1. Canadian Diabetes Association 2013 Clinical Practice Guidelines Targets for Glycemic Control Chapter 8 S. Ali Imran, Rémi Rabasa-Lhoret, Stuart Ross

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

3. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Questions to Address What should the A1C be for most people & why? Who should we be more aggressive with & why? Who should we be less aggressive with & why?

5. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association DCCT N = 1441 T1DM Intensive (≥ 3 injections/day or CSII) vs. \ Conventional (1-2 injections per day)

6. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Reduction in Retinopathy The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986. Primary PreventionSecondary Intervention 76% RRR (95% CI 62-85%) 54% RRR (95% CI 39-66%) RRR = relative risk reduction CI = confidence interval

7. Solid line = risk of developing microalbuminuria Dashed line = risk of developing macroalbuminuria DCCT: Reduction in Albuminuria 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 guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association RRR = relative risk reduction CI = confidence interval

8. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Reduction in Neuropathy The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.

9. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653. DCCT/EDIC: Early intensive therapy reduced the risk of nonfatal MI, stroke or death from CVD 57% risk reduction (P=0.02; 95% CI: 12–79%) MI, stroke or CV death Conventional treatment Intensive treatment 01234567891011121314151617 18 19 20 21 Years since entry 0.12 0.10 0.08 0.06 0.04 0.02 0.00

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

11. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Holman RR et al. N Engl J Med 2008;359.

12. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 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 Legacy Effect of Earlier Glucose Control Holman R, et al. N Engl J Med 2008;359.

13. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association To achieve A1C ≤7.0% 2013

15. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association ADVANCE N = 11,140 T2DM Intensive (A1C ≤6.5% with gliclazide MR) vs. Standard glycemic control

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

17. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association ADVANCE: Treatment Effect on the Primary Microvascular Outcomes 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 ADVANCE Collaborative Group. N Engl J Med 2008;358:24.

18. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association BENEFIT HYPO- GLYCEMIA

20. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Consider A1C 7.1-8.5% if … Limited life expectancy High level of functional dependency 2013

21. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Moorhouse P, Rockwood K. J R Coll Physicians Edinb 2012;42:333-340.

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

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

24. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Individualizing A1C Targets which must be balanced against the risk of hypoglycemia Consider 7.1-8.5% if: 2013

25. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 1 1.Glycemic targets should be individualized based on age, duration of diabetes, risk of severe hypoglycemia, presence or absence of cardiovascular disease, and life expectancy [Grade D, Consensus].

26. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 2 and 3 2.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] 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].

27. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 4 4.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

28. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 4 (continued) 4.(Continued) 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] : – Multiple co-morbidities – History of recurrent severe hypoglycemia – Hypoglycemia unawareness – Longstanding diabetes for whom it is difficult to achieve an A1C ≤7.0%, despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy 2013

29. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 5 5.In order to achieve an A1C of ≤7.0%, people with diabetes should aim for: – A FPG or preprandial PG target of 4.0-7.0 mmol/L and a 2-hr postprandial PG target of 5.0-10.0 mmol/L [Grade B, Level 2, for type 1 diabetes; Grade B, Level 2, for type 2 diabetes]. – If an A1C target of <7.0% cannot be achieved with a postprandial PG target of 5.0 to 10.0 mmol/L, further postprandial BG lowering to 5.0-8.0 mmol/L should be achieved [Grade D, Consensus, for type 1 diabetes; Grade D, Level 4 for type 2 diabetes].

30. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association CDA Clinical Practice Guidelines http://guidelines.diabetes.cahttp://guidelines.diabetes.ca – for professionals 1-800-BANTING (226-8464) http://diabetes.ca http://diabetes.ca – for patients