loss Meltzer et al CMAJ 1998;159(Suppl):S1-29.

  38. Oral Antihyperglycemic Agents: Biguanides (metformin) LIVER MUSCLE • May cause GI side effects • Introduce slowly! • Contraindicated in renal/hepatic insufficiency • Lactic acidosis (0.03 cases/1000 patient years) • Dose 250 – 500 mg BID/TID, to max of 2500 mg/d Meltzer et al CMAJ 1998;159(Suppl):S1-29.

  39. Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs) • New class of oral agents • Designed to increase insulin sensitivity • Pioglitazone, rosiglitazone LIVER ADIPOSE TISSUE MUSCLE Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

  40. Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs) Mechanism: • Activate the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor • Expressed in adipose tissue, large colon, hematopoietic cells • Involved in efficient energy storage and adipogenesis • Activation of the gene in adipose tissue leads to: • Apoptosis of larger fully differentiated adipocytes (insulin resistant) • Differentiation of pre-adipocytes into small metabolically active adipose cells Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

  41. Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs) Net effect: • Increased insulin sensitivity • Increased insulin-dependent glucose uptake • Improved glycemic profile • Reduction in triglyceride levels • Increased LPL activity Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

  42. Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs) Effect on glycemic control when combined with other oral agents: Pioglitazone: HbA1c: 0.8% - 1.3% FBG: 2.1 – 3.2 mmol/L Rosiglitazone: HbA1c: 1.0% – 1.2% FBG: 2.4 – 2.9 mmol/L Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

  43. Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs) Effect on lipid control when combined with other oral agents: Pioglitazone: Triglycerides: decrease 20% HDL: increase 10% Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

  44. Thiazolidinediones Side effects: • Edema/fluid retention - 4% • Congestive heart failure • Weight gain – 4.5 kg • Ovulation – polycystic ovarian syndrome Contraindications: • Elevated liver function tests (>2.5 x upper limit of normal) • Class 2,3,4 heart failure • Edema Monitoring: Liver function tests every 2 months for 1 year

  45. Thiazolidinediones:Clinical aspects • Dosing: • Pioglitazone: 15-45 mg daily • Rosiglitazone: 2-4 mg bid or 4-8 mg qd • Half-life: • Pioglitazone: 16-24 h • Rosiglitazone: 3-4 h • Initial effect: 2-4 weeks • Full effect: 8-12 weeks

  46. Sites of Action of Currently Available Therapeutic Options LIVER MUSCLE ADIPOSE TISSUE PANCREAS GLUCOSE PRODUCTION Biguanides Thiazolidinediones PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Biguanides) INSULIN SECRETION Sulfonylureas Meglitinides INTESTINE GLUCOSE ABSORPTION Alpha-glucosidase inhibitors Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5.

  47. Oral Antihyperglycemic Agents: Sulfonylureas • Stimulate pancreatic insulin release • First-generation: tolbutamide, chlorpropamide • Second-generation: Glyburide, gliclazide • HbA1c: 1 – 2% • Weight gain: 2 – 3 kg • Risk of severe hypoglycemia: 1 – 1.5%/year PANCREAS Meltzer et al CMAJ 1998;159(Suppl):S1-29.

  48. Oral Antihyperglycemic Agents: Meglitinides • Stimulate pancreatic insulin release • Repaglinide • Rapid onset and short duration of action • Lowers fasting and postprandial glucose levels • HbA1c: 1.5% • May cause hypoglycemia PANCREAS Balfour, Faulds Drugs Aging 1998;13:173-80.

  49. Oral Antihyperglycemic Agents: Alpha-glucosidase inhibitors • Slows gut absorptionof starch and sucrose • Acarbose • Attenuates postprandial increases in blood glucose levels • GI side effects • Not associated with hypoglycemia or weight gain INTESTINE Salvatore, Giugliano Clin Pharmacokinet 1996;30:94-106.

  50. Stepwise approach to type 2 diabetes Nonpharmacologic therapy Oral agent monotherapy Oral agent combination therapy Bedtime insulin and oral agents Insulin 2–4 times/day

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