Novel drug lowers triglycerides, does not reduce cardiovascular events

Novel drug lowers triglycerides, does not reduce cardiovascular events

Triglyceride levels are routinely measured as part of a preventative cardiac evaluation, and lowering triglycerides with multiple classes of medications is common medical practice. However, in a large randomized trial of the novel drug pemafibrate, researchers found no reduction in the rates of heart attacks, strokes or cardiovascular deaths over five years, even though the drug reduced triglycerides by 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 highly effective in lowering triglycerides and what we call residual cholesterol. However, we have seen no evidence of a reduction in the serious clinical events that patients and clinicians are concerned about. These results are both puzzling and clinically important.”

Aruna Pradhan, MD, MPH, lead author, study co-chair, Brigham’s Division of Cardiovascular Medicine

PPARα agonists, such as fibrates, are a class of drugs that reduce triglyceride levels in the bloodstream through multiple mechanisms. Pemafibrate, developed by Kowa Company, Ltd as a selective PPARα modulator (SPPARMα), is licensed for use in Japan and some other Asian countries; Traditional fibrate drugs such as fenofibrate are approved for use around the world including the United States

The clinical trial, known as PROMINENT and sponsored by 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 fibrate trials conducted a decade ago. However, the primary endpoint of the PROMINENT trial, myocardial infarction, stroke, need for coronary bypass or angioplasty, or cardiovascular death, occurred in 572 participants randomly assigned to pemafibrate and 560 participants randomly assigned to placebo, resulting in no statistical difference between the groups. However, pemafibrate was generally well tolerated and appeared to reduce rates of nonalcoholic fatty liver disease (NAFLD), an important condition in individuals with diabetes and obesity.

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The authors note that the results for pemafibrate in relation to NAFLD require external replication; Several other clinical trials of pemafibrate in NAFLD are currently underway.

“We studied a patient population that is at high risk, and the best method of treatment for them remains an open question,” said senior author Paul Ridker, MD, co-chair of the study and director of the Center for Cardiovascular Disease Prevention at the Brigham. "Unlike studies of fibrates conducted a decade ago, our study was conducted at a time when almost all participants were taking statin therapy, so the relevance of triglyceride lowering in today's medical practice remains uncertain."

The new PROMINENT data add to recent controversies and debates about the utility of triglyceride lowering in the contemporary care of patients at risk for heart disease. In 2020, results from the STRENGTH study of omega-3 fatty acids showed an approximately 20% reduction in triglycerides with no benefit to clinical events. In contrast, the 2019 REDUCE-IT trial of icosapent ethyl showed a significant reduction in clinical events, but this was not related to the same 20% reduction in triglycerides seen in that trial.

Other studies of triglyceride lowering using 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.

Source:

Brigham and Women's Hospital

Reference:

Pradhan, AD, et al. (2022) Triglyceride lowering with pemafibrate to reduce cardiovascular events. New England Journal of Medicine. doi.org/10.1056/NEJMoa2210645.

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