Addressing Fenofibrates’ Lack of Cardiovascular Benefit, With Payal Kohli, MD, FACC

Despite increasing evidence indicating their ineffectiveness and a recent decision by the US Food and Drug Administration (FDA) to update their labeling information to reflect their lack of cardiovascular benefit, fenofibrates are still actively being prescribed to reduce cardiovascular risk, both alone and in combination with statins.1,2

On October 14, 2025, in response to a Citizen Petition from the organization HealthyWomen, the FDA changed the labels for fenofibrates, highlighting the fact that they are not associated with any cardiovascular benefits. Substantial evidence in support of this action was released as far back as November 2022, with the publication of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study.1,3

Despite this, fenofibrates are still widely prescribed for this indication. A 2021 Harris poll highlighted that >50% of all cardiologists and primary care providers surveyed believed that fenofibrates reduce cardiovascular risk. Additionally, this poll demonstrated that 38% of the cardiologists and 42% of the primary care providers believed that the FDA has approved taking fenofibrates with statins – this approval was overturned in 2016.2

The editorial team at HCPLive met with Payal Kohli, MD, FACC, founder and medical director of Cherry Creek Heart and associate adjunct professor in the division of cardiology at Duke University School of Medicine, to discuss the impetus for the label change and what can be done for patients currently taking fenofibrates. Kohli spoke on the need for greater awareness surrounding the label change and action by clinicians to limit future prescriptions and thus potential harm.

“The most important thing is to really clarify the new evidence without creating patient alarm or eroding patient trust,” Kohli told HCPLive. “Oftentimes, patients are scratching their heads and saying, ‘well, you told me to take this for the last 20 years, what’s changed?’ And this is where it’s really important to talk about some of the modern trials that have really put the nail in the coffin on the facts that fibrates, and fenofibrate specifically, are not cardiovascular risk-reducing agents.”

PROMINENT was a randomized, parallel, double-blind, placebo-controlled trial aiming to evaluate pemafibrate among patients with type 2 diabetes (T2D) and hypertriglyceridemia. Pemafibrate, a selective peroxisome proliferator-activated receptor a modulator, was expected to display cardioprotective effects among this patient group, as prior trials seemed to have indicated this.3

Investigators included patients with T2D and triglyceride levels between 200 and 499 mg/dL, as well as high-density lipoprotein cholesterol (HDL-C) ≤40 mg/dL. Patients with type 1 diabetes, uncontrolled diabetes, untreated or inadequately treated hypo- or hyperthyroidism, severe heart failure, severe kidney disease, or severe liver disease were excluded. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, or coronary revascularization. Secondary outcomes included median change in triglyceride and apolipoprotein B levels from baseline, as well as all-cause mortality, venous thromboembolism, and any adverse renal event.3

A total of 10,497 patients were enrolled in the study. Of these, 5240 patients were randomly assigned to receive pemafibrate 0.2 mg twice daily, while 5257 patients would receive matching placebo. Patients had a mean age of 64 years, and 46% had a duration of diabetes ≥10 years. Median follow-up duration was 3.4 years. Medan HDL-C was 33 mg/dL, and median LDL-C was 78 mg/dL. 96% of patients were on a statin during treatment.3

Ultimately, the primary outcome occurred in 3.6% of the pemafibrate group versus 3.5% of the placebo group, illustrating no significant cardiovascular effect (P = 0.67). All-cause mortality also occurred in 2.4% of the pemafibrate group versus 2.3% of the placebo group. Although the treatment arm saw substantially greater reductions in triglyceride, these data provided the primary impetus for HealthyWomen’s petition and the FDA’s recent decision to change label data.3

“This really does emphasize the point that you don’t want to continue what is known as clinical inertia, where you just keep doing what you’ve been doing,” Kohli said. “You want to be active and thoughtful every time you see a patient, and to ask yourself, ‘Does they still need this medication?’ I don’t just continue it because it has been that way for a long time, and I don’t just continue because it treats the number – I want to try to treat the risk.”

Editor’s Note: Kohli reports disclosures with Amgen, GE/Skyword, Family Heart, Astra Zeneca, Bristol-Myers Squibb, Merck, and others.

References

1. US Food and Drug Administration. Final Response Letter from FDA CDER to HealthyWomen. Regulations.gov. June 9, 2025. Accessed January 6, 2026. https://www.regulations.gov/document/FDA-2024-P-1988-0005

2. US Food and Drug Administration. Citizen Petition from HealthyWomen. Regulations.gov. April 23, 2024. Accessed January 6, 2026. https://www.regulations.gov/document/FDA-2024-P-1988-0001

3. Bavry A, Bhatt D. Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes – PROMINENT. ACC. February 27, 2023. Accessed January 6, 2026. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2022/11/04/14/15/prominent