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THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY (ACCORD) Dr. Anita Chekuri CVA Ltd.

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Presentation on theme: "THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY (ACCORD) Dr. Anita Chekuri CVA Ltd."— Presentation transcript:

1 THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY (ACCORD) Dr. Anita Chekuri CVA Ltd

2 Background  Epidemiologic analyses suggest that the risk for CVD in patients with diabetes increases in a graded fashion with increases HbA1c, BP, LDL, and TG and with a decrease in HDL.  Diabetics without Hx of MI have same risk of a coronary event as do non-diabetics with previous MI  To determine whether CVD event rates can be reduced in patients with T2DM who are at high risk for CVD events by intensively targeting 3 important CVD risk factors: hyperglycemia, dyslipidemia, and elevated blood pressure. Buse J. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial: Design and Methods The American Journal of Cardiology 2007;99: Haffner SM, Lehto S, Ronnemaa T, Pyöräla K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:

3 2 X 2 Factorial Design BP trial Lipid trial Glycaemic trial SBP<110 mmHg SBP<140 mmHg Group A Group B Total HbAIC < 6% HbAIC % Total Buse J. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial: Design and Methods The American Journal of Cardiology 2007;99:21-33.

4 Eligibility  Stable Type 2 Diabetes for 3+ months  A1C >7.5% AND 7.5% AND <9% (more meds) OR <11% (fewer meds)  Age previous CVD events OR  Age with:  anatomical ASCVD, albuminuria, LVH OR  > 2 CVD risk factors (dyslipidemia, hypertension, smoking, obesity)  BMI < 45; Cr < 1.5 (133 uM)  No frequent/recent serious hypoglycemia  Able/willing to take insulin, do glucose monitoring  Eligible for BP or Lipid Trial  LDL mg/dl  HDL < 55 mg/dl (women, blacks), < 50 (all others)  TG <750 (not on lipid therapy) or <400 (on lipid therapy) The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

5 ACCORD Glycaemic Control Arm Dr. Anita Chekuri CVA Ltd

6 Background  An increase of 1% in the HbAIC is associated with an increase of 18% in the risk of cardiovascular events 1  Determine whether therapeutically targeting normal HbAIC levels (< 6.0%) would reduce the rate of cardiovascular events, as compared to targeting HbAIC from 7.0 to 7.9% 2  The finding of higher mortality in the intensive- therapy group led to termination of the intensive regimen 17 months before the scheduled end of the study 2 1 Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141: The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

7 Randomization BP trial Lipid trial Glycaemic trial SBP<110 mmHg SBP<140 mmHg Group A Group B Total HbAIC < 6% HbAIC % Total The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

8 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.  Intensive glycaemic control arm terminated in 3.5 years (instead of 5.6 years as planned for) The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

9 Intensive (N = 5128) Standard (N = 5123) Age Women Median DM Duration 1010 Previous CVD Event White/Black64.4/ /18.9 Current Smoker Mean BMI Mean SBP/DBP 136.2/ /75.0 Mean/Median A1C 8.3 / 8.1 Mean FG Mean LDL / HDL 105 / 47 Baseline Characteristics The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

10 Median Glycated Hemoglobin Levels at Each Study Visit The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

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12 Adverse Events, Clinical Measures, Tobacco Use, and Use of Nonglycemic Medication after Randomization The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

13 Primary and Secondary Outcomes The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

14 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:

15 Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

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

17 Intensive Group Standard Group # Events ** n%n% to > **Cumulative number of events Number of Participants With One or More Severe Hypoglycemia Events Requiring Medical Assistance (n and %) The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

18 OverallNever Experienced a Hypoglycemic Event Experienced Hypoglycemic Event Intensive Glycemia 1.4% / year (257 Deaths) 1.3% / year (223 Deaths) 2.8% / year (34 Deaths) Standard Glycemia 1.1% / year 1.1% / year (203 Deaths) 1.1% / year (186 Deaths) 4.9% / year (17 Deaths) HazardRatio (95% CI) 1.22 (1.01, 1.46) 1.24 (1.02, 1.50) 0.54 (030, 0.96) Mortality By Treatment Group and Severe Hypoglycemia Mortality Higher in Intensive Group Mortality Higher in Standard Group Interaction P < 0.01 The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

19 Intensive Strategy Higher Mortality Higher Rates of Hypoglycemia Intensive Strategy Higher Rates of Hypoglycemia Higher Mortality Can we blame it all on hypoglycaemia? No! And can ACCORD distinguish these? The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

20 Observations  Targeting HbAIC levels below 6.0% increased the 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  Longer time duration increases benefits of mortality from non-fatal MI, but also increases risk of death The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

21 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:

22 Observations  Targeting HbAIC levels below 6.0% increased the 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  Longer time duration increases benefits of mortality from non-fatal MI, but also increases risk of death The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

23 ACCORD Lipid Control Arm Dr. Anita Chekuri CVA Ltd

24 Background  To investigate whether combination therapy of statin (lower LDL) + fibrate (raise HDL, lower TG), as compared to statin monotherapy was superior in reducing rate of CV events in high risk Type 2 diabetics The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

25 Method  5518 high risk for CV events on Simvastatin started at randomization  Treatment group – add fenofibrate at 1 month  Placebo group  Follow-up- 4.7 years The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

26 Randomization BP trial Lipid trial Glycaemic trial SBP<110 mmHg SBP<140 mmHg Group A Group B Total HbAIC < 6% HbAIC % Total The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

27 Outcomes  Primary:  First occurrence of nonfatal MI, nonfatal Stroke, or death from CV disease  Secondary:  Primary plus revascularization or hospitalization for CCF (expanded macrovascular outcome)  Combination of fatal coronary event, nonfatal MI, or unstable angina (major coronary disease events)  Death from any cause  Hospitalization due to HF The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

28 Results  Mean LDL decrease of  to 81.1 in Fenofibrate group  to 80.0 in placebo group The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

29 The ACCORD Study Group. N Engl J Med 2010; /NEJMoa Lipid Values

30 The ACCORD Study Group. N Engl J Med 2010; /NEJMoa Prespecified Primary and Secondary Outcomes

31 The ACCORD Study Group. N Engl J Med 2010; /NEJMoa Kaplan-Meier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death

32 The ACCORD Study Group. N Engl J Med 2010; /NEJMoa Hazard Ratios for the Primary Outcome in Prespecified Subgroups

33 Observations  No significant difference in primary outcome between groups  In subgroup analysis, sex difference was significant. Men seemed to benefit from Fenofibrate.  Suggestion of heterogenisity with baseline TG and HDL levels. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

34 Thank You  Any Questions?


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