Increased triglyceride levels are tied to elevated cardiovascular risk, but there’s mixed evidence about whether lowering those levels also lowers the incidence of major adverse cardiovascular events.
Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention in the Division of Preventive Medicine at Brigham and Women’s Hospital, Aruna D. Pradhan, MD, MPH, also affiliated with the Center, and colleagues addressed this issue in the PROMINENT trial of pemafibrate, a selective peroxisome proliferator–activated receptor α (PPARα) agonist that lowers plasma triglyceride levels. The investigators found that although pemafibrate therapy was associated with reduced levels and certain other lipids, it did not reduce the risk of cardiovascular events. They published their report in The New England Journal of Medicine.
Methods
PROMINENT was a double-blind, randomized, placebo-controlled trial conducted at 876 sites in 24 countries. It was sponsored by Kowa Research Institute, a subsidiary of Kowa, the manufacturer of pemafibrate.
Patients were eligible if they had a diagnosis of type 2 diabetes, a fasting triglyceride level of 200 to 499 mg/dL, a high-density lipoprotein cholesterol level ≤40 mg/dL and a low-density lipoprotein cholesterol level ≤100 mg/dL.
10,538 patients who demonstrated ≥75% adherence during a 21-day placebo run-in trial were randomly assigned 1:1 to receive pemafibrate (one 0.2-mg tablet twice daily) or matching placebo. 10,497 patients composed the intention-to-treat population:
- Primary prevention cohort—Men ≥50 years old and women ≥55 years old who did not have atherosclerotic cardiovascular disease (CVD) (n=3,471; 33%)
- Secondary prevention cohort—Patients ≥18 years old who had established atherosclerotic CVD (n=7,026; 67%)
Trial enrollment began in March 2017 and was completed in September 2020. On March 18, 2022, after reviewing interim data, the data and safety monitoring board recommended early termination because of futility. Efficacy follow-up ended on April 8, 2022, and the last trial visit occurred in July 2022. The median follow-up was 3.4 years (maximum, 5.0 years).
Changes in Lipids
Compared with placebo, the effects of pemafibrate on lipid levels at four months were:
−26.2% for triglycerides
−25.8% for very low density lipoprotein (LDL) cholesterol
−25.6% for remnant cholesterol (transported in triglyceride-rich lipoproteins)
−27.6% for apolipoprotein C-III
+4.8% for apolipoprotein B
+5.1% for LDL cholesterol
+0.8% for total cholesterol (not significant)
−0.2% for non-HDL cholesterol (not significant)
Efficacy Endpoints
The primary endpoint was the composite of myocardial infarction, ischemic stroke, any coronary revascularization or death from cardiovascular causes.
A primary endpoint event occurred in 572 patients in the pemafibrate group and 560 in the placebo group (HR, 1.03; P=0.67). The effect of pemafibrate was also nonsignificant for all prespecified secondary cardiovascular endpoints, including death from cardiovascular causes, and for death from any cause.
There was no apparent heterogeneity in treatment effect across any prespecified subgroup, including women and patients in the primary or secondary prevention cohorts.
Adverse Events
The total incidence of serious adverse events was no greater in the pemafibrate group than the control group. Venous thromboembolism and renal adverse events were significantly more frequent with pemafibrate. Intriguingly, hepatic adverse events and cases of nonalcoholic fatty liver disease were significantly less frequent in the pemafibrate group.
The Controversy Continues
96% of patients in this trial concomitantly used a statin, including 69% who received high-intensity statin therapy. These findings cast more doubt on triglyceride lowering as a method of reducing residual cardiovascular risk, especially among patients on high-intensity statin therapy.
The lack of benefit shown in this trial suggests enhanced clearance of triglyceride-rich lipoprotein remnant particles from the circulation—rather than their conversion to LDL particles—may be needed to nullify the atherogenic effects of the remnants in patients with hypertriglyceridemia. Ongoing clinical trials are investigating agents that lower levels of triglycerides and remnant particles via alternative mechanisms.
As of this writing, pemafibrate is not approved in the U.S.