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NEW ORLEANS -- Bempedoic acid (Nexletol) provided compelling clinical benefit in terms of primary and secondary cardiovascular prevention for statin-intolerant patients who need cholesterol lowering, according to the CLEAR Outcomes trial.

Cementing its place in the arsenal of nonstatin therapies, the ATP citrate lyase inhibitor met the primary endpoint in reducing major adverse cardiovascular events (MACE) over placebo over a median 40.6 months of follow-up (11.7% vs 13.3%, HR 0.87, 95% CI 0.79-0.96), reported Steve Nissen, MD, of Cleveland Clinic, at the American College of Cardiology (ACC) annual meeting. The results were published simultaneously in the . Developer Esperion released the top-line findings in .

Out of the individual endpoints of this composite outcome, bempedoic acid's effect was significant for coronary revascularization (6.2% vs 7.6%, HR 0.81, 95% CI 0.72-0.92) and myocardial infarction (MI; 3.7% vs 4.8%, HR 0.77, 95% CI 0.66-0.91), but not fatal or nonfatal stroke nor deaths from cardiovascular causes.

"The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins," Nissen said at the ACC late-breaking trial session.

Bempedoic acid was associated with excess gout and cholelithiasis, as well as small increases in serum creatinine, uric acid, and hepatic-enzyme levels. There was, however, no uptick in muscle-related effects, which is often a point of contention between statin prescribers and patients who do not adhere to therapy because of real or perceived adverse effects (AEs).

Eugene Yang, MD, of UW Medicine in Seattle, said it was "fantastic" that clinicians now have something that clearly shows a benefit, for patients who don't want to take an injection or statin, with back-up from primary and secondary prevention evidence.

Although the latest findings should boost uptake of bempedoic acid, cost remains an important issue. It is questionable how the drug will ultimately fit into the armamentarium of treatment, suggested Yang at an ACC press conference. Yang was not involved in the CLEAR Outcomes trial.

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

"Anecdotally I've found it harder to get approved than other lipid-lowering therapies, although with these trial results, perhaps this will change," commented Eric Brandt, MD, MHS, of University of Michigan in Ann Arbor.

Robert Rosenson, MD, of Mount Sinai in New York City, echoed the difficulty convincing insurance companies to pay for bempedoic acid. "They say it's nonformulary, that they won't even consider it," he told MedPage Today.

He also remarked on the small absolute benefit of the drug in CLEAR Outcomes in relation to its premium price point. "For the price of the drug, the other alternatives like PCSK9 inhibitors or inclisiran [Leqvio] make more sense for those [statin-intolerant] patients," said Rosenson, who was not involved in the trial.

In the present study, mean baseline LDL cholesterol was 139.0 mg/dL between active treatment and control groups. After 6 months, this fell to 107.0 mg/dL with bempedoic acid versus 136.0 mg/dL with placebo, a decrease of approximately 22%.

Nissen said that bempedoic acid is more likely to be used in clinical practice in combination with ezetimibe (Zetia) for a 38% total reduction in LDL cholesterol, which is comparable to what is achieved with 40 mg simvastatin or 20 mg atorvastatin.

In CLEAR Outcomes, eligible people thought to be statin-intolerant entered a 4-week run-in period during which they received single-blind placebo and were assessed on whether they experienced AEs or were not adherent by pill count. Patients successfully completing this run-in period were randomly assigned bempedoic acid (daily oral dose of 180 mg) or matching placebo.

Nissen's group had 13,970 adults randomized from 2016 to 2019. This cohort had a mean age of 65.5 and was 48.2% women. Many had pre-existing diabetes (45.6%) and a previous cardiovascular event (69.9%). Users of statins and ezetimibe accounted for 22.7% and 11.5%, respectively, of the study cohort.

Primary prevention patients seemed to derive greater clinical benefit from bempedoic acid than the secondary prevention cohort on subgroup analysis.

The investigators cautioned that the trial did not include populations with lower LDL cholesterol levels and those taking conventional statin doses, so it's unknown if the drug would reduce events for these groups.

Bempedoic acid's recommends analyzing lipid levels within 8 to 12 weeks of initiation and a warning that bempedoic acid may increase blood uric acid levels and risk of tendon rupture or injury. Users are advised to avoid concomitant use of bempedoic acid with simvastatin >20 mg and with pravastatin >40 mg.

Statins remain the guideline-recommended front-line treatment for lipid lowering despite the controversy over supposed AEs in some patients.

When such a patient complains of statin intolerance, best practice right now is to review the history of statin use and associated symptoms and still consider statin therapy, Brandt said. Individuals should have tried using statins at the lowest approved daily dose to be called statin intolerant, and some people may even try going down to a statin dose every other day instead of daily, he added.

"You try and you try and you try," Nissen said, but "if you cannot convince the patient to take a statin we need to offer the alternative."

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