Effects of combination lipid therapy in type 2 diabetes mellitus

Abstract

Background: We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease.

Methods: We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.

Results: The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction).

Conclusions: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

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 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129.

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 of 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.

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 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129.