‘Simply stunning’: Bempedoic acid may cut CVD risk for primary prevention patients by 30%
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Key takeaways:
- Bempedoic acid significantly reduced risk for major adverse CV events in high-risk primary prevention patients compared with placebo.
- The drug was well tolerated by those unable or unwilling to take statins.
SAN DIEGO — In adults with elevated cardiovascular risk but without a prior clinical event and deemed statin intolerant, bempedoic acid reduced risk for major adverse CV events by 30% compared with placebo, researchers reported.
In a prespecified analysis of the CLEAR Outcomes trial that assessed only primary prevention patients — including 66% with diabetes — researchers also demonstrated that, compared with placebo, bempedoic acid (Nexletol, Esperion Therapeutics) reduced risk for CV death by 39%, all-cause death by 27% and myocardial infarction by 39%. CLEAR Outcomes was unique for its inclusion criteria: only participants who signed 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 an important wake-up call for the medical community,” 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, said during an interview. “We are dealing with a situation where less than half of these primary prevention patients are currently being treated with cholesterol-lowering medications. We want patients and providers to know that this is an important area to address.”
Unmet need for primary prevention
As Healio previously reported, pooled data from CLEAR Outcomes that included both primary and secondary prevention patients demonstrated bempedoic acid reduced risk for major CV events by 13% compared with placebo, including a 23% lower risk for MI. The drug was FDA approved in 2020 for lowering LDL, but the effects of the drug on CV outcomes had not been previously assessed. The trial included 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.
“In recent years, almost all studies of cholesterol-lowering agents — PCSK9 inhibitors, ezetimibe — studied only secondary prevention patients because the event rates are higher, studies can be shorter and you get answers sooner,” Nissen told Healio. “But the medical community has forgotten about what we learned about cholesterol lowering in primary prevention because the studies were done a long time ago. We decided to include 30% of the patients in CLEAR Outcomes who were high-risk, primary prevention. When the study was completed, we emphasized the pooled results. However, there appeared to be, at least for the primary endpoint, some heterogeneity with a greater effect size in primary prevention. We chose to subsequently explore that.”
For the prespecified analysis, researchers analyzed data from primary prevention participants randomly assigned 180 mg oral bempedoic acid daily (n = 2,100) or placebo (n = 2,106). The primary efficacy measure was time from randomization to the first occurrence of any component of a composite of CV death, nonfatal MI, nonfatal stroke or coronary revascularization. The mean age of participants was 68 years; 59% were women and 66% had diabetes.
The findings were presented as a late-breaking poster at the American Diabetes Association Scientific Sessions and simultaneously published in JAMA.
From a mean baseline of 142.5 mg/dL, compared with placebo, bempedoic acid reduced LDL by 21.3% and high-sensitivity C-reactive protein by 21.5% from a baseline of 2.4 mg/L.
At 39 months, researchers observed a 30% reduction in risk for the four-point component of major adverse CV events, with an adjusted HR of 0.7 (95% CI, 0.55-0.89; P = 002), and a 36% reduction risk for the three-point component of CV death, stroke and MI (aHR = 0.64; 95% CI, 0.48-0.84; P < .001). Assessing individual endpoint components, researchers observed a 39% reduction in MI risk vs. placebo (aHR = 0.61; 95% CI, 0.39-0.98), a 39% reduction in CV death risk (aHR = 0.61; 95% CI, 0.41-0.92) and a 27% reduction in all-cause mortality risk (aHR = 0.73; 95% CI, 0.54-0.98).
Absolute risk reductions were similarly large, Nissen said: a 2.3% reduction among those who received bempedoic acid for the four-point composite endpoint, for a number needed to treat of 43.
“What we found was simply stunning,” Nissen told Healio. “We know that somewhere in the range of 10% to 15% of patients report unacceptable adverse effects from statins. In this trial we included only those patients because bempedoic acid was designed to allow cholesterol reduction for patients that could not tolerate statins. Having said that, we think the results of this secondary analysis are equally applicable for cholesterol-lowering treatments with other drugs, particularly with statins, which are widely available, inexpensive and generally well tolerated except in a minority of patients.
“The message here is, yes, this was bempedoic acid and, yes, this was statin-intolerant patients,” Nissen said. “But the benefits for patients in a high-risk, primary prevention group are quite large. This message is not getting through, or it has been forgotten due to a lack of contemporary data.”
Bempedoic acid not a substitute for statins
In a related editorial, Dhruv S. Kazi, MD, MSc, MS, associate director of the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, director of the cardiac critical care unit at Beth Israel Deaconess Medical Center and associate professor at Harvard Medical School, cautioned that bempedoic acid is not a statin substitute but rather a “good plan B” for people at high-risk for atherosclerotic CVD who are deemed statin intolerant. Patients are also likely to face substantially higher out-of-pocket costs for bempedoic acid than for a generic statin, leading to cost-related nonadherence, Kazi wrote.
“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,” Kazi wrote. “First, treatment with a high-intensity statin produces larger reductions in LDL level than treatment with bempedoic acid (50% vs. 16% over 4 years). Second, a vast body of evidence supports the long-term safety and effectiveness of statins, including reduction in all-cause mortality. Third, most patients who discontinue a statin due to symptoms may tolerate a statin when challenged in the future, whether it is the same dose, same statin at a lower dose or a different statin.”
References:
- Kazi DS. JAMA. 2023;doi:10.1001/jama.2023.9854.
- Nissen SE, et al. JAMA. 2023;doi:10.1001/jama.2023.9696.
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Nissen SE, et al. Outcomes for primary prevention patients in the CLEAR Outcomes trial. Presented at: American Diabetes Association Scientific Sessions; June 23-26, 2023; San Diego.
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