Fact checked byRichard Smith

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March 04, 2023
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Bempedoic acid an ‘effective alternative’ for statin-intolerant patients: CLEAR Outcomes

Fact checked byRichard Smith
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NEW ORLEANS — In the CLEAR Outcomes trial, bempedoic acid reduced risk for major CV events by 13% compared with placebo, including a 23% lower risk for MI, among adults with a history of CVD or at high risk deemed statin intolerant.

Perspective from Howard Weintraub, MD

Bempedoic acid (Nexletol, Esperion Therapeutics) was FDA approved in 2020 for lowering LDL, but the effects of the drug on CV outcomes have not been assessed, according to Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic and Cardiology Today Editorial Board member.

ACC Convention Center
Bempedoic acid reduced risk for major CV events by 13% vs. placebo, including a 23% lower risk for MI, among adults with a history of CVD or at high risk deemed statin intolerant.
Image: Regina Schaffer, Senior Staff Writer

“Statin intolerance is one of the most vexing problems that we face in cardiology, but also in family practice and internal medicine,” Nissen told Healio. “Patients come to see us and have clear indications for treatment with a statin, and they say they cannot tolerate the drugs. We have needed a clear approach that will work.”

Assessing statin intolerant patients

Steven E. Nissen

Nissen and colleagues analyzed data from 13,970 adults from 1,250 sites across 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and had or were at high risk for CVD. To enroll, prospective participants needed to sign a statin intolerance confirmation form, stating they were unable to tolerate statins even though they would reduce the person’s risk for MI, stroke or death.

“This is the first trial designed to exclusively enroll statin-intolerant patients,” Nissen said in an interview.

The mean age of participants was 66 years; 48% were women, 91.5% were white and 45% had diabetes. Approximately 30% of participants were high-risk primary prevention and 70% were secondary prevention patients. Baseline statin use for both groups was 22.9%.

Researchers randomly assigned patients to 180 mg oral bempedoic acid once daily (n = 6,992) or placebo (n = 6,978) and followed the cohort for a median of 40.6 months. Mean baseline LDL was 139 mg/dL.

The primary endpoint was a four-component composite of major adverse CV events, defined as CV death, nonfatal MI, nonfatal stroke or coronary revascularization.

The findings were presented at the American College of Cardiology Scientific Session and simultaneously published in The New England Journal of Medicine.

At 6 months, LDL reduction in the bempedoic acid group was a median 29.2 mg/dL lower than in the placebo group; the observed difference was 21.1 percentage points in favor of bempedoic acid.

The incidence of a primary endpoint event was lower with bempedoic acid than with placebo (11.7% vs. 13.3%; HR = 0.87; 95% CI, 0.79-0.96; P = .004). Similarly, incidence of CV death, nonfatal MI and nonfatal stroke was lower with bempedoic acid vs. placebo (HR = 0.85; 95% CI, 0.76-0.96; P = .006), as was fatal or nonfatal MI (HR = 0.77; 95% CI, 0.66-0.91; P = .002) and coronary revascularization (HR = 0.81; 95% CI, 0.72-0.92; P = .001).

Researchers did not observe any significant effect of bempedoic acid on fatal or nonfatal stroke, CV death and death from any cause.

“The results speak for themselves,” Nissen told Healio. “There was a very robust reduction in the primary endpoint. The first three key secondary endpoints were statistically significant. The drug was well tolerated.”

Adverse events minimal

The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid and hepatic-enzyme levels.

“This did not increase the risk for diabetes, which we have seen with statins,” Nissen said.

Nissen said the addition of other therapies, including PCSK9 inhibitors, narrowed the LDL differences between the groups over time.

“We have established that this drug, approved in 2020 to lower LDL, reduces CV morbidity,” Nissen told Healio. “It did not reduce CV mortality; however, none of the contemporary studies have shown a mortality benefit, including the very powerful PCSK9 inhibitors. It is difficult in the contemporary era to show a reduction in death.

“For patients who cannot tolerate guideline-recommended doses of statins that need an LDL reduction, we have established that bempedoic acid is an effective alternative therapy,” Nissen said.

While presenting the findings, Nissen said that management of patients unable or unwilling to take statins represented a “challenging and frustrating” clinical issue — and said bempedoic acid may provide a solution.

“Regardless of whether this problem represents the nocebo effect or actual intolerance, these high-risk patients need effective alternative therapies,” Nissen said during the presentation.

‘Continue efforts’ to provide statins

In a related NEJM editorial, John H. Alexander, MD, MHS, cardiologist and professor of medicine at Duke University School of Medicine and member in the Duke Clinical Research Institute, wrote that the findings of CLEAR Outcomes are compelling and will — and should — increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.

“It is premature, however, to consider bempedoic acid as an alternative to statins,” Alexander wrote. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”

John F. Keaney Jr., MD, professor at the University of Massachusetts Medical School in Worcester, noted in another NEJM editorial that bempedoic acid can also be used as an adjunct to statin and nonstatin therapies to produce an additional 16% to 26% reduction in LDL; however, it is not yet clear to what extent adjunctive bempedoic acid will further reduce risk for CV events.

“This issue can only be addressed with specific trials powered to detect the effect of bempedoic acid on clinical events,” Keaney wrote. “However, at least in statin-intolerant patients, data from the CLEAR Outcomes trial indicate that bempedoic acid may reduce both the LDL cholesterol level and the risk of cardiovascular events.”

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