Fibrate Therapy Does Not Reduce Cardiovascular Events in Patients with Mild-to-Moderate Hypertriglyceridemia

Mr. Pool is a 64-year-old man with high blood pressure while taking lisinopril, diabetes (HbA1c level, 7.3), obesity (BMI, 32 kg/m²), and dysplipidemia while taking statin therapy (elevated triglyceride of 270 mg/dL and low HDL of 33 mg/dL and LDL of 79 mg/dL). Would he benefit further from fibrate therapy to reduce the risk of cardiovascular events?

Hypertriglyceridemia is a common condition encountered in primary care, affecting nearly 30% of adults, and is associated with increased risk of cardiovascular events, all-cause mortality, and pancreatitis, especially at levels >1000 mg/dL. Lifestyle changes, such as weight loss and reduction of alcohol and excessive carbohydrate consumption, are important in the treatment of patients with elevated triglycerides. Statin therapy is also generally considered useful monotherapy to lower triglyceride levels and is associated with a reduction in cardiovascular events. Fibrates are the drugs of choice to reduce the risk for pancreatitis, especially when triglyceride levels are >1000 mg/dL.

In a recent double-blind trial published in NEJM, investigators randomized nearly 10,500 individuals with diabetes and mild-to-moderate hypertriglyceridemia (200–499 mg/dL) to receive pemafibrate or placebo. After a median follow-up of 3.4 years, pemafibrate showed a significant treatment effect (26%) in the reduction of triglyceride levels (-31.1% vs -6.9% in the placebo group) but did not significantly reduce the composite primary outcome of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or cardiovascular death (hazard ratio, 1.03; 95% CI 0.91-1.15).

An editorialist from the Veterans Affairs/Baylor College of Medicine notes that “fibrates should not be used to reduce the risk of atherosclerotic cardiovascular disease among statin-treated patients, although they may still have a role to play in decreasing the risk of pancreatitis associated with severe hypertriglyceridemia and perhaps nonalcoholic fatty liver disease. Alternatively, triglyceride lowering without decreases in the apolipoprotein B level will probably not suffice if therapies in development are to produce meaningful decreases in the risk of atherosclerotic cardiovascular disease.”

In the clinical example above of a patient with mild-to-moderate hypertriglyceridemia while taking a statin, the addition of fibrate therapy will not reduce the risk of cardiovascular events.

The following NEJM Journal Watch summary provides more details of the study:

Karol E. Watson, MD, PhD, FACC, reviewing Das Pradhan A et al. N Engl J Med 2022 Nov 5

Elevated triglyceride levels are associated with increased cardiovascular risk. However, clinical trials of triglyceride lowering, including with fibrates, have not improved cardiovascular outcomes (e.g., NEJM JW Cardiol Mar 2017 and JAMA Cardiol 2017; 2:370). Pemafibrate — a fibrate with potent, selective peroxisome proliferator–activated receptor-alpha activity — is licensed for clinical use in Japan but not the U.S. To assess whether pemafibrate reduces cardiovascular risk beyond mere triglyceride lowering, investigators in the multinational, manufacturer-funded PROMINENT trial (NCT03071692. opens in new tab) randomized 10,497 patients with type 2 diabetes, triglyceride levels of 200–499 mg/dL, and HDL-cholesterol levels ≤40 mg/dL to receive hemafibrite (0.2 mg twice daily) or matching placebo.

The study included patients without prior atherosclerotic cardiovascular disease (ASCVD; age eligibility, ≥50 years for men and ≥55 for women) and those with established ASCVD (67% of all participants; aged ≥18 years). All participants were maintained on guideline-directed lipid-lowering therapy (or were statin-intolerant) and had LDL-cholesterol levels ≤100 mg/dL.

By 4 months, pemafibrate lowered median triglyceride levels by an absolute 26.2%, compared with placebo, and had beneficial effects on other lipid parameters such as HDL cholesterol. Surprisingly, though, pemafibrate significantly raised LDL cholesterol and apolipoprotein B relative to placebo. During a median follow-up of 3.4 years, pemafibrate showed no advantage over placebo in the primary efficacy endpoint — nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or cardiovascular death (hazard ratio, 1.03; 95% CI, 0.91–1.15) — and was associated with increased incidences of adverse renal events and venous thromboembolism. Pemafibrate was associated, however, with reduced incidence of nonalcoholic fatty liver disease.

Comment: Fibrates are among the most widely prescribed triglyceride-lowering medications, but PROMINENT is one of multiple fibrate trials in the statin era to show no cardiovascular-event reduction. Even in a high-risk population, pemafibrate did not reduce cardiovascular events and had worrisome adverse effects, despite lowering triglyceride levels. Clinicians should prioritize use of agents, such as statins, that have known cardiovascular-outcome benefits.

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James Yeh, MD, MPH, is an internist and assistant physician at the Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. He serves as the head team internist for the New England Revolution. His clinical and academic interests are in evidence-based medicine, medical education, continuing medical education, cardiopulmonary diseases, cardiovascular risk reduction, critical illness, care transition, polypharmacy, and health communication. He was a NEJM editorial fellow in 2015–2016.