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Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes.
JAMA Cardiol. 2017 04 01; 2(4):370-380.JC

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.

Authors+Show Affiliations

Memphis Veterans Affairs Medical Center and University of Tennessee Health Sciences Center, Memphis.Columbia University College of Physicians and Surgeons, New York, New York.Wake Forest School of Medicine, Wake Forest, North Carolina.University of Washington, Seattle.University of North Carolina, Chapel Hill.Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Ontario, Canada.Columbia University College of Physicians and Surgeons, New York, New York.HealthPartners Institute, Minneapolis, Minnesota.Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.Diabetes Endocrine Nutrition Group, Mentor, Ohio.Columbia University College of Physicians and Surgeons, New York, New York.University of North Carolina, Chapel Hill.McMaster Medical Center, Hamilton, Ontario, Canada.University of Washington, Seattle.Berman Center for Outcomes and Clinical Research, Minneapolis, Minnesota.Cleveland Veterans Affairs Medical Center, Cleveland, Ohio.Colorado School of Public Health, Aurora, Colorado.National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, Bethesda, Maryland.National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, Bethesda, Maryland.Wake Forest School of Medicine, Wake Forest, North Carolina.No affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28030716

Citation

Elam, Marshall B., et al. "Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes." JAMA Cardiology, vol. 2, no. 4, 2017, pp. 370-380.
Elam MB, Ginsberg HN, Lovato LC, et al. Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes. JAMA Cardiol. 2017;2(4):370-380.
Elam, M. B., Ginsberg, H. N., Lovato, L. C., Corson, M., Largay, J., Leiter, L. A., Lopez, C., O'Connor, P. J., Sweeney, M. E., Weiss, D., Friedewald, W. T., Buse, J. B., Gerstein, H. C., Probstfield, J., Grimm, R., Ismail-Beigi, F., Goff, D. C., Fleg, J. L., Rosenberg, Y., & Byington, R. P. (2017). Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes. JAMA Cardiology, 2(4), 370-380. https://doi.org/10.1001/jamacardio.2016.4828
Elam MB, et al. Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes. JAMA Cardiol. 2017 04 1;2(4):370-380. PubMed PMID: 28030716.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes. AU - Elam,Marshall B, AU - Ginsberg,Henry N, AU - Lovato,Laura C, AU - Corson,Marshall, AU - Largay,Joseph, AU - Leiter,Lawrence A, AU - Lopez,Carlos, AU - O'Connor,Patrick J, AU - Sweeney,Mary Ellen, AU - Weiss,Daniel, AU - Friedewald,William T, AU - Buse,John B, AU - Gerstein,Hertzel C, AU - Probstfield,Jeffrey, AU - Grimm,Richard, AU - Ismail-Beigi,Faramarz, AU - Goff,David C,Jr AU - Fleg,Jerome L, AU - Rosenberg,Yves, AU - Byington,Robert P, AU - ,, PY - 2016/12/29/pubmed PY - 2019/5/31/medline PY - 2016/12/29/entrez SP - 370 EP - 380 JF - JAMA cardiology JO - JAMA Cardiol VL - 2 IS - 4 N2 - 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. SN - 2380-6591 UR - https://www.unboundmedicine.com/medline/citation/28030716/Association_of_Fenofibrate_Therapy_With_Long_term_Cardiovascular_Risk_in_Statin_Treated_Patients_With_Type_2_Diabetes_ L2 - https://jamanetwork.com/journals/jamacardiology/fullarticle/10.1001/jamacardio.2016.4828 DB - PRIME DP - Unbound Medicine ER -