Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes

ACCORDION Study Investigators

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)370-380
Number of pages11
JournalJAMA Cardiology
Volume2
Issue number4
DOIs
StatePublished - Apr 1 2017

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Fenofibrate
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Type 2 Diabetes Mellitus
Cardiovascular Diseases
HDL Cholesterol
Lipids
Therapeutics
Hypertriglyceridemia
Placebos
HDL Lipoproteins
LDL Cholesterol
Triglycerides
Outcome Assessment (Health Care)
Fibric Acids
Fatal Outcome
Dyslipidemias
Ambulatory Care Facilities
African Americans
Population
Canada

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. / ACCORDION Study Investigators.

In: JAMA Cardiology, Vol. 2, No. 4, 01.04.2017, p. 370-380.

Research output: Contribution to journalArticle

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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.",
author = "{ACCORDION Study Investigators} and Elam, {Marshall B.} and Ginsberg, {Henry N.} and Lovato, {Laura C.} and Marshall Corson and Joseph Largay and Leiter, {Lawrence A.} and Carlos Lopez and O’Connor, {Patrick J.} and Sweeney, {Mary Ellen} and Marshall Elam and Friedewald, {William T.} and Buse, {John B.} and Gerstein, {Hertzel C.} and Jeffrey Probstfield and Richard Grimm and Faramarz Ismail-Beigi and Goff, {David C.} and Fleg, {Jerome L.} and Yves Rosenberg and Byington, {Robert P.}",
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T1 - Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes

AU - ACCORDION Study Investigators

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 - Elam, Marshall

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.

AU - Fleg, Jerome L.

AU - Rosenberg, Yves

AU - Byington, Robert P.

PY - 2017/4/1

Y1 - 2017/4/1

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.

AB - 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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