Triglyceride levels are routinely measured as part of a preventive cardiac work-up, and lowering triglycerides with various classes of drugs is standard medical practice. However, in a major randomized trial of the new drug pemafibrate, researchers found no reduction in the rates of heart attack, stroke or cardiovascular death over a five-year period, even though the drug lowered triglycerides by a 26 percent compared to placebo. The study was led by researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health System, and included more than 10,000 participants. The new data were presented today at the annual meetings of the American Heart Association Scientific Sessions and published simultaneously in the New England Journal of Medicine.
“Pemafibrate was very effective in reducing triglycerides and what we call residual cholesterol,” said lead author Aruna Pradhan, MD, MPH, of the Brigham Division of Cardiovascular Medicine, who served as co-chair of the essay “However, we saw no evidence of a reduction in hard clinical events that patients and clinicians are concerned about. These findings are both puzzling and clinically important.”
PPARα agonists such as fibrates are a class of drugs that lower the level of triglycerides in the bloodstream through several mechanisms. Pemafibrate, developed by Kowa Company, Ltd as a selective modulator of PPARα (SPPARMα), is licensed for use in Japan and some other Asian countries; Conventional fibrate drugs such as fenofibrate are approved for use worldwide, including in the US
The clinical trial, known as PROMINENT and sponsored by the Kowa Research Institute, Inc., included 10,497 patients with type 2 diabetes, elevated triglyceride levels and low HDL cholesterol levels, a group that had shown promising results in trials with fibrous made a decade ago. However, the PROMINENT trial’s primary endpoint of heart attack, stroke, need for coronary bypass grafting or angioplasty, or cardiovascular death occurred in 572 participants randomized to pemafibrate and 560 assigned to placebo, and none statistical difference between groups. Pemafibrate, however, was generally well tolerated and appeared to reduce rates of non-alcoholic fatty liver disease (NAFLD), an important condition among people with diabetes and obesity.
The authors note that the findings of pemafibrate regarding NAFLD will need external replication; Several clinical trials are currently underway with pemafibrate in the setting of NAFLD.
“We studied a patient population that is at high risk, and the best course of treatment for them remains an open question,” said lead author Paul Ridker, MD, trial co-chair and director of the Center for Prevention of Cardiovascular Diseases of the Brigham. . “In contrast to fibrate studies done a decade ago, our trial was conducted at a time when almost all participants were taking statin therapy, so the relevance of triglyceride lowering in contemporary medical practice remains being uncertain”.
The new PROMINENT data add to the recent controversy and debate over the utility of triglyceride lowering in the contemporary care of patients at risk for heart disease. In 2020, results from the FORCE trial of omega-3 fatty acids showed an approximately 20 percent reduction in triglycerides with no benefit in clinical events. Conversely, in 2019, the REDUCE-IT trial of icosapent ethyl showed a significant reduction in clinical events, but this was not related to the same 20 percent reduction in triglycerides also seen in that trial.
Further trials of triglyceride reduction through alternative pathways (such as ApoCIII and ANGPTL3 inhibition) may help clarify these issues.
“What PROMINENT teaches us, once again, is that we cannot know the truth without large randomized placebo-controlled clinical trials,” Ridker said.
Disclosures: Pradhan has received research grants from Kowa Pharmaceutical Europe Co. Ltd., Kowa Research Institute, Inc. and Denka Company, Ltd.; receives compensation for consulting services from Optum, Novo Nordisk, and Reliant Medical Foundation; and receives conference compensation from Medtelligence and NACE. Ridker has received research grants from Novartis, Kowa, Amarin, Pfizer, Esperion, and the NHLBI; has been a consultant for Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Uptton, Omeicos, Health Outlook, Montai Health, New Amsterdam, Boehringer-Ingelheim, Angiowave, RTI; Horizon Therapeutics and Cardio Therapeutics; and receives compensation for service on the Advisory Board of Peter Munk (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). Disclosures for co-authors can be found in NEJM.
Funding: The PROMINENT trial was funded by Kowa Research Institute, Inc. through an institutional grant from the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital.
Document cited: Pradhan, AD et al. “Triglyceride lowering with pemafibrate for the reduction of cardiovascular events” NEJM DOI: 10.1056/NEJMoa2210645
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