CHICAGO – 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.
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.
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.