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Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society

Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes. Blood glucose: is lower better for diabetic patients?. Miracle of insulin.

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Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society

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  1. Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes Blood glucose: is lower better for diabetic patients?

  2. Miracle of insulin Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset 4

  3. Chronic complications of hyperglycemia Hyperglycaemia ??

  4. Type 2 UKPDS 8  7% 17-21% 24-33% - Type 1 DCCT 9  7% 76% 54% 60% Type 2 Kumamoto 9  7% 69% 70% - HbA1c Retinopathy Nephropathy Neuropathy Glycemic Control on Diabetic MicrovascularComplications DCCT Research Group, NEJM 1993, Ohkubo et al., Diab Res Clin Pract 1995, UKPDS Group, Lancet 1998

  5. 24% 25% 33% 21% P = 0.000054 P = 0.015 P = 0.046 P = 0.0099 UKPDS:Intensiveglycemic control reduces microvascular complications Cataract extraction All microvascular endpoints Microalbuminuria Retinopathy

  6. Rationale for near-normoglycemia Lessons from UKPDS: Better control means fewer complications EVERY 1% reduction in HBA1C REDUCED RISK* -21% 1% Deaths from diabetes -14% Heartattacks Microvascular complications -37% Peripheral vascular disorders -43% *p<0.0001 UKPDS 35. BMJ 2000; 321: 405-12

  7. chronic complications of hyperglycemia Hyperglycaemia ??

  8. Risk of myocardial infarction is increased in type 2 diabetes * † 60% No prior myocardial infarction Prior myocardial infarction 40% Risk of fatal or non-fatal myocardial infarction * † 20% 0% Non diabetic subjects Type 2 diabetic subjects n = 1,304 69 890 169 Seven-year incidence in a Finnish-based cohort *P < 0.001 vs no prior MI †P < 0.001 vs no diabetes Adapted from Haffner SM. New Engl J Med 1998; 339:229–234.

  9. Recent Studies Evaluating Effect of GlycemicControl on CVD • ACCORD • ADVANCE • VADT

  10. ACCORD: Action to Control Cardiovascular Risk in Diabetes • 10,251 Enrollees • 60% male 40% female • Mean age 62.2 • Baseline HgA1c 8.1% • BMI - 32 • 30% macrovasculardx • Duration DM: 10 years • Majority of intensive group on 3-5 oral agents plus insulin • Hypoglycemia 3 times greater in intensive group

  11. 9.0 8.5 Standard therapy 8.0 7.5 A1C (%) 7.0 6.5 6.0 Intensive therapy 0 0 1 2 3 4 5 6 Time (years) ACCORD: Treatment effects on glucose control ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

  12. ACCORD: Treatment effect on primary outcome 25 20 Standard therapy HR 0.90 (0.78-1.04)P = 0.16 15 Patients with events (%) 10 Intensive therapy 5 0 0 1 2 3 4 5 6 Time (years) Primary Outcome: NFMI, NF Stroke or CVD Death ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

  13. Intensive glycaemic control arm terminated in 3.5 years (instead of 5.6 years as planned for) February 7, 2008

  14. 25 20 HR 0.94 (0.84-1.06)P = 0.32 Standard control 15 10 Intensive control 5 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) ADVANCETreatment effect on primary macrovascular outcome CV death, MI stroke Cumulative incidence (%) • ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

  15. VADT - Veterans Administration Diabetes Trial • Primary Endpoint: no difference in CVD outcomes • Standard: 29.3% (predicted – 40%) • Intensive: 27.4% (predicted – 31.6%)

  16. The intensive approach led toconfusion over the best approach • It does not result in a significantly lower number of major CVA after 5 y • It led to more death • Reasons for the higher mortality in the intensive-therapy group are unknowns • Many factors could be implicated :

  17. The intensive approach led toconfusion over the best approach • Many factors could be implicated : • The severe hypoglycemia ? • The degree of reduction in A1c ? • The relatively short intervention period (3.7 years) ? • The observed The role of various drugs, drug combinations or drug interactions; weight gain ? • interaction between the blood-pressure and hyperlipidemia and glycemia trials with respect to mortality ? It led to more death

  18. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus Lipid Values The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

  19. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus Mean Systolic Blood-Pressure Levels at Each Study Visit The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

  20. Survival as a function of HbA1c in people with type 2 diabetes Currie CJ, Peters JR, Tynan A et al.:Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481–89

  21. Cardiovascular safety of diabetes drugs The Truth Is Not So Sweet • The goal of marely lowering blood glucose levels in diabetes is too simplistic • With respect to CVD it appears important how you lower blood sugar as well as how much • Diabetes drugs, even within the same “class” may yield dramaticallydifferent CV outcomes

  22. Conclusion: is lower better for diabetic patients? • The optimal mechanism, speed, and extent of glycated hemoglobin reduction are different for differing populations • Yes For patients with recently diagnosed diabetes, aggressive treatment will lower cardiovascular risk • No : • Forpatients who have diabetes of more than 15 years’ duration and are older and have other comorbidities, less aggressive treatment is indicated • And For all patients, treatment of the dyslipidemia and hypertension that are associated with diabetes further reduces CVD risk

  23. The Promise Land of diabetes therapy Thank you Merci شكراً

  24. Number of Participants With One or More Severe Hypoglycemia Events Requiring Medical Assistance (n and %) **Cumulative number of events The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

  25. IntensiveStrategy Higher Rates of Hypoglycemia Higher Mortality Can we blame it all on hypoglycemia? Intensive Strategy Higher Rates of Hypoglycemia Higher Mortality No! The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

  26. ACCORD: Study design N = 10,251 with T2DM and existing CVD or additional CV risk factors BP trial (n) Lipid trial* (n) SBP <120mg Hg SBP <140mg Hg Group A Group B A1C <6% 1178 1193 1383 1374 5128 Glycemia trial A1C7.0%-7.9% 1184 1178 1370 1391 5123 2362 2371 2753 2765 4733 5518 *Statin + fibrate vs statin, treatment group assignment blinded until end of trialPrimary outcome: CV death, MI, stroke ACCORD Study Group. Am J Cardiol. 2007;99(suppl):21i-33i.www.accordtrial.org

  27. A1c Levels at Baseline, at the Intensive-Therapy Group's Transition to Standard Therapy, and After the Transition in the ACCORD Trial

  28. Any benefits mortality Tight glycemic control

  29. Intervention TrialMedian follow-up 10.0 years Intervention Trial + Post-trial monitoringMedian follow-up 16.8 years RR=0.88 (0.79-0.99) P=0.029 Conventional Sulfonylurea/Insulin Conventional Sulfonylurea/Insulin Any Diabetes-related Endpoint:legacy effect

  30. DCCT/EDIC; Memory effect Metabolic Results DCCT Intervention Training EDIC Observation Conventional EDIC mean 8.2% Intensive EDIC mean 8.0% 1 2 3 4 5 6 7 8 9 DCCT EDIC S t u d y Y e a r DCCT/EDIC Study Research Group, NEJM 2005

  31. Outcomes • Primary • First occurrence of nonfatal MI, nonfatal Stroke, or death from CV disease. • Secondary • Death from any cause. • Also measured the effect of the intervention on microvascular disease, hypoglycemia, cognition, and quality of life. The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

  32. Observations Targeting HbAIC levels below 6.0% increasedthe rate of death from any cause after a mean of 3.5 years Magnitude of reduction Speed of reduction Rate of hypoglycaemia Adverse drug interactions at high doses The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

  33. The intensive approach led toconfusion over the best approach • Many factors could be implicated : • The patients selection ?

  34. The intensive approach led toconfusion over the best approach • Many factors could be implicated : • The patients selection ? • The severe hypoglycemia ?

  35. The intensive approach led toconfusion over the best approach • Many factors could be implicated : • The patients selection ? • The severe hypoglycemia ? • The degree of reduction in A1c ?

  36. 9.0 8.5 Standard therapy 8.0 7.5 A1C (%) 7.0 6.5 6.0 Intensive therapy 0 0 1 2 3 4 5 6 Time (years) ACCORD: Treatment effects on glucose control ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

  37. The intensive approach led toconfusion over the best approach • Many factors could be implicated : • The patients selection ? • The severe hypoglycemia ? • The degree of reduction in A1c ? • The relatively short intervention period (3.7 years) ?

  38. The intensive approach led toconfusion over the best approach • Many factors could be implicated : • The patients selection ? • The severe hypoglycemia ? • The degree of reduction in A1c ? • The relatively short intervention period (3.7 years) ? • The observed The role of various drugs, drug combinations, or drug interactions; weight gain ? • to

  39. ADVANCE: Action in Diabetes and Vascular Disease Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazide combination in >55 y/o Type 2 DM • 11,140 Enrollees • 60% male 40% female • Mean age 66 • 50% macrovascular dx • 10% microvascular Baseline HgA1c: 7.51% “standard” : 7.30% Intensive: 6.53%

  40. 10.0 9.0 8.0 Standard control 7.0 P < 0.001 6.0 Intensive control 5.0 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) ADVANCETreatment effect on glucose control Mean A1C (%) • ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

  41. ADVANCE • 11,140 Patients, Age ~66, With Type 2 DM, And High CV Risk • Intensive (A1c 6.4%) vs Conventional (A1c 7.3%) • Benefit with regard to microvascular complications • NoExcess Mortality In Intensive Group

  42. VADT - Veterans Administration Diabetes Trial • BMI 31.3 • Majority had multiple CV risk factors • 72% HTN • 40% macrovascular dx • 62% retinopathy • 43% neuropathy • 1742 Enrollees • 97% male • Mean age 60.4

  43. confusion over the best approach to cardiovascular risk reduction

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