Bempedoic acid cuts CV events in statin-intolerant patients

The use of bempedoic acid significantly reduced the risk of major adverse cardiovascular events (MACE) in patients with high cholesterol who are intolerant to statins in the phase III CLEAR* Outcomes trial presented at ACC.23/WCC.

Bempedoic acid cut the composite primary endpoint of cardiovascular death, myocardial infarction (MI), stroke, or coronary revascularization by 13 percent. It also lowered low-density lipoprotein cholesterol (LDL-C) by 21 percent.

“Statins are the cornerstone of LDL-C lowering therapy, with mounds of evidence showing their efficacy not only in lowering cholesterol but in reducing the complications of high cholesterol, such as MI, stroke, and death,” said lead author Dr Steven Nissen from the Heart, Vascular & Thoracic Institute at Cleveland Clinic in Cleveland, Ohio US.

“Most people can take statins, but some cannot,” he pointed out. Although bempedoic acid is FDA-approved as a non-statin lipid-lowering option, its effects on CV outcomes have not been assessed, Nissen added.

CLEAR Outcomes investigators assessed whether bempedoic acid can reduce adverse CV events among patients for whom primary or secondary prevention of CVD is clinically indicated, but unable or unwilling to take statins due to unacceptable adverse effects. [ACC.23/WCC, abstract 402-06]

This event-driven, double-blind, placebo-controlled trial analysed 13,970 statin-intolerant patients (mean age 65.5 years, 48 percent female) who had a baseline median LDL-C level of 139.0 mg/dL. Participants were randomized to receive either oral bempedoic acid 180 mg daily (n=6,992) or placebo (n=6,978). The four-component MACE (composite of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization) was assessed, followed by hierarchical testing of the key secondary endpoints.

At a median follow-up of 40.6 months, the risk of the composite of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization was significantly reduced in favour of the bempedoic acid (hazard ratio [HR], 0.87; p=0.004).

With this result, the trial proceeded to assess the first key secondary endpoint, the three-component MACE (CV death, nonfatal MI, or nonfatal stroke). Outcome was significantly lower for bempedoic acid than for placebo (8.2 percent vs 9.5 percent; HR, 0.85; p=0.006).

As early as 6 months, patients treated with bempedoic acid vs those taking placebo achieved greater reductions in LDL-C (21.7 percent vs 0.6 percent) and high-sensitivity CRP levels (22.2 percent vs 2.4 percent), which were maintained throughout the 60-month treatment period.

“We’re very pleased with the results,” Nissen said. “People who couldn’t tolerate a statin did tolerate bempedoic acid and had a very good outcome. We are glad that we were able to demonstrate this level of efficacy on the outcomes that really matter to patients.”

When individual components of MACE were evaluated separately, bempedoic acid significantly reduced the risk of fatal and nonfatal MI by 23 percent (HR, 0.77; p=0.002) and coronary revascularization by 19 percent (HR, 0.81; p=0.001) compared with placebo.

There was also a lower risk of fatal and nonfatal stroke and hospitalization for unstable angina in the bempedoic acid group than the placebo group (HR, 0.85 and 0.66, respectively), though these findings did not reach statistical significance. The treatment had no effect on the risk of CV death and all-cause mortality, Nissen noted.

In terms of safety, the overall incidence of serious treatment-emergent adverse events (TEAEs) was similar between the bempedoic acid and placebo groups (25.2 percent vs 24.9 percent), as were the rates of AEs leading to drug discontinuation (10.8 percent vs 10.4 percent).

Importantly, a lower incidence of new-onset diabetes was observed with bempedoic acid than placebo (16.1 percent vs 17.1 percent).

“I think all of you know that statins do slightly increase the risk of diabetes, but in this study, bempedoic acid did not,” Nissen said.

However, there was a slight increase in the occurrence of gout and cholelithiasis (1 percent each) with bempedoic acid. “Nevertheless, the drug was well tolerated in a mixed population of primary and secondary prevention patients unable or unwilling to take statins.”

Overall, the four-component MACE was reduced by 13 percent, the three-component MACE by 15 percent, MI by 23 percent, and coronary revascularization by 19 percent, all favouring bempedoic acid over placebo.

“These findings establish bempedoic acid as an effective approach to reduce major CV events in statin-intolerant patients,” Nissen summarized. “This is the first study to directly address the problem of statin-intolerant patients. We achieved what we hoped to achieve — a very positive result in this population.”

“We can no longer ignore and not treat risk factors in patients who are at high risk for CV outcomes,” commented ACC President Dr Edward Fry, who is unaffiliated with the study. “I think it is incumbent upon us, as practitioners, to be engaged directly in educating our patients to stay away from unproven therapies.”

Echoing the same statement, discussant Dr Eugene Yang from the University of Washington in Bellevue, Washington, US, was more straightforward. “We do have something now that clearly shows a benefit. For those who do not want to take an injection and a statin due to intolerances, we now have [an oral non-statin lipid-lowering option] with good evidence.”

 

*CLEAR: Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen