1. Lower the better; the case for glucose Professor Taner DAMCI Istanbul University Cerrahpaşa Medical School, TURKEY

2. Epidemiology suggests high glucose is toxic

3. Blood glucose and CV risk N = 17,869 men, aged 40–64 years; follow-up 33 years Brunner EJ et al. Diabetes Care. 2006;29:26-31. *Relative to baseline group of all men with blood glucose <83 mg/dL 83 mg/dL OGTT blood glucose (mg/dL) 5472108 90126144162180 1.6 1.2 0.8 0.4 0.0 -0.4 CHD mortality (log hazard ratios)*

4. Adjusted relative hazard of coronary heart disease in 1321 individuals without diabetes (A) and 1626 individuals with diabetes (B), adjusted for age, sex, and race and plotted on the log scale. All adjusted relative hazards are centered at hemoglobin A1c (HbA1c) = 5.2%, and the graphed lines are shown for the fifth to 95th percentiles of HbA1c level. The solid black line in A is from a single-knot linear spline model (knot at HbA1c = 4.6%). The dotted gray line is from a linear spline model with knots at the quintiles of HbA1c. In B, the solid black line is from a linear model; the gray dotted line is from a linear spline model with knots at the quintiles of HbA1c level. The normal range for HbA1c in persons without diabetes (4%-6%) is indicated by the dotted vertical lines in A. The current target for glycemic control in persons with diabetes (HbA1c = 7%) is indicated by the vertical dotted line in B. Arch Intern Med. 2005 Sep 12;165(16):1910-6. Adjusted relative hazard of coronary heart disease in 1321 individuals without diabetes (A) and 1626 individuals with diabetes (B)

5. Diabetic milleu is a toxic soup with hyperglycemia, lipids, oxidative stress and combination of drugs….

6. Effect of postprandial hyperglycemia on the arterial wall Meal Hyperglycemia Hyperlipidemia Haller H. Diab Res Clin Pract 1998;40:S43–S49. Oxidative stress Endothelial damage Atherosclerosis

7. Adjusted Hazard Ratios for Self-Reported Diagnosed Diabetes and Coronary Heart Disease, Ischemic Stroke, and Death from Any Cause, According to the Baseline Glycated Hemoglobin Value. Selvin E et al. N Engl J Med 2010;362:800-811.

8. BMJ. 2006 Jan 14;332(7533):73-8. Epub 2005 Dec 21

9. Lowering glucose in a diabetic patient decreases macro and microvascular complications.

10. Glucose Control Study Summary UKPDS The intensive glucose control policy maintained a lower HbA 1c by mean 0.9 % over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: 12%for any diabetes related endpointp=0.029 25%for microvascular endpoints p=0.0099 16%for myocardial infarctionp=0.052 24%for cataract extractionp=0.046 21%for retinopathy at twelve yearsp=0.015 33%for albuminuria at twelve years p=0.000054

11. Kaplan-Meier Curves for Four Prespecified Aggregate Clinical Outcomes Holman RR et al. N Engl J Med 2008;359:1577-1589

12. DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-53. DCCT/EDIC: Intensive glucose control reduces long-term CV risk  42% (95% CI 9%–63%) P = 0.02  57% (95% CI 12%–79%) P = 0.02 Cumulative incidence of any first CV event Cumulative CV death, nonfatal MI, stroke Time (years) Conventional 52 events Intensive 31 events Conventional 25 events Intensive 11 events 0 0.12 0.08 0.10 0.06 0.04 0.02 05101520 0 0.12 0.08 0.10 0.06 0.04 0.02 05101520 N = 1441 with type 1 diabetes

13. Glucose Control at Baseline and during Follow-up, According to Glucose-Control Strategy The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

14. Cumulative Incidences of Events, According to Glucose-Control Strategy The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

15. Normoglycemia does not necessarily mean increased hypoglycemia

16. Hypoglycemia is a side effect of treatment not of good metabolic control

17. Annual Rates of Severe Hypoglycemia According to Treatment Assignment and Adverse Clinical Outcomes among Patients with Severe Hypoglycemia. Zoungas S et al. N Engl J Med 2010;363:1410-1418.

18. How about ACCORD ?

19. Kaplan–Meier Curves for the Primary Outcome and Death from Any Cause. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559.

20. Spline curves displaying the risk of all-cause mortality with the two treatment strategies over the range of average A1C from 6.0 to 9.0%. The curves represent the linear part of the proportional hazards models derived from values for intervals of average A1C from model 3. For clarity, the figure omits values 9%; ∼ 5% of deaths are excluded from this plot at the lower end and also at the higher end of the A1C range, but these data are included in the models. The bold orange line represents the intensive treatment strategy group, the bold blue line represents the standard group, and the finer colored lines represent the 95% CIs for each group.

22. Change in HbA1c by group; two subsets can be created based on likely improvement Can we predict future improvement in glycaemic control?. Diabetic Medicine 25 (2), 170-173 2008

23. It is inappropriately intensive treatment “ not good glycemic control ” which increase the risk.

24. We have to individualize diabetes treatment. Most of the time side effects are a result of confectionary treatments.

25. So we should achive as low HbA1c as possible in an individual patient without causing hypoglycemia and weight gain. We have the tools.