Triglyceride Lowering Fails to Show CV Benefit in Large Fibrate Trial

Twenty-Five Percent Reduction Has No Effect

Ted Bosworth

November 05, 2022

Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

"Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy," reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

The trial, called PROMINENT, was presented at the American Heart Association scientific sessions.

It is the most recent in a series of trials that have failed to associate a meaningful reduction in TGs with protection from a composite MACE endpoint. This is a pattern that dates back 20 years, even though earlier trials did suggest that hypertriglyceridemia was a targetable risk factor.

No Benefit From Fibrates Seen in Statin Era

"We have not seen a significant cardiovascular event reduction with a fibrate in the statin era," according to Karol Watson, MD, PhD, director of the UCLA Women's Cardiovascular Health Center, Los Angeles.

Prior to the availability of statin therapy, there was evidence of benefit from TG lowering. In the Helsinki Heart Study, for example, the fibrate gemfibrozil was associated with a 34% (P < .02) reduction in the incidence in coronary heart disease among middle-aged men with dyslipidemia that included elevated TGs.

In the statin era, which began soon after the Helsinki Heart Study was published in 1987, Dr. Watson counted at least five studies with fibrates that had a null result.

In the setting of good control of LDL cholesterol, "fibrates have not been shown to further lower CV risk," said Dr. Watson, who was invited by the AHA to discuss the PROMINENT trial.

In PROMINENT, 10,497 patients with type 2 diabetes were randomized to pemafibrate, a peroxisome proliferator-activated receptor a (PPAR-a) agonist, or placebo. Pemafibrate is not currently available in North America or Europe, but it is licensed in Japan for the treatment of hypertriglyceridemia.

The primary efficacy endpoint of the double-blind trial was a composite endpoint of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death.

The patients were eligible if they had TG levels from 200 to 400 mg/dL and HDL cholesterol levels of 40 mg/dL or below. Pemafibrate in a dose of 0.2 mg or placebo were taken twice daily. About two-thirds had a prior history of coronary heart disease. The goal was primary prevention in the remainder.

After a median follow-up of 3.4 years when the study was stopped for futility, the proportion of patients reaching a primary endpoint was slightly greater in the experimental arm (3.60 vs. 3.51 events per 100 patient-years). The hazard ratio, although not significant, was nominally in favor of placebo (hazard ratio, 1.03; P = .67).

When events within the composite endpoint were assessed individually, there was no signal of benefit for any outcome. The rates of death from any cause, although numerically higher in the pemafibrate group (2.44 vs. 2.34 per 100 patient years), were also comparable.

 

Lipid Profile Improved as Predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation (2022 Nov 5. doi: 10.1056/NEJMoa2210645).

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

"I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level," speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results (N Engl J Med. 2022 Nov 5. doi: 10.1056/NEJMe2213208).

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

"In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL," Dr. Virani explained in an attempt to unravel the interplay of these variables.

 Although this study enrolled patients "who would be predicted to have the most benefit from a TG-lowering strategy," Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However,  it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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