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. Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris) 1.5 Million Canadians Have Diabetes Mellitus 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. 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

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 - 59Follow-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. Does an intensive glucose control policy reduce the risk of complications for people with Type 2 diabetes? UK Prospective Diabetes Study

13. 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

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 develops allocate 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 develops on sulphonylurea add metformin move to insulin therapy on insulin, transfer to complex regimens

16. Actual Therapy

17. HbA 1c 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. Does metformin in overweight diabetic patients have any advantages or disadvantages? UK Prospective Diabetes Study

29. Randomisation Main Randomisation 4209 Overweight 1704 Non overweight 2505 Conventional Policy 411 Intensive Policy 1293 Metformin 342 Insulin or Sulphonylurea 951

30. Any diabetes related endpoint M v I p=0.0034 overweight patients M v C p=0.0023

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

32. Myocardial Infarction M v I p=0.12 overweight patients M v C p=0.010

33. Microvascular endpoints M v I p=0.39 overweight patients M v C p=0.19

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

35. Metformin in Overweight Patients compared with conventional policy 32% risk reduction in diabetes-related endpoints p=0.0023 42% risk reduction in diabetes-related deaths p=0.017 36% risk reduction in all cause mortalityp=0.011 39% 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. Meltzer et al CMAJ 1998;159(Suppl):S1-29. Oral Antihyperglycemic Agents: Biguanides (metformin) 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 MUSCLELIVER

38. Meltzer et al CMAJ 1998;159(Suppl):S1-29. Oral Antihyperglycemic Agents: Biguanides (metformin) 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 MUSCLELIVER

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

40. Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30. 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

41. Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30. 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

42. Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30. 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

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

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 GLUCOSE ABSORPTION GLUCOSE PRODUCTION Biguanides Thiazolidinediones MUSCLE PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Biguanides) PANCREAS INSULIN SECRETION Sulfonylureas Meglitinides ADIPOSE TISSUE LIVER Alpha-glucosidase inhibitors INTESTINE 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 Meltzer et al CMAJ 1998;159(Suppl):S1-29. PANCREAS

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 Balfour, Faulds Drugs Aging 1998;13:173-80. PANCREAS

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

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

51. Stepwise Approach to the Treatment of Type 2 Diabetes Oral agent monotherapy Agent should be tailored to individuals (sulfonylurea medications, metformin, alphaglucosidase inhibitor, insulin sensitizer) Oral combination therapy Maximum dose of agent and/or agents from other classes add maximum dose of each Insulin injections, 1–4/day Insulin doses and number of injections should be adjusted to achieve target glucose levels To maximize benefits, each intervention should be reassessed within 2–4 months, and the next level of therapy considered if target not achieved. Non pharmacologic therapy Lifestyle modification: nutrition physical activity correction of risk factors Bedtime insulin +/– oral agents This approach results in better glucose control with a smaller dose of insulin

52. Goals of insulin therapy Achieve optimal glycemic control Minimize adverse effects: –Weight gain –Hypoglycemia –Inconvenience

53. Insulin action OnsetPeakDuration (min)(hrs)(hrs) Regular15-602-4 5 - 8 NPH2.5-3.05-713-16 Regular – with meals NPH - basal

54. Limitations of Regular Human Insulin Limitations of Regular Human Insulin Slow onset of activity: –Should be given 30 to 45 minutes before meals –Inconvenient for patients - less flexibility Insulin not peaking during peak absorption of food: –Inadequate post-prandial control Long duration of activity: –Lasts up to 8 hours –Potential for late post-prandial hypoglycemia –Need for additional snacks

55. Insulin action OnsetPeakDuration (min)(hrs)(hrs) Lispro10-151-1.54-5 Regular15-602-4 5 - 8 NPH2.5-3.05-713-16

56. Objectives for the Development of Short-Acting Insulin Analogues 360 180 300 240 120 60 0 0 120180240300360420 0 10 20 30 60 50 40 Humalog s.c. Time (minutes) Graph adapted from Pampanelli S et al. Diabetes Care, 1995: 18;11:1452-1459. Insulin (mg/mL) Pancreatic insulin OGT Regular insulin (–5 min.) Regular insulin (–30 min.)

57. Post-prandial Glucose Control in 772 Patients with Type 2 Diabetes Mellitus Post-prandial Glucose Control in 772 Patients with Type 2 Diabetes Mellitus Anderson JH et al. Arch Int Med 1997;157:1249-55 2 hour pc blood glucose was significantly reduced with lispro 2 hour post prandial glucose rise (mmol/L)

58. Hypoglycemia in 772 Patients with Type 2 Diabetes Mellitus Hypoglycemia in 772 Patients with Type 2 Diabetes Mellitus Anderson JH et al. Arch Int Med 1997;157:1249-55 hypoglycemia reduced by 7.3% with lispro insulin ( 3.43 to 3.18 episodes/30 days/pt, p<0.02) severe hypoglycemia was rare overnight hypoglycemia reduced by 36% with lispro insulin (0.73 to 0.47 episodes/30 days/pt, p<.001)

59. Lispro Insulin in Type 1 Diabetes Systematic review – 8 trials Lispro insulin vs. regular insulin 2576 patients with type 1 diabetes mellitus Follow-up: 4 – 12 months Severe hypoglycemia: 3.1% vs. 4.4%, p=0.024 Brunelle RL Diabetes Care 1998;21:1726-31.

60. Lispro –Allows patients to inject at time of meal –Significantly reduces post-prandial blood glucose levels –Reduces the incidence of hypoglycemia –Can improve the HbA1c –Offers improved flexibility and convenience

61. Pre-mixed Insulin –Convenient –Less injections per day –Adjustments in basal and meal time insulin more difficult –Preparations: 30/70 – 30% regular insulin/70% NPH insulin Other ratios available Mix25 – 25% lispro/75% NPH insulin

62. Insulin regimens Many different potential regimens! –Oral + hs insulin (NPH) –Oral + AM insulin (NPH) –Pre-mixed insulin with breakfast and supper –Short-acting with meals + bedtime NPH –Pre-mixed with breakfast, short acting at supper, and bedtime HPH

63. Insulin regimens All equivalent glycemic control. Weight gain less with bedtime insulin. Less hypoglycemia and weight gain with metformin (vs. glyburide) Regime will depend on patient preferences and ability to achieve glycemic goals!

64. CDA Guidelines for Glucose Control Meltzer et al CMAJ 1998;159(Suppl):S1-29. Gerstein HC et al CDA’s UKPDS Position Statement.

65. Blood Pressure Control Study UK Prospective Diabetes Study

66. Blood Pressure Control Study - to determine whether a tight blood pressure control policy can reduce morbidity and mortality in Type 2 diabetic patients

67. Randomisation

68. Blood Pressure : Tight vs Less Tight Control cohort, median values Less tight control Tight control

69. mmHg baselinemean over 9 years Less tight control 160 / 94154 / 87 Tight control161 / 94144 / 82 difference1 / 010 / 5 pn.s.<0.0001 ACE inhibitor159 / 94144 / 83 Beta blocker159 / 93143 / 81 difference0 / 01 / 1 pn.s. n.s. / p=0.02 Mean Blood Pressure

70. Therapy requirement

71. Any diabetes-related endpoints risk reduction 24% p=0.0046

72. Diabetes-related deaths risk reduction 32% p=0.019

73. Myocardial Infarction risk reduction 21% p=0.13

74. Heart Failure risk reduction 56% p=0.0043

75. Stroke risk reduction 44% p=0.013

76. Microvascular endpoints risk reduction 37% p=0.0092

77. Do ACE inhibitors or Beta Blockers have any specific advantages or disadvantages? UK Prospective Diabetes Study

78. Aggregate Clinical Endpoints

79. UK Prospective Diabetes Study An intensive glucose control policy HbA 1c 7.0 % vs 7.9 % reduces risk of –any diabetes-related endpoints 12% p=0.030 –microvascular endpoints 25% p=0.010 –myocardial infarction 16% p=0.052 A tight blood pressure control policy 144 / 82 vs 154 / 87 mmHg reduces risk of –any diabetes-related endpoint 24% p=0.005 –microvascular endpoint 37% p=0.009 –stroke 44% p=0.013

80. Renal Disease in Diabetes Blood pressure control ACE - inhibition Angiotensin receptor blockade

81. Diabetes: The Most Common Cause of ESRD Primary Diagnosis for Patients Who Start Dialysis Diabetes 50.1% Hypertension 27% Glomerulonephritis 13% Other 10% United States Renal Data System. Annual data report. 2000. No. of patients Projection 95% CI 1984 1988 1992 1996 2000 2004 2008 0 100 200 300 400 500 600 700 r 2 =99.8% 243,524 281,355 520,240 No. of dialysis patients (thousands)

82. Blood pressure control Decreases development of microalbuminuria Decreases rate of decline in glomerular filtration rate UKPDS:29% RRR for microalbuminuria Absolute risk reduction: 8.2% Meta-analysis of RCTs of diabetic nephropathy: 10 mm Hg improvement – 0.18 ml/min/month

83. ACE-inhibition Role in patients with Type 1 diabetes and nephropathy –Prevent death, dialysis, and transplantation Role in patients with microalbuminuria –Reduce rate of diabetic nephropathy Role in patients with Type 2 diabetes at high risk of cardiac complications –Reduce risk of MI, stroke, and cardiovascular death

84. Type 1 Diabetes and nephropathy Lewis and colleagues, 1993 409 patients Captopril vs. placebo Follow-up 3.5 years Outcome: Death, dialysis, renal transplant Placebo arm:21% Captopril arm:11%

85. Microalbuminuria Systematic review of randomized controlled trials Follow-up: >1 year RR for proteinuria: 0.35 (0.24 – 0.53) ARR 16.3%NNT 6 No demonstrated effect on renal function

86. HOPE 9297 patients: >55 years of age - clinical vascular disease or diabetes mellitus + 1 other cardiovascular risk factor - no history of heart failure - randomly allocated to ramipril or placebo - followed for a mean of 5 years - outcome: MI, stroke, or CVS death 1137 patients: diabetes mellitus with no clinical manifestations of cardiovascular disease

87. HOPE Results: - ramipril arm: 14.1% - placebo arm:17.7% Relative risk: 78% (95% CI 70% - 86%) Consistent across all subgroups, including patients with diabetes and no CVS disease

89. MICRO-HOPE: ACEI Reduces the Risk of MI, Stroke, and CV Death in Patients With Diabetes HOPE Study Investigators. Lancet. 2000;335:253. CombinedMIStrokeCV death 15.3 10.2 4.2 6.2 19.8 12.9 6.1 9.7 0 5 10 15 20 25 30 Ramipril Placebo 25% RR P=0.0004 22% RR P=0.01 33% RR P=0.0074 37% RR P=0.0001 Primary events

90. Angiotensin Receptor Blockers 3 recent publications Effect of angiotensin receptor blockers in patients with Type 2 diabetes mellitus and nephropathy or microalbubinuria

91. IRMA 2: IRbesartan MicroAlbuminuria Type 2 Diabetes Mellitus in Hypertensive Patients Irbesartan (150 mg and 300 mg) vs. other antihypertensive medications –(excl ACEIs, ARBs, dihydropyridine Ca ++ ch. blockers) 590 patients Hypertension, type 2 diabetes, and microalbuminuria Follow-up: 2 years

92. IRMA 2: Results Nephropathy rate: –5.2% among patients treated with 300 mg irbesartan/day –9.7% among patients treated with 150 mg irbesartan/day –14.9% among those treated with conventional therapy (P=0.0004) Reduction in microalbuminuria to normal levels (33% vs 20%; P=0.006) BP control similar across study arms

93. IDNT: Irbesartan Type 2 Diabetic Nephropathy Trial Patients: 1715 patients with NIDDM, HT, proteinuria (≥900 mg/24 h), serum creatinine 88 – 265 µmol/l Treatment regimen: Irbesartan 300mg, amlodipine 10mg, or placebo (± conventional therapy); target BP 135/85 1  End points: Combined incidence of doubling of sCr, ESRD, and death 2  End points: cardiovascular events Follow-up: 2.6 years

94. IDNT: Results Incidence of the composite endpoint (CrX2, ESRD, death): –Irbesartan:32.6% –Amlodipine:41.1% –Placebo:39.0% Effects of irbesartan independent of effects on BP No effect on mortality or cardiovascular outcomes

95. Patients: 1513 patients with NIDDM, nephropathy, serum creatinine 115 - 265 Treatment regimen: Losartan vs placebo (± conventional therapy) 1  End point: Combined incidence of doubling of sCr, ESRD, and death 2  End points: CV events, proteinuria Follow-up: 3.4 years RENAAL: Reduction of Endpoints in NIDDM With the AII Antagonist Losartan

96. RENAAL: Results Incidence of the composite endpoint (CrX2, ESRD, death): –Losartan:43.5% –Placebo:47.1%, –RRR 16%, p=0.02 Effects of losartan independent of effects on BP No effect on mortality or cardiovascular outcomes

97. Diabetes Clinical Cases

98. Case 1 60 y.o. ♂, mildly obese Inferior myocardial infarction 6 months ago Echocardiogram: mild left ventricular dysfunction Started on glyburide 5 mg bid post-discharge Fasting blood glucose values currently 8 – 10

99. Case 1 – Points for discussion High risk for cardiac complications –Aggressive risk factor modification Diet and exercise review Role for insulin Role for metformin - UKPDS

100. Case 2 50 y.o. ♀; Type 2 DM for 6 years; uses 30/70 bid Poor glycemic control despite increasing doses Persistently elevated fasting blood glucose values Progressive weight gain Lab: LDL 3.2 ↑microalb/creat. ratio

101. Case 2 – Points for discussion Often difficult to achieve optimal control with 30/70 bid –Insulin adjustment difficult –Nocturnal hypoglycemia and Somogyi effect common NPH action (hrs):Onset: 2.5-3.0 Peak: 5-7Dur’n: 13-16 ↑ LDL: Treat lipid abnormalities aggressively ↑ microalb/Cr ratio: 24-hour urine to confirm –If abnormal: optimize glycemic control + ACE - inhibitor

102. Case 3 40 y.o. ♀; Type 1 diabetes for 15 years Regular with meals (fixed doses) and NPH qhs Sub-optimal glycemic control; HbA1c 8.5% Frequent hypoglycemia BP 150/80 Urine: 1 + proteinuria

103. Case 3 – Points for discussion Lyspro insulin –Less post-prandial hyperglycemia –Less hypoglycemia Adjust insulin doses according to CHO content Probable nephropathy: –24-hour urine; ACE-inhibition; aggressive BP control

104. Case 4 65 y.o. ♂; Type 2 diabetes for 7 years Glyburide 10 mg bid; metformin 1000 mg bid Fasting blood glucose values: 10 – 12 Lipid profile: ↑ TG, ↓ HDL, normal LDL

105. Case 4 – Points for discussion Diet and exercise review Consider insulin sensitizer –e.g. pioglitazone, rosiglitazone

106. Case 5 75 y.o. ♀; Type 2 diabetes for 12 years Main complaint: pain in feet at night Physical examination: callus formation, ↓ monofilament sensation

107. Case 5 – Points for discussion Neuropathic pain: –Tricyclic antidepressant –Gabapentin –Capsaicin Foot care: –Education – inspection, walking barefoot –Footwear –Nail care