While pemafibrate, a novel medication designed to lower triglycerides and increase HDL levels, did lower triglycerides, VLDL-C, remnant cholesterol, and ApoCIII among adults with Type 2 diabetes, it did not reduce rates of cardiovascular events in these patients, according to findings from the PROMINENT trial presented Nov. 5 at AHA 2022 in Chicago and simultaneously published in the New England Journal of Medicine.

The study enrolled nearly 10,500 adults with high triglycerides, low HDL and Type 2 diabetes from 24 countries between March 2017 and September 2020 and randomly assigned them to pemafibrate or placebo for an average of three years. Nearly one-fifth of participants were from the U.S., more than 25% were women, roughly 20% were Hispanic and 3% were Black. The average age was 64 years and nearly all were taking a statin and more than 50% had Type 2 diabetes for more than 10 years at the time of the study.

Overall results found pemafibrate reduced triglyceride levels by 26% compared with placebo. However, it did not appear to reduce the risk of cardiovascular disease, with about one out of 10 study participants in both groups dying from cardiovascular disease or experiencing a heart attack, stroke, or other cardiovascular event over the course of three year. Researchers also noted that pemafibrate was associated with an increase in LD-C and an increased risk of venous thromboembolism and renal adverse events.

"These data highlight the complexity of lipid mediators of residual risk in statin-treated insulin resistant patients," said Aruna D. Pradhan, MD, MPH, MSc, who presented the findings. "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." He added that the results "cannot exclude the possibility that the observed increase in LDL-C and ApoB negated any benefit of triglyceride reduction."

Going forward, Pradhan said, "We need to find another solution to this problem. This medication class is the second most commonly used group, after statins, to lower lipid levels and while the medication did not increase cardiovascular disease risk, the study raises new questions about the best way to treat patients with Type 2 diabetes and hypertriglyceridemia who continue to experience a high rate of cardiovascular events." He noted that "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."

In a related editorial comment, Salim S. Virani, MD, PhD, FACC, poses the question, "What do these findings mean for the future of fibrates and other therapies that primarily target triglycerides?" He answers 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."

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Cardiac Surgery and Arrhythmias, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Vascular Medicine

Keywords: AHA Annual Scientific Sessions, AHA22, Apolipoproteins, Apolipoproteins B, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Dyslipidemias, Heart Disease Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Ischemic Stroke, Lipoproteins, HDL, Metabolic Syndrome, Myocardial Infarction, Myocardial Revascularization, Peroxisome Proliferator-Activated Receptors, Primary Prevention, Renal Insufficiency, Risk Factors, Triglycerides, Venous Thromboembolism

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