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Original Investigation
December 28, 2016

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

Author Affiliations
  • 1Memphis Veterans Affairs Medical Center and University of Tennessee Health Sciences Center, Memphis
  • 2Columbia University College of Physicians and Surgeons, New York, New York
  • 3Wake Forest School of Medicine, Wake Forest, North Carolina
  • 4University of Washington, Seattle
  • 5University of North Carolina, Chapel Hill
  • 6Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Ontario, Canada
  • 7HealthPartners Institute, Minneapolis, Minnesota
  • 8Atlanta Veterans Affairs Medical Center, Atlanta, Georgia
  • 9Diabetes Endocrine Nutrition Group, Mentor, Ohio
  • 10McMaster Medical Center, Hamilton, Ontario, Canada
  • 11Berman Center for Outcomes and Clinical Research, Minneapolis, Minnesota
  • 12Cleveland Veterans Affairs Medical Center, Cleveland, Ohio
  • 13Colorado School of Public Health, Aurora, Colorado
  • 14National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, Bethesda, Maryland
JAMA Cardiol. Published online December 28, 2016. doi:10.1001/jamacardio.2016.4828
Key Points

Question  Does fenofibrate reduce cardiovascular disease risk in statin-treated patients with type 2 diabetes?

Findings  In this posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes Lipid Study, fenofibrate therapy was associated with reduced cardiovascular disease 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.

Meaning  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.

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.

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