By Michael H. Crawford, MD, Editor
SYNOPSIS: Researchers studied pemafibrate vs. placebo in patients with type 2 diabetes, mild-to-moderate triglyceride elevations, and low levels of HDL and well-controlled LDL cholesterol. Despite a 31% reduction in triglyceride levels, there was no improvement in the risk of cardiovascular outcomes over a median follow-up of 3.4 years.
SOURCE: Pradhan AD, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923-1934.
Researchers designed a multinational, double-blind, randomized, controlled trial to test the drug pemafibrate (PF), a potent, selective peroxisome proliferator-activated receptor alpha blocker. The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial was sponsored by Kowa, the manufacturers of PF.
Pradhan et al enrolled patients with type 2 diabetes, triglyceride (TG) levels of 200 mg/dL to 499 mg/dL and an HDL cholesterol level of 40 mg/dL or lower. Patients were either age 50 years or older (men) or age 55 years or older (women) with no known cardiovascular (CV) disease or who were age 18 years or older with known CV disease. Eligible patients could be taking a statin, record LDL cholesterol levels of 70 mg/dL or lower, or could not tolerate statins and recorded an LDL cholesterol level of ≤ 100 mg/dL. Patients with other significant organ system diseases were excluded. The primary efficacy endpoint was a combination of myocardial infarction (MI), ischemic stroke, coronary revascularization, or CV death.
Enrollment started in 2017, and the trial ended early because of futility in 2022. A total of 10,538 patients (median age was 64 years, 28% were women) were enrolled at 876 sites in 24 countries (about one-quarter from the United States and Canada). Their median TG level was 271 mg/dL, their median HDL level was 33 mg/dL, and their median LDL level was 78 mg/dL. Patients were randomized 1:1 to either PF or placebo and followed every two months until month 8, and every four months thereafter. The median follow-up was 3.4 years, and the maximum was five years.
TG levels decreased by 31% in the PF group and 7% in the placebo group. Other lipid levels were unchanged — except for LDL cholesterol, which increased 14% in the PF group and 3% in the placebo group at four months. PF did not alter the primary outcome endpoint significantly (HR, 1.03; 95% CI, 0.91-1.15; P = 0.67), nor was any component of the primary outcome or the outcome in any subgroup. There was no difference in the number of serious adverse events between PF and placebo. However, there were adverse renal events, which were more frequent in the PF group (HR, 1.12; 95% CI, 1.04-1.20; P = 0.004), and venous thromboembolism (HR, 2.05; 95% CI, 1.35-3.17; P < 0.001). Conversely, nonalcoholic fatty liver disease was less frequent in the PF group (HR, 0.78; 95% CI, 0.63-0.96; P = 0.02). The investigators concluded the incidence of CV events in patients with diabetes, elevated TG levels, and low HDL and LDL cholesterol who were taking PF despite TG lowering was not lower on PF compared to placebo.
COMMENTARY
PF joins the list of drugs that reduce TG levels by 20% to 30% that have failed to prevent adverse CV outcomes, such as high doses of n-3 fatty acids, niacin, and fenofibrate. Icosapent ethyl reduces CV risk, but this effect is unrelated to TG levels. Disappointingly, the authors did not identify any subgroup in which CV event rates were reduced, such as women, the primary prevention and secondary prevention groups and the intensity of statin therapy, nor the baseline levels of other lipids. Also, although serious side effects were not different from placebo, adverse renal and thromboembolic events were more common, as has been seen with fenofibrate in previous studies. A potential reason for this lack of effect on CV outcomes, which Pradhan et al admitted cannot be refuted, is the levels of LDL cholesterol increased on PF. Thus, we need new agents without effects on LDL cholesterol that lower TG levels.
Generally, the patient population was well treated at baseline, with about 80% on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Ninety-five percent were taking a statin, and 70% were taking a high-intensity statin. However, only 10% were on a glucagon-like peptide-1 analogue, and 17% were on a sodium-glucose cotransporter 2 agent, both of which can improve CV outcomes. Perhaps this was not an optimally treated group for diabetes, and the results could have been different had it been. We are left with the traditional approach to managing patients with diabetes and TG levels between 200 mg/dL and 500 mg/dL — namely, good diabetes control, a low carbohydrate diet, and exercise.
Researchers studied pemafibrate vs. placebo in patients with type 2 diabetes, mild-to-moderate triglyceride elevations, and low levels of HDL and well-controlled LDL cholesterol. Despite a 31% reduction in triglyceride levels, there was no improvement in the risk of cardiovascular outcomes over a median follow-up of 3.4 years.
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