Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes

Abstract

Importance: Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk.

Objective: To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes.

Design, setting, and participants: Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals).

Interventions: Passive follow-up of study participants previously treated with fenofibrate or masked placebo.

Main outcomes and measures: Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups.

Results: The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95).

Conclusions and relevance: Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings.

Trial registration: clinicaltrials.gov Identifier: NCT00000620.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ginsberg reports receiving grants and personal fees from Merck outside the submitted work. Dr Largay reports grants from the National Institutes of Health/National Heart, Lung, and Blood Institute during the conduct of the study; personal fees from AstraZeneca, Sanofi Aventis, Takeda, and Vivus; and grants from Andromeda, Boehringer Ingelheim, GI Dynamics, Halozyme, Hoffman-LaRoche, Immune Tolerance Network, Johnson and Johnson, Lexicon, Lilly, Medtronic, Merck, Novo Nordisk, Orixigen, Phase Bio, National Institute of Allergy and Infectious Diseases, Sanofi Aventis, Takeda, and Tolerx; and personal fees from Quadrant Healthcare, Medical Logix, Creative Educational Concepts, Institute for Medical and Nursing Education, and Global Academy for Medical Education outside the submitted work. Dr Largay is an employee of AstraZeneca as a Clinical Science Liaison in Diabetes Medical Affairs. Dr Leiter reports personal fees from Aegerion; grants and personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Servier; and grants from GlaxoSmithKline and Pfizer outside the submitted work. Dr Buse reports grants and fees from Eli Lilly, Bristol-Myers Squibb, GI Dynamics, Amylin, Orexigen, Merck, Novo Nordisk, AstraZeneca, Takeda, Sanofi, and Lexicon; fees from Hoffmann-La Roche, Liposcience, Elcylex, Metavention, vTv Pharma (formerly Transtech Pharma), Dance Biopharm, Quest, and Medtronic Minimed; personal fees from PhaseBio; and grants from Tolerex, Osiris, Halozyme, Pfizer, Johnson and Johnson, Andromeda, Boehringer-Ingelheim, GlaxoSmithKline, Astellas, MacroGenics, Intarcia Therapeutics, and Scion NeuroStim outside the submitted work. Dr Buse is a member of a variety of nonprofit boards including American Diabetes Association, DiabetesSisters, Taking Control of Your Diabetes, AstraZeneca Healthcare Foundation, Bristol-Myers Squib Together on Diabetes Foundation, and the National Diabetes Education Program. Dr Gerstein reports grants and personal fees from Sanofi, Lilly, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck; grants from Jansen; and personal fees from Abbott, Berlin Chemie, Amgen, Kaneq Bioscience, Roche, and GlaxoSmithKline outside the submitted work. Dr Probstfield reports grants and personal fees from Sanofi. Dr Ismail-Beigi reports grants from the National Institutes of Health and Novo Nordisk and fees from Eli Lilly, Thermalin Diabetes, and COVANCE outside the submitted work. Dr Goff reports grants from the National Institutes of health outside the submitted work. Dr Byington reports personal fees from Eli Lilly and Company. No other disclosures were reported.

Figures

Figure 1.. Action to Control Cardiovascular Risk in Diabetes (ACCORD)/ACCORD Follow-On Study (ACCORDION) CONSORT Diagram

In the ACCORD study, eligible participants underwent 2 sequential randomizations, the first to intensive vs standard glycemia therapy followed by a second randomization to intensive vs standard blood pressure or lipid treatment in a double 2 × 2 factorial design. In the ACCORD lipid trial, participants were randomized to either fenofibrate or placebo on a background of statin therapy. Following completion of ACCORD, a total of 4644 surviving Lipid trial participants agreed to extended passive (nontreatment) follow-up in ACCORDION. Rates of occurrence of cardiovascular end points during the original study and during extended follow-up were assessed in all study participants with censoring for the last date of follow-up.

Figure 2.. Kaplan-Meier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death

The cumulative incidence of the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (A), the expanded macrovascular outcome (a combination of the primary outcome plus revascularization or hospitalization for congestive heart failure) (B), and death from any cause (C) or from cardiovascular causes (D) during follow-up.

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. P values are for tests for interaction. HDL-C indicates high-density lipoprotein and LDL-C indicates low-density lipoprotein cholesterol. 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 0.0112.