Pemafibrate reduces triglycerides, but not CV events, in patients with T2D, hypertriglyceridemia

Despite reducing triglyceride levels, pemafibrate does not reduce the risk of cardiovascular (CV) events among patients with type 2 diabetes (T2D) and hypertriglyceridemia, according to results of the PROMINENT trial presented at AHA 2022.

“We were very surprised by our findings,” said study author Associate Professor Aruna Pradhan from Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, US.

“Many of us in the scientific community thought lowering triglycerides with this medication class in this population should have worked because high triglycerides are a pretty good marker of who’s at risk. Unfortunately, our results showed no lowering of CV event rates,” she said.

Associate Professor Aruna Pradhan (Image: AHA)

Participants (n=10,497; median age 64 years, 27.5 percent female) in this multinational, double-blind trial had T2D, mild to moderate hypertriglyceridemia (200–499 mg/dL; median 271 mg/dL), low HDL cholesterol (HDL-C) levels (≤40 mg/dL; median 33 mg/dL), and high CV risk. They were randomized to receive oral pemafibrate (0.2 mg BID) or placebo. All patients were on guideline-directed lipid-lowering therapy and had LDL cholesterol (LDL-C) levels ≤100 mg/dL (median 78 mg/dL).

Sixty-seven percent of patients had pre-existing cardiovascular disease (CVD), 46 percent had T2D for >10 years, and median HbA_1c was 7.3 percent. Ninety-six percent were on statins, with 69 percent on high-intensity statins. Eighty percent were on ACE* inhibitors or ARBs*. Median BMI was 32 kg/m².

At 4 months, patients in the pemafibrate group had reduced levels of triglycerides (–26.2 percent), very-low-density lipoprotein cholesterol (–25.8 percent), remnant cholesterol (–25.6 percent), and apolipoprotein C-III levels (–27.6 percent) compared with those in the placebo group.

At a median follow-up of 3.4 years, the composite of nonfatal myocardial infarction, ischaemic stroke, coronary revascularization, or CVD-related death did not significantly differ between patients who received pemafibrate and placebo (hazard ratio [HR], 1.03, 95 percent confidence interval [CI], 0.91–1.15; p=0.67). [AHA 2022, session LBS.01; N Engl J Med 2022;387:1923-1934]

“There was no significant heterogeneity across pre-specified subgroups, including women, those in the primary or secondary prevention groups, by statin intensity, or in participants having baseline triglycerides, HDL-C, or LDL-C above or below the population median,” Pradhan said.

All-cause mortality also did not significantly differ between the pemafibrate and placebo groups (HR, 1.04, 95 percent CI, 0.91–1.20).

Serious adverse events (AEs) occurred at a comparable rate between pemafibrate and placebo recipients (HR, 1.04, 95 percent CI, 0.98–1.11), as did infection-related AEs, including COVID-19 (HR, 0.97, 95 percent CI, 0.92–1.02) and musculoskeletal AEs (HR, 0.94, 95 percent CI, 0.88–1.01). However, venous thromboembolism was doubled in the pemafibrate than placebo group (HR, 2.05, 95 percent CI, 1.35–3.17) and renal AEs also more common with pemafibrate (HR, 1.12, 95 percent CI, 1.04–1.20).

In contrast, the incidence of non-alcoholic fatty liver disease was reduced among patients assigned to pemafibrate vs placebo (HR, 0.78, 95 percent CI, 0.63–0.96), a finding, the authors said, requires further investigation.

Triglycerides are associated with an elevated risk of CVD, though the impact of reducing their levels remains uncertain, said Pradhan and co-authors.

“We need to find another solution to this problem,” said Pradhan. “This medication class is the second most commonly used group, after statins, to lower lipid levels and while the medication did not increase CVD risk, the study raises new questions about the best way to treat patients with T2D and hypertriglyceridemia who continue to experience a high rate of CV events – one in 10 by 3 years despite being on statin therapy and having fairly good control of LDL,” she said.

“These data cannot exclude the possibility that the observed increase in LDL-C and apolipoprotein B negated any benefit of triglyceride reduction,” she added.