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THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY (ACCORD)

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Presentation on theme: "THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY (ACCORD)"— 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;99:21-33. 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<110mmHg SBP<140mmHg Group A Group B Total HbAIC < 6% 1178 1193 1383 1374 5128 HbAIC % 1184 1370 1391 5123 2362 2371 2753 2765 4733 5518 10251 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 <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 events1 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 study2 in middle-aged and older people with T2DM and either established CVD or additional cardiovascular risk factors 1Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141: 2The 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<110mmHg
Group A Group B Total HbAIC < 6% 1178 1193 1383 1374 5128 HbAIC % 1184 1370 1391 5123 2362 2371 2753 2765 4733 5518 10251 The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

8 Outcomes Primary Secondary
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) cardiovascular causes included death from myocardial infarction, heart failure, arrhythmia, invasive cardiovascular interventions, cardiovascular causes after noncardiovascular surgery, stroke, unexpected death presumed to be from ischemic cardiovascular disease occurring within 24 hours after the onset of symptoms, and death from other vascular diseases The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

9 Baseline Characteristics
Intensive (N = 5128) Standard (N = 5123) Age 62.2 Women 38.7 38.4 Median DM Duration 10 Previous CVD Event 35.6 34.8 White/Black 64.4/19.7 64.5/18.9 Current Smoker 14.3 13.7 Mean BMI 32.2 Mean SBP/DBP 136.2/74.8 136.5/75.0 Mean/Median A1C 8.3 / 8.1 Mean FG 175 176 Mean LDL / HDL 105 / 47 The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 9

10 Median Glycated Hemoglobin Levels at Each Study Visit
6.7%, 7.5% 4 months The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

11

12 Adverse Events, Clinical Measures, Tobacco Use, and Use of Nonglycemic Medication after Randomization Table 3. 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
Table 4. 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
Figure 2. 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
Figure 3. Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups. Data regarding glycated hemoglobin levels at baseline are presented for 10,288 patients because a baseline level was not available for 23 patients. Horizontal bars represent the 95% confidence interval, and vertical dashed lines indicate the overall hazard ratio. The size of each square is proportional to the number of patients. 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 compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors. The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 16

17 Number of Participants With One or More Severe Hypoglycemia Events
Requiring Medical Assistance (n and %) Intensive Group Standard Group # Events ** n % 1 400 7.8 130 2.5 2 82 1.6 34 0.7 3 to 5 43 0.8 10 0.2 >5 6 0.1 **Cumulative number of events The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 17

18 Experienced a Hypoglycemic Event
Mortality By Treatment Group and Severe Hypoglycemia Overall Never 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 (203 Deaths) (186 Deaths) 4.9% / year (17 Deaths) Hazard Ratio (95% CI) 1.22 (1.01, 1.46) 1.24 (1.02, 1.50) 0.54 (030, 0.96) 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: 18

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

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 compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors. The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 20

21 Kaplan-Meier Curves for the Primary Outcome and Death from Any Cause
Figure 2. 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 compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors. The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 22

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- 2765 Placebo group- 2753 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<110mmHg
Group A Group B Total HbAIC < 6% 1178 1193 1383 1374 5128 HbAIC % 1184 1370 1391 5123 2362 2371 2753 2765 4733 5518 10251 The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med DOI: /NEJMoa

27 Outcomes Primary: Secondary:
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 100.0 to 81.1 in Fenofibrate group
101.1 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 Lipid Values Figure 1. Lipid Values. Shown are mean plasma levels of total cholesterol (Panel A), low-density lipoprotein (LDL) cholesterol (Panel B), and high-density lipoprotein (HDL) cholesterol (Panel C) and median levels of triglycerides (Panel D) at baseline, 4 months, 8 months, 1 year, and annually thereafter. Nominal P values for differences between the study groups at 4 months and at the end of the study were, respectively: total cholesterol, P<0.001 and P=0.02; LDL cholesterol, P=0.11 and P=0.16; HDL cholesterol, P<0.001 and P=0.01; and triglycerides, P<0.001 for both comparisons with the use of nonparametric tests. End-of-study visits were those that occurred in early 2009 and included follow-up at years 4, 5, 6, and 7. The I bars represent 95% confidence intervals. To convert the values for cholesterol to millimoles per liter, multiply by To convert the values for triglycerides to millimoles per liter, multiply by Mean LDL decrease of to 81.1 in Fenofibrate group and to 80.0 in placebo group The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

30 Prespecified Primary and Secondary Outcomes
Table 2. Prespecified Primary and Secondary Outcomes. The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

31 Kaplan-Meier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death
Figure 2. Kaplan-Meier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death. Shown are the cumulative incidence of the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (Panel A), the expanded macrovascular outcome (a combination oaf the primary outcome plus revascularization or hospitalization for congestive heart failure) (Panel B), and death from any cause (Panel C) or from cardiovascular causes (Panel D) during follow-up. The insets show close-up versions of the graphs in each panel. The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

32 Hazard Ratios for the Primary Outcome in Prespecified Subgroups
Figure 3. Hazard Ratios for the Primary Outcome in Prespecified Subgroups. The horizontal bars represent 95% confidence intervals, and the vertical dashed line indicates the overall hazard ratio. The size of each square is proportional to the number of patients. P values are for tests for interaction. To convert the values for cholesterol to millimoles per liter, multiply by To convert the values for triglycerides to millimoles per liter, multiply by The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

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. Perhaps only certain subgroups benefitted. Would have used more strict inclusion criteria if only testing for lipids. Use of fenofibrate instead of genfibrozil as in Helsinki Heart study and VA-HIT (no background statin). 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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