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):1923-1934. doi: 10.1056/NEJMoa2210645. Epub 2022 Nov 5.
High 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.
In 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.
Among 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.
Among 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.).
甘油三酯水平升高与心血管风险增加相关，但降低这些水平是否会降低心血管事件的发生率尚不确定。Pemafibrate 是一种选择性过氧化物酶体增殖物激活受体 α 调节剂，可降低甘油三酯水平并改善其他脂质水平。
在一项多中心、双盲、随机、对照试验中，我们将 2 型糖尿病、轻中度高甘油三酯血症（甘油三酯水平 200 至 499mg/dL）且高密度脂蛋白（HDL）胆固醇水平低于或等于 40mg/dL 的患者随机分配接受 pemafibrate（每天两次 0.2mg 片剂）或匹配的安慰剂。符合条件的患者正在接受指南指导的降脂治疗，或者如果不产生不良反应则无法接受他汀类药物治疗，且低密度脂蛋白（LDL）胆固醇水平低于 100mg/dL。主要疗效终点是复合非致命性心肌梗死、缺血性中风、冠状动脉血运重建或心血管原因导致的死亡。
在 10497 名患者（66.9%有既往心血管疾病）中，中位基线空腹甘油三酯水平为 271mg/dL，HDL 胆固醇水平为 33mg/dL，LDL 胆固醇水平为 78mg/dL。中位随访时间为 3.4 年。与安慰剂相比，pemafibrate 在 4 个月时对血脂水平的影响为：甘油三酯降低 26.2%，极低密度脂蛋白（VLDL）胆固醇降低 25.8%，残留在胆固醇（脂蛋白重塑后经脂肪分解和脂蛋白转运的富含甘油三酯的脂蛋白中的胆固醇）降低 25.6%，载脂蛋白 C-III 降低 27.6%，载脂蛋白 B 降低 4.8%。pemafibrate 组有 572 例患者发生主要终点事件，安慰剂组有 560 例（风险比，1.03；95%置信区间，0.91 至 1.15），任何预先指定的亚组均无明显的效应修饰。两组严重不良事件的总体发生率无显著差异，但 pemafibrate 与更高的不良肾脏事件和静脉血栓栓塞发生率相关，而非酒精性脂肪性肝病发生率较低。
在 2 型糖尿病、轻中度高甘油三酯血症和低 HDL 和 LDL 胆固醇水平的患者中，与安慰剂相比，接受 pemafibrate 治疗的患者心血管事件发生率并未降低，尽管 pemafibrate 降低了甘油三酯、VLDL 胆固醇、残留在胆固醇和载脂蛋白 C-III 水平。（由 Kowa 研究所资助；PROMINENT ClinicalTrials.gov 编号，NCT03071692。）
