medwireNews: Treatment with pemafibrate does not reduce the risk for cardiovascular events in people with type 2 diabetes, despite substantial reductions in triglycerides, report the PROMINENT trial investigators.
The 5240 participants randomly assigned to receive pemafibrate – a selective peroxisome proliferator-activated receptor α modulator – achieved a median 31.1% reduction in measured fasting triglyceride levels during 4 months of treatment, compared with a 6.9% reduction in the 5257 people given placebo.
In addition, median calculated very-low-density lipoprotein cholesterol levels decreased by a corresponding 35.0% and 10.5%, calculated remnant cholesterol by 31.3% versus 15.6%, and measured apolipoprotein C-III levels by 27.8% versus 0.0%.
However, levels of low-density lipoprotein (LDL) cholesterol increased more in the pemafibrate than placebo group, at a median of 14.0% versus 2.9%, and there was no between-group difference in overall non-high-density lipoprotein (HDL) cholesterol levels.
This is “consistent with known effects of pemafibrate on cholesterol trafficking between lipoproteins,” write Aruna Das Pradhan (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and study co-authors in The New England Journal of Medicine.
During a median follow-up of 3.4 years, the primary composite clinical endpoint of myocardial infarction, ischemic stroke, hospitalization for unstable angina, or death from cardiovascular causes occurred at incidence rates of 3.60 and 3.51 per 100 person–years in the pemafibrate and placebo groups, respectively, with no significant difference between the two.
There were also no differences for the individual components of the primary endpoint or for any secondary clinical endpoints.
The trial participants either had established atherosclerotic cardiovascular disease and were aged 18 years or older or were free of it but were aged at least 50 years for men and 55 years for women. They all had type 2 diabetes and a fasting triglyceride level of 200–499 mg/dL and an HDL cholesterol level of no more than 40 mg/dL.
The vast majority of participants were taking a statin, with more than two-thirds taking a high-dose statin, so the researchers note that their LDL cholesterol levels were “at or close to guideline-recommended targets.”
“Nonetheless, our data cannot rule out the possibility that the observed increases in apolipoprotein B and LDL cholesterol levels in the pemafibrate group negated any benefit of reduction in triglyceride or remnant cholesterol levels,” they write.
“Thus, our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy.”
Picking up on this point in a linked editorial, Salim Virani (Baylor College of Medicine, Houston, Texas, USA) writes that, “for therapies that lower triglyceride levels to be effective, they probably have to have mechanisms to increase clearance of triglyceride-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL.”
He describes the trial as “a teachable moment for the clinical trial community,” noting that PROMINENT was negative despite focusing on a population expected to do well based on analyses of large trials with more general populations.
“[T]hese findings highlight the importance of rigorously confirming post hoc findings before implementing them in clinical practice,” Virani concludes.
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group
N Engl J Med 2022; doi:10.1056/NEJMoa2210645
N Engl J Med 2022; doi:10.1056/NEJMe2213208