Abstract
BackgroundThe 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.MethodsThe 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.Results853 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).ConclusionsFibrate 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
Highlights
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
Study participants and setting The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial was a randomized, double 2 × 2 factorial design study, which evaluated the effects of intensive glycemic control, intensive blood pressure control, and combined fibrate statin treatment, on the prevention of cardiovascular disease in people with type 2 diabetes mellitus (T2DM) [26]
The starting dose of open-labeled simvastatin were determined by presence of cardiovascular disease and the dose of masked fenofibrate/placebo were determined by calculated glomerular filtration rate at randomization
Summary
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. A meta-analysis of 14 randomized trials which included more than 18,000 people with diabetes, found that for every mmol/L reduction in LDL cholesterol there was a 21% proportional reduction in the risk of a major vascular event [4]. This proportional risk reduction is similar to that observed in people without diabetes [5], but because the baseline absolute risk is on average higher in people with diabetes, the absolute benefits are greater. There is evidence from Mendelian randomization studies that high triglycerides are causally related to CVD, and so drug therapy targeting this lipid abnormality could help to further reduce CVD risk in people with T2DM [12,13,14]
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