Bempedoic Acid Gets ‘Huge’ Win for Primary Prevention in the Statin-Intolerant

SAN DIEGO — Bempedoic acid (Nexletol) prevented cardiovascular events in high-risk, statin-intolerant patients who had not yet had an event, a subgroup analysis from the CLEAR Outcomes trial confirmed.

In these patients, bempedoic acid was associated with a large decrease in risk of major adverse cardiovascular events (MACE) compared with placebo over a median 39.9 months of follow-up (5.3% vs 7.6%; adjusted HR 0.70, 95% CI 0.55-0.89), reported Steven Nissen, MD, a cardiologist at the Cleveland Clinic in Ohio, at the American Diabetes Association (ADA) Scientific Sessions here.

Subgroup results of the more than 4,000 primary prevention patients with high cholesterol but no history of incident cardiovascular disease in the masked, randomized trial were simultaneously published in JAMA.

During an ADA press briefing, Nissen emphasized the significance of the results, stating, “I have been doing cardiovascular trials for 30 years, and I can tell you we have never seen a hazard ratio as favorable as this. This is a huge reduction in morbidity and mortality.”

The present findings support main results from the nearly 14,000-person CLEAR Outcomes trial, presented earlier this year, which showed bempedoic acid’s 13% reduction of MACE in a wider cohort covering both primary and secondary prevention patients. By the time of that presentation, it had already been suspected that primary prevention patients seemed to derive greater clinical benefit from bempedoic acid than the secondary prevention cohort on subgroup analysis.

In order to be eligible for the trial, individuals considered potentially statin-intolerant entered a 4-week run-in period during which they received single-blind placebo and were assessed on whether they experienced adverse events or were not adherent by pill count. Candidate participants successfully completing this run-in period were randomly assigned bempedoic acid or matching placebo.

Bempedoic acid is FDA approved for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol.

Nissen stressed the need for alternative treatment among patients who are unable or unwilling to use statins in the real world.

“Let me tell you what the bottom line here is. Only about half of the patients that were like the patients in our trial, in the United States are receiving cholesterol-lowering drugs. We are undertreating a vulnerable population that needs better treatment. This study is a wake-up call that we need to lower cholesterol in patients with risk factors — and particularly, if they have diabetes,” he said.

Nissen also told MedPage Today that the preventative nature of treating patients who have not had a cardiovascular event is an important issue that should be brought up among practitioners and their patients.

“A message to clinicians should be very clear — identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug if they have high cholesterol,” said Nissen. “And that’s, you know, in the eye of the beholder, but these patients have reasonably high cholesterol levels. We only lower them modestly, and we’ve gotten huge benefits, in many ways, almost unprecedented benefits.”

Nevertheless, some adverse events were seen among primary prevention patients taking bempedoic acid. These included excess gout (2.6% vs 2.0% with placebo), cholelithiasis (2.5% vs 1.1%), and hyperuricemia (12.1% vs 6.3%), as well as a higher frequency of kidney adverse events (10.3% vs 8.1%) and elevations in hepatic enzyme levels (4.5% vs 2.6%).

There was, notably, no uptick in the muscle-related symptoms often cited as a cause for statin discontinuation.

Cardiologist Dhruv Kazi, MD, MSc, MS, of Harvard Medical School in Boston, noted the importance of the findings of the study, but encouraged caution among clinicians hoping to replace statins with bempedoic acid in their practice.

“Bempedoic acid is an effective therapeutic option for appropriately selected statin-intolerant individuals who would have met the eligibility criteria for the study based on elevated predicted risk of cardiovascular events, presence of high levels of coronary calcium, or concurrent diabetes,” wrote Kazi in an editorial. “But even in this higher-risk group, bempedoic acid should not be considered a substitute for statins, which remain the first-line therapy for primary prevention for several reasons.”

In CLEAR Outcomes, there were 2,100 statin-intolerant people who were randomized to receive bempedoic acid treatment (180 mg daily) and 2,106 who got placebo instead. Of this population, 59% were women, the average patient age was 68 years, and 66% had diabetes. Over 90% of patients in both groups were white.

Investigators were masked to patient results, but were notified if an individual’s LDL cholesterol level was 25% or higher than their baseline, allowing for treatment adjustment.

After 6 months of treatment, bempedoic acid reduced LDL cholesterol levels by 21.3% and reduced high-sensitivity C-reactive protein levels by 21.5%.

Bempedoic acid’s clinical benefits were supported by various secondary endpoints compared with placebo:

• Combined cardiovascular death, myocardial infarction (MI), or stroke (4.0% vs 6.4%; HR 0.64, 95% CI 0.48-0.84)
• MI (1.4% vs 2.2%; HR 0.61, 95% CI 0.39-0.98)
• Cardiovascular death (1.8% vs 3.1%; HR 0.61, 95% CI 0.41-0.92)
• All-cause mortality (3.6% vs 5.2%; HR 0.73, 95% CI 0.54-0.98)

The drug had no significant impact on coronary revascularization or stroke in the primary prevention cohort.

Limitations to the subgroup study include the possibility of false-positive results due to multiple testing and play of chance. “However, the consistency of event reduction for the primary endpoint, secondary endpoints, and components of endpoints strengthens the likelihood that these results are reliable,” the study authors argued.

Other limitations include the data’s potential non-generalizability to people with lower pretreatment LDL cholesterol and those meeting alternative criteria for cardiac risk, two groups not included in the present report.