• N. Engl. J. Med. · Nov 2022

    Randomized Controlled Trial

    Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

    • Aruna Das Pradhan, Robert J Glynn, Jean-Charles Fruchart, Jean G MacFadyen, Elaine S Zaharris, Brendan M Everett, Stuart E Campbell, Ryu Oshima, Pierre Amarenco, Dirk J Blom, Eliot A Brinton, Robert H Eckel, Marshall B Elam, João S Felicio, Henry N Ginsberg, Assen Goudev, Shun Ishibashi, Jacob Joseph, Tatsuhiko Kodama, Wolfgang Koenig, Lawrence A Leiter, Alberto J Lorenzatti, Boris Mankovsky, Nikolaus Marx, Børge G Nordestgaard, Dénes Páll, Kausik K Ray, Raul D Santos, Handrean Soran, Andrey Susekov, Michal Tendera, Koutaro Yokote, Nina P Paynter, Julie E Buring, Peter Libby, Paul M Ridker, and PROMINENT Investigators.
    • From the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (A.D.P., R.J.G., J.G.M., E.S.Z., B.M.E., N.P.P., J.E.B., P.M.R) and the Division of Cardiovascular Medicine (B.M.E.,P.L., P.M.R.), Brigham and Women's Hospital, the Division of Cardiovascular Medicine, Veteran Affairs Boston Health Care System (A.D.P., J.J.), and Kowa Pharma Development (R.O.) - all in Boston; University of Lille, Lille (J.-C.F.) and the Department of Neurology and Stroke Center, Paris Cité University, Paris (P.A.) - both in France; Kowa Research Institute, Morrisville, NC (S.E.C.); the Division of Lipidology, Department of Medicine, University of Cape Town, Cape Town, South Africa (D.J.B.); Utah Lipid Center, Salt Lake City (E.A.B.); the University of Colorado School of Medicine, Aurora (R.H.E.); the University of Tennessee Health Science Center, Memphis (M.B.E.); the Division of Endocrinology, Universitário Hospital João de Barros Barreto, Belém (J.S.F.), and the Heart Institute (InCor), University of São Paulo Medical School Hospital, and Hospital Israelita Albert Einstein (R.D.S.), São Paulo - all in Brazil; Columbia University Vagelos College of Physicians and Surgeons, New York (H.N.G.); Queen Giovanna University Hospital, Sofia, Bulgaria (A.G.); Jichi Medical University, Shimotsuke (S.I.), the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo (T.K.), and Chiba University Graduate School of Medicine, Chiba (K.Y.) - all in Japan; Deutsches Herzzentrum München, Technische Universität München and German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich (W.K.), Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm (W.K.), and Rheinisch-Westfälische Technische Hochschule Aachen, University Hospital Aachen, Aachen (N.M.) - all in Germany; McMaster University and Population Health Research Institute, Hamilton, ON (P.A.) and the Division of Endocrinology and Metabolism, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Docencia, Asistencia Médica e Investigación Clínica Medical Institute-Rusculleda Foundation for Research, Córdoba, Argentina (A.J.L.); Shupyk National Healthcare University of Ukraine, Kyiv (B.M.); Copenhagen University Hospital-Herlev Gentofte, University of Copenhagen, Copenhagen (B.G.N.); the Department of Medical Clinical Pharmacology, University of Debrecen, Debrecen, Hungary (D.P.); the Department of Primary Care and Public Health, Imperial College London, London (K.K.R.), and the Department of Endocrinology, Diabetes, and Metabolism, Manchester University Hospital NHS Foundation Trust, Manchester (H.S.) - both in the United Kingdom; the Russian Academy of Postgraduate Medical Education, Moscow (A.S.); and the Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland (M.T.).
    • N. Engl. J. Med. 2022 Nov 24; 387 (21): 192319341923-1934.

    BackgroundHigh triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.MethodsIn a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.ResultsAmong 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.ConclusionsAmong patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).Copyright © 2022 Massachusetts Medical Society.

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