This transcript has been edited for clarity.
At the recent American Heart Association meeting, the results of the PROMINENT study were presented. While it was a negative study, I think it's important to look at both positive and negative studies because we learn from both.
This study was designed to look at the effects of triglyceride lowering with a drug known as pemafibrate to reduce cardiovascular disease risk. Pemafibrate is not on the market, and it is a selective peroxisome proliferator–activated receptor alpha (PPAR-α) agonist. This was a large randomized controlled trial in people with type 2 diabetes and triglyceride levels of 200-499 and HDL cholesterols of 40 mg/dL or less.
This was a huge international study. They screened over 35,000 people and ended up enrolling 10,497 patients. About 67% of these patients — so, slightly over two-thirds — had prior cardiovascular disease. Coming in to the trial, the median triglyceride level was 271 mg/dL, HDL of 33, and a low LDL of 78.
The mean age was 64. One third were female, 20% were Hispanic, and 96% — almost all — were on a statin. A relatively small percentage, 9%, were on a GLP-1 receptor agonist, and 17% were on an SGLT2 inhibitor. All of these factors were well balanced between the two groups. The baseline A1c was 7.3%, representing reasonable glycemic control.
The primary efficacy endpoint was nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death due to CVD causes. Because fibrates increase the efficiency of conversion of triglyceride-rich lipoprotein remnants to LDL rather than increasing their removal by the liver, in patients treated with fibrates, LDL and ApoB levels can increase. Centralized monitoring of ApoB levels was done, and ezetimibe was added if the ApoB levels increased to balance out this potential rise.
Now, in terms of the results, pemafibrate worked. It lowered everything it was supposed to lower. It lowered triglycerides, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels by 26%-28%. There was, as anticipated, a 12.3% increase in LDL cholesterol and a 5.1% increase in HDL cholesterol levels.
However, after a median follow-up of 3.4 years, there was no difference. None. The lines looked exactly the same in terms of the primary endpoint between placebo and pemafibrate, and there was no difference in any prespecified subgroup. Basically, it didn't work in terms of outcomes, but it did work in terms of lowering triglycerides and other related particles.
Pemafibrate was associated with a significantly higher incidence of adverse renal events and venous thromboembolism. However, it was associated with a lower incidence of nonalcoholic fatty liver disease.
The reason these authors did this study, in part, I believe, is because even though we have many other negative studies, within those negative studies, there have been subgroups that seem to respond. One of the subgroups where we were hoping for a response was in patients with type 2 diabetes.
To name a few of those studies that were essentially negative, there was the high-dose omega-3 fatty acid supplementation study known as STRENGTH, AIM-HIGH with niacin, and FIELD with fenofibrate. All of these showed reductions in triglyceride levels, but overall, no improvement in cardiovascular outcomes.
I think these findings are interesting because it's a good lesson in why outcomes trials are needed. We can improve surrogate markers such as lipid levels, but this may not matter in terms of what means the most, which is an actual reduction in cardiovascular events.
We obviously need much more research into what we can do to further lower the cardiovascular risk in patients who have high triglyceride levels and low HDL cholesterol levels.
Anne L. Peters, MD, is a professor of medicine at the University of Southern California (USC) Keck School of Medicine and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts, and three books, on diabetes and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.
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Cite this: Anne L. Peters. Pemafibrate Didn't Improve CV Outcomes in Patients With T2D - Medscape - Nov 21, 2022.