Pemafibrate in Hypertriglyceridemia: Treating Patients or Numbers?

Pemafibrate in Hypertriglyceridemia: Treating Patients or Numbers?
Joy Xie, PharmD
Community-University Health Care Center

Background: Triglycerides are atherogenic and a component of very low-density lipoprotein. Hypertriglyceridemia has been shown to increase atherosclerotic cardiovascular disease (ASCVD) risk. Previous studies of medications used to lower triglycerides have found no reduction in cardiovascular risk despite significant improvements in triglyceride levels. Pemafibrate is a potent and selective peroxisome proliferator-activated receptor alpha (PPARα) modulator that is known to decrease triglyceride levels. Previous subgroup analyses suggest that this medication could improve cardiovascular outcomes in patients with hypertriglyceridemia and low levels of low-density lipoprotein (LDL).

Purpose: To determine if triglyceride-lowering with pemafibrate is also associated with an improvement in cardiovascular outcomes in adults with type 2 diabetes and mild-to-moderate hypertriglyceridemia.

Study Design: This double-blind, randomized, placebo-controlled, event-driven trial was conducted in 24 countries with enrollment taking place between March 2017 and September 2020. The study included two cohorts: the primary-prevention cohort included men ≥50 years and women ≥55 years without a history of ASCVD, and the secondary-prevention cohort included adults ≥18 years with established ASCVD. To be eligible, participants had to have a diagnosis of type 2 diabetes, a fasting triglyceride level of 200-499 mg/dL, high-density lipoprotein (HDL) of ≤40 mg/dL, and LDL of ≤70 mg/dL with or without lipid-lowering therapy or LDL ≤100 mg/dL and unable to receive statin therapy. Those with type 1 diabetes; poorly controlled diabetes or thyroid disease; or severe heart failure, kidney disease, or liver disease were excluded. Participants were randomized to receive either pemafibrate 0.2 mg twice daily or placebo. The initial primary outcome was a composite of myocardial infarction, ischemic stroke, hospitalization for unstable angina needing unplanned coronary revascularization (later modified to include any coronary revascularization event), or death from cardiovascular causes. Notable secondary outcomes included the original primary outcome, composite of the primary outcome or hospitalization for heart failure, and new or worsening peripheral artery disease.

Results: A total of 10,497 patients were included in the intention-to-treat population. Baseline characteristics between the two treatment groups were balanced: the median age was 64 years, 27.5% were female, 85.8% were white, and 19.4% were Hispanic or Latinx. One-third of participants were part of the primary-prevention cohort. At baseline, 95.7% of the the trial population was on a statin, and 80.1% were on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. The median fasting lipid profile showed a triglyceride level of 271 mg/dL, HDL of 33 mg/dL, and LDL of 78 mg/dL. The median HbA1c was 7.3% in both groups. At four months, the pemafibrate group saw a 31.1% reduction in triglycerides compared to 6.9% with placebo. There was a 14.0% increase in LDL cholesterol in the pemafibrate group; however, no change in total or non-HDL cholesterol. With regard to clinical outcomes, the primary composite endpoint occurred in 572 patients in the pemafibrate group and 560 patients in the placebo group (HR, 1.03; 95% CI, 0.91-1.15; P=0.67). The original primary composite endpoint occurred in 432 patients in the pemafibrate group and 417 patients in the placebo group (HR, 1.04; 95% CI, 0.91-1.19). There was no statistical difference in any other secondary cardiovascular endpoints between the two groups. The pemafibrate group demonstrated an increase in renal adverse effects (HR, 1.12; 95% CI, 1.04-1.20; P=0.004) and venous thromboembolism (HR, 2.05; 95% CI, 1.35-3.17; P<0.001) compared to placebo. However, the treatment group experienced fewer hepatic adverse events (HR, 0.83; 95% CI, 0.69-0.99; P=0.04), including fewer reported nonalcoholic fatty liver disease (HR, 0.78; 95% CI, 0.63-0.96; P=0.02).

Conclusions: Despite previous subgroup analyses suggesting that triglyceride-lowering therapy could improve cardiovascular risk in patients with hypertriglyceridemia, low HDL, and concomitant type 2 diabetes, this study continues to support previous conclusions that statistically significant triglyceride-lowering is not associated with reduction in cardiovascular risk.

Key Point: This trial demonstrated that despite significant reductions in triglycerides in the treatment group, pemafibrate was not associated with a statistically or clinically significant reduction in ASCVD risk. These conclusions support current treatment guidelines which recommend initiation or intensification of statin therapy and lifestyle modifications to manage hypertriglyceridemia prior to initiation of fibrate therapy.


  1. Das Pradhan A, Glynn RJ, Fruchart J-C, et al. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med. 2022;387(21):1923-1934