1. Diabetes and Nephrology Symposium November 19 th,2014 Optimizing Glycemic control in CKD Presented by Laila Bishara MD, FRCPC

2. Disclosure Financial Disclosure Grants/research support: None Speakers bureau/honoraria: Eli Lilly, Sanofi Aventis, Merck and NovoNordisk Consulting fees: None T

3. Learning objectives To identify the role of glycemic control in various stages of CKD To individualize patient’s glycemic goals in CKD To review the therapeutic options for glucose control and the limitations and risks in patients with CKD

4. CKD in Diabetes ACR ≥2.0 mg/mmol and / or eGFR <60 mL/min 2013

5. Stages of Diabetic Nephropathy Note: change in definition of microalbuminuria ACR ≥2.0 mg/mmol 2013

6. Case 1 56 year old man works as a bank manager Non-smoker and consumes alcohol occasionally. Type 2 diagnosed 3 years ago. No known coronary artery disease Hypertension controlled on ramipril 10 mg. On Atorvastatin 10 mg. Received dietary education at the time of diagnosis His HbA1C was 6.6 to 7.3% in the first 12 months, then went up gradually Metformin was added and titrated up to 1000 mg bid. Over the following year, he was switched to Janumet 50 mg/ 1 gm bid Recent blood work: HbA1C 7.9 %. LDL 1.8, TC/HDL 3.5. ACR: < 2 mg/ mmol eGFR > 60 ml/ minute

7. Case 1 What is the HbA1C target for this patient ? Would glycemic control impact on his risk for developing nephropathy? Anti-hyperglycemic agents needed to bring him in target?

8. Case 2 54 year old woman Type 2 diabetes diagnosed 6 years ago. Hypertension and dyslipidemia treated No known coronary artery disease or any macrovascular disease Medications: Rosuvastatin 10 mg, Coversyl 8 mg, Metformin 1 gm bid, Onglyza 5 mg and Glicalzide MR 60 mg ACR on 2 different occasions 5 mg/ mmol eGFR: > 60 ml/ minute LDL 1.7, blood pressure 125/75 HbA1C: 8.7% not changed significantly from 8.9% 3 months ago

9. Case 2 What is the HbA1C target for this patient ? Would glycemic control impact on the course of nephropathy? Agents needed to bring her on target?

10. Case 2 What if ACR was 30 mg/ mmol? What if eGFR was lower? Glycemic target? Agents?

11. Targets Checklist A1C ≤7.0% for MOST people with diabetes A1C ≤6.5% for SOME people with T2DM A1C 7.1-8.5% in people with specific features 2013

13. Type 1 Diabetes

14. DCCT N = 1441 T1DM Intensive (≥ 3 injections/day or CSII) vs. \ Conventional (1-2 injections per day)

15. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986. 34% RRR (p<0.04) 43% RRR (p=0.001) 56% RRR (p=0.01) Primary PreventionSecondary Intervention Solid line = risk of developing microalbuminuria Dashed line = risk of developing macroalbuminuria DCCT: Reduction in Albuminuria RRR = relative risk reduction CI = confidence interval guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

16. deBoer IH et al. Arch Intern Med 2011;171(5):412-420. HR 1.92 (p<0.05) HR 0.64 (95% CI 0.40-1.02) Return to normoalbuminuria Macroalbuminuria HR = hazard ratio CI = confidence interval guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association EDIC: Continued Reduction in Albuminuria

17. EDIC: Early Glycemic Control Reduces Long-term Risk of Impaired GFR Risk reduction with intensive therapy 50% (95% CI 18-69; p=0.006) DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-76.

18. Type 2 Diabetes

19. UKPDS: N = 3867 T2DM 0 6 8 9 03691215 A1C (%) Conventional 7.9% Intensive 7.0% 7 UKPDS Study Group. Lancet 1998:352:837-53.

20. UKPDS 33: relative risk reduction with intensive treatment Relative risk reduction for intensive treatment (%) Intensive treatment reduced HbA 1c by 0.9% for a median of 10 years in 3,867 patients with type 2 diabetes * p < 0.05 ** p < 0.01 Any diabetes endpoint Microvascular endpoint MI Cataract extraction Retinopathy (12 years) Albuminuria (12 years) 0 10 20 30 * ** * * Lancet 1998;352:837–53

21. Holman RR et al. N Engl J Med 2008;359.

22. After median 8.5 years post-trial follow-up Aggregate Endpoint 19972007 Any diabetes related endpoint RRR: 12%9% P: 0.029 0.040 Microvascular disease RRR: 25%24% P: 0.00990.001 Myocardial infarction RRR: 16%15% P: 0.0520.014 All-cause mortality RRR: 6%13% P: 0.440.007 Holman R, et al. N Engl J Med 2008;359. UKPDS: Post-trial Monitoring “Legacy Effect” guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

24. ADVANCE N = 11,140 T2DM Intensive (A1C ≤6.5% with gliclazide MR) vs. Standard glycemic control

25. ADVANCE: Glucose Control Follow-up (months) Mean A1C (%) Standard control 7.3% Intensive control 6.5% 10.0 9.0 8.0 7.0 6.0 5.0 0.0 0612182430364248546066 p < 0.001 ADVANCE Collaborative Group. N Engl J Med 2008;358:24.

26. New/worsening nephropathy, retinopathy 66 Cumulative incidence (%) Follow-up (months) HR 0.86 (0.77-0.97) p = 0.01 Standard control Intensive control 25 20 15 10 5 0 06121824303642485460 Adapted from: ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72. ADVANCE Collaborative Group. N Engl J Med 2008;358:24. ADVANCE: Primary Microvascular Outcomes

27. BENEFIT HYPO- GLYCEMIA

28. Case 1 56 year old man Type 2 diagnosed 3 years ago. No known coronary artery disease Hypertension controlled on Ramipril 10 mg. On Atorvastatin 10 mg. Janumet 50 mg/ 1 gm bid Recent blood work: HbA1C 7.9 %. LDL 1.8, TC/HDL 3.5. ACR: < 2 mg/ mmol eGFR > 60 ml/ minute

29. Case 1 HbA1C target ? Would glycemic control impact on his risk for developing nephropathy? Anti-hyperglycemic agents needed to bring him in target?

30. 2013 CDA Recommendations Therapy in most individuals with type 1 or type 2 diabetes should be targeted to achieve an A1C ≤ 7.0% in order to reduce the risk of microvascular [Grade A, Level 1A] and, if implemented early in the course of disease, macrovascular complications [Grade B, Level 3] An A1C ≤6.5% may be targeted in some patients with type 2 diabetes to further lower the risk of nephropathy [Grade A, Level 1] and retinopathy [Grade A, Level 1], but this must be balanced against the risk of hypoglycemia [Grade A, Level 1].

31. A fter Metformin? Depends … Patient characteristicsAgent characteristics Degree of hyperglycemiaBG lowering efficacy & durability Risk of hypoglycemiaRisk of inducing hypoglycemia WeightEffect on weight Comorbidities (renal, cardiac, hepatic) Contraindications & side effects Access to treatmentCost and coverage Patient preferencesOther 2013

32. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

33. Case 2 54 year old woman Type 2 diabetes diagnosed 6 years ago. Hypertension and dyslipidemia treated No known coronary artery disease or any macrovascular disease Medications: Rosuvastatin 10 mg, Coversyl 8 mg, Metformin 1 gm bid, Onglyza 5 mg and Glicalzide MR 60 mg ACR on 2 different occasions 5 mg/ mmol eGFR: > 60 ml/ minute LDL 1.7, blood pressure 125/75 HbA1C: 8.7% not changed significantly from 8.9% 3 months ago

34. Case 2 What is the HbA1C target for this patient ? Would glycemic control impact on the course of nephropathy? Agents needed to bring her on target?

35. 2013 guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

36. Case 2 What if the ACR was 30 mg/mmol ?

37. Case 2 What if the eGFR was 45?

39. Issues with low GFR Mostly stages 4 and 5 CKD Most oral agents need to be stopped, few exceptions. Insulin is the preferred therapy Risk of hypoglycemia is higher.

40. Adapted from: Product Monographs as of March 1, 2013; CDA Guidelines 2008; and Yale JF. J Am Soc Nephrol 2005; 16:S7-S10. Antihyperglycemic Agents and Renal Function Not recommended / contraindicated Safe Caution and/or dose reduction Repaglinide Metformin 30 60 Saxagliptin Linagliptin Glyburide 30 50 Thiazolidinediones 30 GFR (mL/min): < 15 15-29 30-59 60-89 ≥ 90 CKD Stage: 5 4 3 2 1 Gliclazide/Glimepiride 15 30 Liraglutide 50 Exenatide 30 50 Acarbose 25 Sitagliptin 50 15 2.5 mg 15 30 50 mg 25 mg guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

41. Intensification of Therapy in T2D Progressive deterioration of  -cell function Lifestyle changes OHA monotherapy and combinations Basal Add basal insulin and titrate Basal Plus Add bolus insulin at one meal A1C above target FBG above target A1C above target Basal bolus Additional bolus doses at other meals as needed FBG at target A1C above target OHA=oral hypoglycemic agent 41 Raccah D et al. Diabetes Metab Res Rev 2007;23(4):257-264. Nathan DM et al. Diabetologia 2006;49:1711–1721. Woerle H. Arch Intern Med 2004;164:1627–1632.

42. Types of Insulin

43. Types of Insulin (continued)

44. Serum Insulin Level Time Analogue Bolus: Apidra, Humalog, NovoRapid Human Basal: Humulin-N, Novolin ge NPH Analogue Basal: Lantus, Levemir Human Bolus: Humulin-R, Novolin ge Toronto guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

45. Time Serum Insulin Level Human Premixed : Humulin 30/70, Novolin ge 30/70 Analogue Premixed: Humalog Mix25, NovoMix 30 guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

46. How to dose? “Whatever you pick will be WRONG … and that’s okay!”

47. You will inject ______ units of insulin each night (0.1 unit per kg) You will continue to increase by 1 unit every night until your blood sugar level is _______ mmol/L before breakfast If hypoglycemia Basal insulin 10 4-7

48. Basal Plus or Basal-Bolus If full Basal-Bolus: 0.4 to 0.5 u/kg = TDI 50% bolus, 50% basal (or 60:40) OR Add 10% of basal dose as bolus insulin ac meal (4- T study) OR Add 2 units and self-titrate (START protocol) OR Add 4 units and self-titrate (STEP protocol) Harris, S et al. START study. As presented at the CDA / CSEM conference in Vancouver, BC, October 2012. Meneghini L, Mersebach H, Kumar S, et al. Endocrine Practice 2011;17:727-36.

49. Premixed 0.4 to 0.5 units / kg Traditionally: 2/3 in the AM + 1/3 in the PM Practically 50% am and 50% evening

50. Case 4 62 year old man Type 1 diabetes since age 10 On insulin pump HbA1C inadequate over the years: 9 to 10% Main barrier is fear of hypoglycemia yet he suffers Hypoglycemia unawareness Retinopathy and Coronary artery disease Nephropathy for the last 10 years, progressed over the last 3 years Last eGFR 15 Discussing dialysis Vs transplant with nephrologist

51. Case 4 Target A1C? Would it impact on that stage of kidney disease? Dialysis Vs Transplant

52. Case 5 77 year old frail woman Weight: 145 lbs Type 2 diabetes for 25 years Retinopathy, neuropathy and nephropathy Coronary artery disease. Bypass surgery 10 years ago and recent angioplasty On insulin for 15 years Currently on Metformin 1 gm bid, Lantus 32 units at night and Humalog 10 to 12 units per meal HbA1C is 8% eGFR: 38 ACR : 20 mg/ mmol

53. Case 5 A1C target? Need to modify treatment?

55. Consider A1C 7.1-8.5% if … Limited life expectancy High level of functional dependency Extensive coronary artery disease at high risk of ischemic events Multiple co-morbidities History of recurrent severe hypoglycemia Hypoglycemia unawareness Longstanding diabetes for whom is it difficult to achieve an A1C ≤ 7%, despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy 2013

56. Recommendation Less stringent A1C targets (7.1 to 8.5% in most cases) may be appropriate in patients with type 1 or type 2 diabetes with any of the following [Grade D, Consensus]: – Limited life expectancy – High level of functional dependency – Extensive coronary artery disease at high risk of ischemic events – Insulin therapy 2013