Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study

Abstract

Background: The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study found no evidence of a beneficial effect of statin-fibrate combined treatment, compared to statins alone, on cardiovascular outcomes and mortality in type 2 diabetes mellitus after 5 years of active treatment. However, a beneficial reduction in major CVD events was shown in a pre-specified sub-group of participants with dyslipidemia. The extended follow-up of this trial provides the opportunity to further investigate possible beneficial effects of fibrates in this group of patients. We aimed to evaluate possible "legacy effects" of fibrate add-on therapy on mortality and major cardiovascular outcomes in patients with dyslipidemia.

Methods: The ACCORD-lipid study was a randomized controlled trial of 5518 participants assigned to receive simvastatin plus fenofibrate vs simvastatin plus placebo. After randomized treatment allocation had finished at the end of the trial, all surviving participants were invited to attend an extended follow-up study (ACCORDION) to continue prospective collection of clinical outcomes. We undertook a secondary analysis of trial and post-trial data in patients who had dyslipidemia. The primary outcome was all-cause and cardiovascular mortality, and secondary outcomes were nonfatal myocardial infarction, stroke, congestive heart failure and major coronary heart disease. We used an intention-to-treat approach to analysis to make comparisons between the original randomized treatment groups.

Results: 853 participants with dyslipidemia had survived at the end of the trial. Most participants continued to use statins, but few used fibrates in either group during the post-trial period. The incidence rates in the fenofibrate group were lower with respect to all-cause mortality, CVD mortality, nonfatal myocardial infarction, congestive heart failure and major coronary heart disease than those in the placebo group over a post-trial follow-up. Allocation to the combined fibrate-statin treatment arm during the trial period had a beneficial legacy effect on all-cause mortality (adjusted HR = 0.65, 95% CI 0.45-0.94; P = 0.02).

Conclusions: Fibrate treatment during the initial trial period was associated with a legacy benefit of improved survival over a post-trial follow-up. These findings support re-evaluation of fibrates as an add-on strategy to statins in order to reduce cardiovascular risk in diabetic patients with dyslipidemia. Trial registration clinicaltrials.gov, Identifier: NCT00000620.

Keywords: Cardiovascular diseases; Dyslipidemia; Fibrate; Legacy effect; Type 2 diabetes.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Plasma lipid levels of patients with dyslipidemia at each study visit. The line charts show the means of lipid levels and corresponding 95% CI at 1/2/3/4 year, exit visit, 1st post-trial visit and last post-trial visit. HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, VLDL-C very low-density lipoprotein cholesterol, PT1 first post-trial clinic visit, PT3 last post-trial clinic visit

Fig. 2

Kaplan–Meier cumulative event curves for primary and secondary outcomes. The Kaplan–Meier curves display the time to event for the all-cause mortality (a) and cardiovascular mortality (b), nonfatal myocardial infarction (c), stroke (d), congestive heart failure (e) and a major coronary heart disease event (f) during trial period, post-trial and the entire study period. The numbers of individuals at risk are shown for each time point