Action to Control Cardiovascular Risk in Diabetes Lipid Trial - ACCORD Lipid

Description:

The goal of the trial was to evaluate treatment with fenofibrate compared with placebo among patients with type 2 diabetes treated with an open-label statin medication.

Hypothesis:

The addition of fenofibrate to statin therapy would be effective in preventing cardiovascular events.

Study Design

  • Parallel

Patients Enrolled: 5,518
Mean Follow Up: 4.7 years
Mean Patient Age: 62 years
Female: 31%

Patient Populations:

  • Patients with type 2 diabetes with an HbA1c ≥7.5%
  • Age 40-79 years with clinical cardiovascular disease or age 55-79 years with subclinical cardiovascular disease or at least two additional cardiovascular risk factors
  • LDL cholesterol level between 60 and 180 mg/dl, HDL cholesterol <55 mg/dl for women and blacks or <50 mg/dl for all others, and triglycerides <750 mg/dl not on lipid therapy or <400 mg/dl on lipid therapy

Primary Endpoints:

  • First occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke

Secondary Endpoints:

  • Combination of the primary outcome plus revascularization or hospitalization for heart failure
  • Combination of a fatal coronary event, nonfatal myocardial infarction, or unstable angina
  • Nonfatal myocardial infarction
  • Fatal or nonfatal stroke
  • Nonfatal stroke
  • All-cause death
  • Cardiovascular death
  • Hospitalization or death due to heart failure

Drug/Procedures Used:

Half of the patients within the initial ACCORD trial with type 2 diabetes and treated with a statin medication were randomized to fenofibrate 160 mg daily (n = 2,765) versus placebo (n = 2,753). The other half of the patients within the initial ACCORD trial were randomized to a systolic blood pressure goal <120 mm Hg versus <140 mm Hg.

Concomitant Medications:

At baseline, the use of insulin was 33%, metformin was 62%, any sulfonylurea was 52%, any thiazolidinedione was 18%, angiotensin-converting enzyme inhibitor was 54%, angiotensin-receptor blocker was 15%, aspirin was 56%, statin was 60%, and any lipid-lowering agent was 65%.

Principal Findings:

Overall, 5,518 patients were enrolled in the study. The mean age was 62 years, 31% were women, 37% had a previous cardiovascular event, mean systolic blood pressure was 134 mm Hg, and mean glycated hemoglobin (HbA1c) was 8.1.

In the fenofibrate group, low-density lipoprotein (LDL) cholesterol decreased from 100 to 81 mg/dl, high-density lipoprotein (HDL) cholesterol increased from 38 to 41.2 mg/dl, and triglycerides decreased from 189 to 147 mg/dl. In the placebo group, LDL cholesterol decreased from 101 to 80 mg/dl (p = 0.16 between groups), HDL cholesterol increased from 38 to 40.5 mg/dl (p = 0.01 between groups), and triglycerides decreased from 186 to 170 mg/dl (p < 0.001 between groups).

The primary outcome, annual rate of cardiovascular mortality, MI, or stroke was 2.2% with fenofibrate versus 2.4% with placebo (p = 0.32).

The primary outcome plus revascularization or hospitalization for congestive heart failure was 5.4%/year versus 5.6%/year (p = 0.30), major coronary event was 2.6%/year versus 2.8%/year (p = 0.26), and all-cause mortality was 1.5%/year versus 1.6%/year (p = 0.33), respectively, for fenofibrate versus control.

Study drug was discontinued because of a decrease in estimated glomerular filtration rate in 2.4% versus 1.1%, respectively. In subgroup analysis, men appeared to benefit, while women appeared to be harmed from fenofibrate therapy (p for interaction = 0.01). Also, a high triglyceride (>203)/low HDL (<35) profile appeared to benefit (p for interaction = 0.06).

Interpretation:

Among diabetic patients at high risk for cardiovascular disease, the addition of fenofibrate to statin therapy was not superior to statin therapy alone. Fenofibrate was not able to reduce rates of cardiovascular disease. Although fenofibrate reduced triglyceride levels, although there was only a small difference in mean HDL cholesterol between groups, which could help to explain lack of benefit. This agent may still have a role among individuals with a high triglyceride/low HDL profile. The possible harm noted among women deserves further study. This study is in contrast to the benefit of gemfibrozil seen in the HHS and VA-HIT trials.

References:

The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;Mar 14:[Epub ahead of print].

Presented by Dr. Henry Ginsberg at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure

Keywords: Fenofibrate, Stroke, Hyperlipidemias, Gemfibrozil, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diabetes Mellitus, Type 2, Blood Pressure, Hypercholesterolemia, Hemoglobin A, Glycosylated, Cholesterol, Heart Failure, Hypolipidemic Agents, Glomerular Filtration Rate, Triglycerides, Hospitalization


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