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.

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.

“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.”

References:

• Alexander JH. N Engl J Med. 2023;doi:10.1056/NEJMe2301490.
• Keaney JF. N Engl J Med. 2023;doi:10.1056/NEJMe2300793.
• Nissen SE, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2215024.

Perspective

Howard Weintraub, MD

This study is relevant and important because it demonstrates the efficacy and safety of a relatively new nonstatin drug that effectively lowers LDL cholesterol, and it is well tolerated by patients who are “statin intolerant.” Further, it shows that when this drug is used in these patients it was able to reduce the frequency of major adverse CV events such as the need for cardiac surgery, fatal heart attacks, CV death and nonfatal stroke.

These findings are significant because they demonstrates that there is a drug that is useful and safe in a population of patients that frequently go untreated. It also demonstrated that even a modest amount of LDL reduction over a 3.5-year period was able to have a very meaningful impact on CV risk. Finally, and very importantly, it was one of the few studies to include a large proportion of women. Women comprised 48% of the participants in this trial, and 46% of the patients had diabetes.

This could be practice changing because many patients are reluctant to use any of the cholesterol-lowering medications due to adverse symptoms with the use of statins. Two important differences were the low incidence of muscle aches and the low incidence of the development of type 2 diabetes. Muscle aches are the most common adverse events from statins, but the development of type 2 diabetes is also reported. There were slightly more patients with elevated liver enzymes and elevations in uric acid were much more frequent.

In this trial, researchers studied patients who have had prior CV events as well as those at increased risk for an event. Both groups saw a meaningful reduction in the combined endpoint. The population of patients who are statin intolerant or perceived as statin intolerant is not a small number of patients. It would be good to have a drug that has been proven in this population but has been shown to reduce events.

There is also the possibility to combine ezetimibe with bempedoic acid. This is available as a single pill and has been shown in clinical trials to lower LDL cholesterol by as much as 35% to 38%.

Howard Weintraub, MD

Clinical Director, Center for the Prevention of Cardiovascular Disease

Clinical Professor, Department of Medicine, Leon H. Charney Division of Cardiology

NYU Langone Health