Pemafibrate Did Not Reduce Risk of Cardiovascular Events in PROMINENT Trial

Aruna D Pradhan, MD, MPH, MSc

The incidence of cardiovascular events was not lowered with pemafibrate use among patients with type 2 diabetes (T2D), mild-to-moderate hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and well-controlled low-density lipoprotein cholesterol (LDL-C) levels, compared to placebo.

However, the data show that levels of triglycerides, very-low-density cholesterol (VLDL), remnant cholesterol, and apolipoprotein C-III levels were observed to be 26 - 28% lower in the pemafibrate group, compared to placebo.

The late-breaking findings from the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial were presented at the American Heart Association Scientific Sessions 2022 in Chicago.

“These data highlight the complexity of lipid mediators of residual risk in statin-treated insulin resistant patients,” said study author Aruna D Pradhan, MD, MPH, MSc, Brigham and Women's Hospital in her presentation. “It is possible that beyond effects on triglyceride rich lipoprotein remodeling, enhanced clearance of lipoproteins derived from remnant catabolism is also needed to neutralize residual risk in hypertriglyceridemia.”

Increased triglyceride levels have been linked to an elevated cardiovascular risk, but it remains uncertain whether lowering triglyceride levels subsequently lowers the incidence of cardiovascular events.

The PROMINENT trial assigned participants to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Pemafibrate is a potent and selective peroxisome proliferator-activated receptor α (PPARα) modulator.

Patients were required to have a diagnosis of T2D, a fasting triglyceride level of 200 to 499 mg per deciliter, and an HDL-C level of 40 mg per deciliter or less. Further eligibility for patients included receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had a documented LDL-C level of 100 mg per deciliter or lower.

Primary efficacy endpoints were the first occurrence of a major adverse cardiovascular event, considered a composite of myocardial infarction, ischemic stroke, coronary revascularization, or cardiovascular death. Safety endpoints included investigator-reported adverse events, renal adverse events, and venous thromboembolism (VTE).

Due to a review of the interim data in March 2020, after 75% of the target number of events had been accrued, the data and safety monitoring board unanimously recommended early termination of the trial as prespecified futility boundaries were crossed. The efficacy follow-up ended in April 2022.

A total of 10,497 patients (66.9% with previous CVD) from 876 clinical sites in 24 countries. composed the intention-to-treat population with balanced characteristics. The median baseline fasting triglyceride level was 271 mg per deciliter, HDL-C level was 33 mg per deciliter, and LDL-C level was 78 mg per deciliter.

Data show the median percentage change in the fasting triglyceride level from baseline to 4 months was -31.1% in the pemafibrate group and -6.9% in the placebo group, associated with a relative between-group difference of -26.2%.

Moreover, the effect of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for VLDL-C, –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.

Following randomization, a primary endpoint event occurred in 572 patients in the pemafibrate group and in 560 patients in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.91 to 1.15; P = .67).

Effects were reported as neutral for all composite secondary cardiovascular endpoints and for the individual components of these endpoints. The incidences of all serious adverse events, infections, and musculoskeletal complications did not differ significantly between each group.

There were more investigator-reported adverse renal events in the pemafibrate group that in the placebo group (1463 patients vs. 1347 patients; HR, 1.12; 95% CI, 1.04 to 1.20; P = .004), but the estimated glomerular filtration rate returned to baseline after pemafibrate or placebo was discontinued.

Additionally, the number of patients with investigator-reported VTE was higher in the pemafibrate group than in the placebo group (71 patients vs 35 patients; HR, 2.05; 95% CI, 1.35 to 3.17; P <.001), while the number of patients with investigator reported nonalcoholic fatty liver disease was lower (155 patients vs 200 patients; HR, 0.78; 95% CI, 0.63 to 0.96; P = .02).

“These data cannot exclude the possibility that the observed increase in LDL-C and ApoB negated any benefit of triglyceride reduction,” Pradhan said. “Ongoing trials of agents that use alternative pathways to lower triglycerides and remnant cholesterol, including ApoCIII and angiopoietin-like protein 3 (ANGPTL3) inhibition, may help to clarify these issues.”

The study, “Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk,” was presented at AHA 2022 and published simultaneously in The New England Journal of Medicine.