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Original Investigation
August 12, 2020

Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial

Author Affiliations
  • 1University of California School of Medicine, San Francisco, Fresno
  • 2TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 3Department of Medicine, CHU Liège, Liège University, Liège, Belgium
  • 4Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
  • 5Amgen, Thousand Oaks, California
  • 6Sydney Medical School, NHMRC Clinical Trials Centre, University of Sydney, Australia
  • 7National Heart and Lung Institute, Imperial College London, United Kingdom
  • 8Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Norway
  • 9Deputy Editor, JAMA Cardiology
JAMA Cardiol. Published online August 12, 2020. doi:10.1001/jamacardio.2020.3151
Key Points

Question  Can further reduction of low-density lipoprotein cholesterol with evolocumab safely and effectively reduce the residual risk in patients with metabolic syndrome and stable atherosclerotic cardiovascular disease?

Findings  In this prespecified analysis of the FOURIER randomized clinical trial of patients with atherosclerotic cardiovascular disease receiving statin, 16 361 individuals with metabolic syndrome were at higher risk for cardiovascular events than 10 981 patients without metabolic syndrome. In these high-risk patients, compared with placebo, evolocumab significantly reduced low-density lipoprotein cholesterol and the risk of cardiovascular events without increasing the risk of safety events, new-onset diabetes, or worsening glycemic control.

Meaning  The PCSK9 inhibitor evolocumab significantly reduced cardiovascular events in patients with atherosclerotic cardiovascular disease and metabolic syndrome without an increase in serious safety events, including new-onset diabetes.


Importance  The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk.

Objective  To investigate outcomes with evolocumab in patients with and without MetS.

Design, Setting, and Participants  The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020.

Interventions  Patients were randomized to evolocumab or placebo.

Main Outcomes and Measures  The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke.

Results  Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS.

Conclusions and Relevance  Patients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk.

Trial Registration  ClinicalTrials.gov Identifier: NCT01764633