Pemafibrate lowers triglycerides but not CV events in type 2 diabetes, mixed dyslipidemia
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CHICAGO — In the PROMINENT trial, pemafibrate lowered triglycerides but did not cut the incidence of CV events compared with placebo in patients with type 2 diabetes and mixed dyslipidemia.
“While pemafibrate reduced triglycerides, VLDL cholesterol, remnant cholesterol [and] apolipoprotein C-III — all the markers we hope to see with a drug like this — by 20% to 30%, it did not reduce CV event rates in patients with type 2 diabetes, mild to moderate hypertriglyceridemia, low HDL and well-controlled LDL cholesterol,” Aruna D. Pradhan, MD, MPH, MSc, associate professor of medicine at Harvard Medical School and associate physician in the division of preventive medicine at Brigham and Women’s Hospital, said during a press conference at the American Heart Association Scientific Sessions.
The PROMINENT trial evaluated efficacy and safety of pemafibrate (Kowa Pharmaceuticals), a highly potent and selective peroxisome proliferator-activated receptor-alpha modulator.
The trial included 10,497 patients with type 2 diabetes, triglyceride levels of 200 to 499 mg/dL and HDL of 40 mg/dL or lower who were randomly assigned to receive pemafibrate 0.2 mg twice daily or matching placebo. Patients were also receiving guideline-recommended lipid-lowering therapy, or had statin intolerance and LDL levels of 100 mg/dL or higher. Background therapy included statins in 96%, with more than two-thirds on high-intensity statins, and ACE inhibitors or angiotensin receptor blockers in 80%. Nine percent were receiving GLP-1 therapy and 17% a SGLT2 inhibitor at baseline.
Two-thirds of the patients had previous CVD. The median age was 64 years, 27.5% were women and 20% were Hispanic. The baseline median fasting triglyceride level was 271 mg/dL, HDL 33 mg/dL and LDL 78 mg/dL.
Patients were followed for a median of 3.4 years.
The trial was terminated early on the basis of futility. At that time, a total of 1,132 primary endpoint events had occurred, with 228 in women.
Efficacy, safety results
At 4 months, the effects of pemafibrate, compared with placebo, on lipid levels included a 26.2% reduction in triglycerides, as well as a 25.8% reduction in VLDL cholesterol, 25.6% reduction in remnant cholesterol, 27.6% reduction in apolipoprotein C-III and 4.8% increase in apolipoprotein B, according to the results.
The primary efficacy endpoint was nonfatal MI, ischemic stroke, coronary revascularization or death from CV causes. A primary endpoint event occurred in 572 patients assigned pemafibrate (3.6 per 100 person-years) vs. 560 assigned placebo (3.51 per 100 person-years; HR = 1.03; 95% CI, 0.91-1.15; P = .67). There was no difference in the incidence of individual components of the primary outcome.
Regarding safety, Pradhan highlighted no significant difference in the overall incidence of serious adverse events, infections and musculoskeletal complications. There was, however, an increased risk in the pemafibrate group for renal adverse events and venous thromboembolism, which Pradhan said is “consistent with prior observations for fenofibrate.”
In an exploratory analysis, pemafibrate was associated with a reduction in total hepatic adverse events and investigator-reported nonalcoholic fatty liver disease, which requires further validation, Pradhan said.
The results were simultaneously published in The New England Journal of Medicine.
Use in the statin era
The researchers concluded in NEJM that “[t]hese neutral findings with pemafibrate are consistent with those from” the STRENGTH trial of high-dose omega-3 fatty acids, AIM-HIGH trial of niacin and the FIELD and ACCORD trials of fenofibrate, and “also partially consistent” with those of the REDUCE-IT trial of icosapent ethyl (Vascepa, Amarin).
During a discussion of the trial, Karol Watson, MD, PhD, FNLA, FACC, FAHA, co-director of the UCLA program in preventive cardiology and member of the Cardiology Today Editorial Board, said the three predominant therapies for triglyceride lowering — niacin, fibrates and EPA-only omega-3 fatty acids — have shown differing effects on CV risk reduction.
“Fibrates are some of the most widely prescribed medications for triglyceride lowering. But these recent fibrate trials ... in the last 20 years do not show cardiovascular benefit, and the big difference is that they were all performed in the statin era,” Watson said. “It seems that, in the statin era, currently tested fibrates do not appear to lower risk. In the PROMINENT trial, despite enrolling a population you would have predicted risk, pemafibrate did not lower events and had worrisome adverse events. We’ve asked this question before of fibrates and we’ve gotten similar answers; it appears that in the statin era with LDL control, the currently available fibrates do not lower CV risk.”
Pradhan said the PROMINENT trial results “highlight the complexity of lipid mediators of residual risk in statin-treated insulin-resistant patients.” According to Pradhan, “it is possible that, beyond effects on triglyceride-rich lipoprotein remodeling, enhanced clearance of lipoproteins derived from remnant catabolism is also needed to neutralize risk in hypertriglyceridemia.” However, Pradhan said, “these data cannot exclude the possibility that the observed increase in LDL cholesterol and apolipoprotein B negated any benefit of triglyceride reduction.”
Looking ahead, “ongoing trials of agents that use alternative pathways to lower triglycerides and remnant cholesterol, including apolipoprotein C-III and angiopoietin-like protein 3 (ANGPTL3) inhibition, may help to clarify these issues,” Pradhan said.
References:
- New medicine reduces triglyceride by 25%, no change in CVD risk in people with Type 2 diabetes. newsroom.heart.org/news/new-medicine-reduces-triglyceride-by-25-no-change-in-cvd-risk-in-people-with-type-2-diabetes. Published Nov. 5, 2022. Accessed Nov. 5, 2022.
- Pradhan AD, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2210645.
Perspective
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Manesh R. Patel, MD, FACC, FAHA, FSCAI
PROMINENT was a randomized trial to see if pemafibrate compared to placebo reduces triglycerides — which it did — and if that reduction led to a difference in CV outcomes — which it didn’t. We have seen several agents — niacin, fibrates and icosapent ethyl — used to reduce triglycerides. Niacin has really not done that; it’s reduced triglycerides but not changed clinical outcomes. Fibrates and pemafibrate now have been shown in randomized trials to reduce triglycerides but not change clinical outcomes. Icosapent ethyl is the remaining agent that has shown reduction, and not dramatic reduction, but shown dramatic CV benefit. So, it may speak to a mechanism. Also at the AHA Scientific Sessions this year, there is presentation of another randomized trial from Japan on high-dose EPA.
Perspective
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Most of us expected that pemafibrate might lower CV events in a population of patients with high triglycerides and low HDL with moderate elevations in LDL. However, there was no reduction in ApoB.
While there was a signal of a possible decrease in NAFLD, there was a modest increased risk for renal events and venous thromboembolic events. So far, we have not found any significant CV event reduction of adding a fibrate to a moderate-intensity statin.
For persons with elevated triglycerides, we need to focus more on better glycemic control via better lifestyle habits and judicious use of metformin, SGLT2 inhibitors, GLP-1 receptor agonists and icosapent ethyl.
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Pradhan AD, et al. LBS.01: The Main Event: Changing Clinical Practice. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
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