Atherosclerotic cardiovascular disease is increased severalfold in most patients with type 2 diabetes, particularly patients who are older and have other risk factors (1,2). These associated risk factors include hypertension, obesity, and dyslipidemia. Diabetic dyslipidemia, which has also been called atherogenic dyslipidemia (a term that describes the lipid abnormalities in people with insulin resistance, metabolic syndrome, and type 2 diabetes), is characterized by elevated plasma triglyceride (TG) levels, low levels of HDL cholesterol, and smaller cholesterol ester–depleted LDL (3). Despite the fact that statins, which mainly lower blood levels of LDL cholesterol, have the same relative effectiveness in type 2 diabetic patients as in nondiabetic subjects, absolute rates of atherosclerotic cardiovascular disease events remained higher in patients with diabetes who participated in all of the statin trials (4,5). These findings have raised interest in the use of combination therapy, particularly the combination of a statin plus a drug that would lower plasma TG levels and raise plasma HDL cholesterol levels.
ACCORD (Action to Control Cardiovascular Risk in Diabetes) was specifically designed to determine the effects of intensive treatment of blood glucose, and either blood pressure (ACCORD Blood Pressure) or plasma lipids (ACCORD Lipid), on atherosclerotic cardiovascular disease outcomes in patients with type 2 diabetes who were at high risk of such an outcome (6). The ACCORD Lipid trial tested the hypothesis that treatment of patients with type 2 diabetes with fenofibrate to increase plasma HDL cholesterol levels and reduce plasma TG concentrations, on the background of simvastatin therapy, would result in additional cardiovascular benefit compared with simvastatin therapy alone (7).
The ACCORD Lipid trial used fenofibrate because 1) data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial indicated that the risk of myositis when fenofibrate was combined with a statin was negligible; 2) fenofibrate was expected to lower TG levels by ~25% and increase HDL cholesterol levels by ~5–10% while having minimal effects on LDL cholesterol concentrations; 3) niacin, an alternative that would have probably had much greater effects on HDL cholesterol, would have caused problems for the glycemic component of ACCORD; and 4) niacin would have also reduced LDL cholesterol significantly, making it difficult to attribute any benefit to changes in TG and HDL cholesterol levels. There were concerns, however, regarding the use of fenofibrate. Thus, although gemibrozil treatment had been beneficial in both a primary prevention nondiabetic population in the Helsinki Heart Study (8) and in a secondary prevention diabetic subgroup in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) (9,10), fenofibrate did not significantly reduce coronary heart disease death or nonfatal myocardial infarction in the FIELD study, which was a mixed primary/secondary prevention trial (11).
A total of 5,518 men and women with type 2 diabetes were enrolled in the ACCORD Lipid trial. All participants received simvastatin (20–40 mg/day) and were also randomly assigned to masked fenofibrate (160 or 54 mg/day, depending on renal function) or placebo. The primary outcome was the first postrandomization occurrence of a nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The mean follow-up was 4.7 years.
The primary outcome occurred at a rate of 2.4%/year in the placebo group and 2.2%/year in the fenofibrate group. This result gave a hazard ratio of 0.92 (95% CI 0.79–1.08), which was not significant (P = 0.32). Thus, the ACCORD Lipid trial did not confirm its primary hypothesis. There were a number of secondary outcomes, including each component of the primary composite outcome tested individually, an expanded cardiovascular outcome, major coronary events, and total mortality. None of these outcomes showed differences that were statistically significant. In some prior fibrate trials, cardiovascular and/or total mortality tended to be increased in fibrate-treated groups. In the ACCORD Lipid trial, annual cardiovascular mortality was 0.77% in the fenofibrate group and 0.83% in the placebo group; total mortality was 1.47% in the fenofibrate group and 1.61% in the placebo group. There was no evidence of increased mortality with fenofibrate.
The ACCORD Lipid trial had 11 prespecified subgroup analyses. The first six were defined by demographic characteristics or allocation to intensive versus standardized glucose control. Of those six subgroups, there was a significant interaction (P = 0.011) for treatment effect by sex; men had an ~16% lower primary event rate on fenofibrate, whereas women had an ~38% greater primary event rate on fenofibrate. Neither of these sex-specific effects of fenofibrate versus placebo was significant.
The second five subgroups were defined by baseline lipids (tertiles for LDL cholesterol, HDL cholesterol, and TG), a subgroup defined by the presence of both a TG level in the upper third and an HDL cholesterol level in the lower third at baseline (dyslipidemic group) versus all others, and groups defined by HbA1c levels above or below 8.0% at baseline. There was a trend for an interaction (P = 0.057) for treatment by lipid levels only for the group with both high TG and low HDL cholesterol compared with all others. The dyslipidemic group had an ~30% lower outcome on fenofibrate compared with placebo (in the absence of a significant interaction P value, statistical analysis was not conducted on the outcome in the dyslipidemic group). There was no difference at all in event rates between the fenofibrate and the placebo groups who were not dyslipidemic. The dyslipidemic group made up ~15% of the overall cohort in the ACCORD Lipid trial.
We do not have an explanation at this time for the difference in outcomes based on sex. There was no sex difference in the primary outcome in the FIELD study (11); additional analyses are underway. Of note, in the subgroup defined by both high TG and low HDL, women, who made up ~20% of that group, had a similar benefit from fenofibrate as the men.
The results from the dyslipidemic subgroup in the ACCORD Lipid trial, which was a prespecified analysis, are similar to post hoc analyses performed in prior fibrate studies, including the Helsinki Heart Study (12), the Bezafibrate Infarction Prevention (BIP) trial (13), and FIELD (14). In each of those trials, analysis of a dyslipidemic subgroup revealed either significantly greater benefit than in the overall trial cohort (11) or the only actual positive outcome in the study (13,14).
Overall, the ACCORD Lipid trial was negative. There is no evidence from this trial to indicate that fenofibrate should be routinely added to a statin for the treatment of lipids in patients with type 2 diabetes. Indeed, routine addition of fenofibrate might be harmful for women with type 2 diabetes. However, the ACCORD data, together with post hoc analyses of three other fibrate trials, suggest that, when TG is >200 mg/dL and HDL is <35 mg/dL after statin therapy has significantly reduced LDL cholesterol levels, fibrate treatment can be considered, at least in men.
This publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were made possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-La Roche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pfizer.
No potential conflicts of interest relevant to this article were reported.