Key Points
- High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would reduce the incidence of cardiovascular events is not clear.
- In the PROMINENT study, patients with dyslipidemia and type 2 diabetes mellitus were randomized to a new cholesterol medication, pemafibrate, or placebo, the primary outcome being a clinical composite endpoint of MI, ischemic stroke, coronary revascularization, or CV death.
- In patients receiving pemafibrate , the incidence of CV events was not lower than those who received placebo, although pemafibrate lowered triglyceride levels, VLDL, and apolipoprotein C-III. There were worrisome adverse events such as an increased risk of venous thromboembolism and renal events in the pemafibrate arm.
While low density lipoprotein (LDL) lowering has remained the backbone of lipid management and a pillar of cardiovascular risk modification, similar robust evidence regarding triglyceride (TG) lowering therapy remains elusive. TG lowering therapies have the potential to offer another major pathway for significant cardiovascular risk reduction and have recently been subject to much attention as new data has yielded promising results, exemplified in the REDUCE-IT trial. In a breaking presentation at the 2022 AHA conference today, Dr. Aruna Pradhan (Brigham and Women’s Hospital, Boston, MA) and colleagues presented their study: “Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabetes,” or the PROMINENT study.
The PROMINENT study was a prospective, randomized clinical trial conducted across more than 20 countries evaluating whether a new fibrate medication, pemafibrate 0.2 mg, administered twice daily in patients with dyslipidemia and type 2 diabetes (T2D), would delay the time to first occurrence of any component of a clinical composite endpoint of nonfatal myocardial infarction (MI), nonfatal ischemic stroke, coronary revascularization, or cardiovascular (CV) death. Patients included in the study had T2D, mild-to-moderate hypertriglyceridemia (TG: 200-499 mg/dl) and low high-density lipoprotein cholesterol levels (HDL-C: ≤40 mg/dl). Additionally, patients had to be taking either moderate-to-high intensity statin therapy or meet specified LDL-C criteria.
Out of a total of 10,4987 enrolled patients (66.9% with previous cardiovascular disease), 5,240 patients were randomized to the treatment group (0.2 mg of pemafibrate twice daily), while 5,257 were randomized to a matching placebo tablet. Each arm had a mean age of 64, with 28% of patients being female, and equal HbA1c medians of 7.3%. Key exclusion criteria included type I diabetes, uncontrolled diabetes, HTN, or thyroid disease, liver disease, or MACE 8 weeks before randomization. Mean levels of pertinent markers were as follows: TG 271 mg/dl, HDL 33 mg/dl, and LDL 78 mg/dL.
The primary outcome was the clinical composite endpoint of nonfatal MI, nonfatal ischemic stroke, coronary revascularization, or CV death at 3.4 years. The trial was in stopped early for futility. Compared with placebo,pemafibrate failed to show a significant difference in the primary outcome (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15; p<0,67). It was noted, however, that patients on study medication had a reduction in TGs of 26.2% and 25.8% for VLDL. Increases in LDL and apolipoprotein C-III were also noted with no difference in the total cholesterol or non-HDL cholesterol levels, a finding consistent with known effects of this drug class. Importantly, the PROMINENT trial also showed some worrisome adverse events including an increased risk of venous thromboembolism (in 71 patients vs. 35 patients; hazard ratio, 2.05; 95% CI, 1.35 to 3.17; p<0.001) and renal events (in 1463 patients vs. 1347 patients; hazard ratio, 1.12; 95% CI, 1.04 to 1.20; p=0.004). Of note, these events were in line with previous observations regarding fenofibrate. Despite the neutral trial, investigators highlighted the lower numbers of nonalcoholic fatty liver disease with pemafibrate than with placebo (in 155 patients and 200 patients, hazard ratio, 0.78; 95% CI, 0.63 to 0.96; p=0.02) which could have potential therapeutic interest and thus a second trial of pemafibrate is under way to evaluate histologic markers of liver fibrosis.
When discussing the implications of the study at AHA, Dr. Pradhan noted that, “this trial highlights the complexity of lipid mediators of residual risk in statin-treated insulin resistant patients”, emphasizing also that “these data cannot exclude the possibility that the observed increase in LDL and ApoB negated any benefit of the triglyceride reduction”. The PROMINENT trial showcased the TG lowering effect of pemafibrate in those with dyslipidemia and T2D, but the medication ultimately did not yield CV risk reduction in this patient population.