Among statin-intolerant patients, treatment with bempedoic acid lowered low-density lipoprotein cholesterol (LDL-C) and effectively reduced the risk of major adverse cardiovascular events (MACE). This was established in the phase 3, double-blind, randomized, placebo-controlled CLEAR Outcomes trial.
Bempedoic acid is a first-in-class, orally administered ATP citrate lyase (ACL) inhibitor that reduces LDL-C. As a prodrug, it is activated in the hepatocyte; thus avoiding potential muscle adverse effects associated with statins. The effects of bempedoic acid on cardiovascular morbidity and mortality had not yet been assessed. Therefore, the CLEAR Outcomes Trial (NCT02993406) was set up, the results of which were presented at the 2023 American College of Cardiology annual meeting by Steven Nissen, MD.1,2
Dr. Nissen explained it was a double-blind, randomized, placebo-controlled trial in patients with statin intolerance who had, or were at high risk for, cardiovascular disease. The 13,970 participants from 32 countries were randomized 1:1 to bempedoic acid 180 mg/day or matching placebo. The primary endpoint was a four-component composite of MACE, defined as non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or cardiovascular death. About one-half of participants (48.1%) were women. The median follow-up was 40.6 months. The mean LDL-C level at baseline was 139.0 mg/dL in both groups.
After 6 months, LDL-C reduction was greater with bempedoic acid than with placebo by 29.2 mg/dL, with an observed difference of 21.1% (-21.7% vs -0.6%). The incidence of a primary endpoint event was significantly lower with bempedoic acid compared with placebo. The primary endpoint was met by 819 (11.7%) and 927 (13.3%) patients, respectively (HR, 0.87; 95% CI, 0.79–0.96; P=0.004). Notably, the HR in women was the same: 0.86. The overall absolute risk reduction was 1.6% (number needed to treat 63).
The following key secondary endpoints were also significant:
- non-fatal stroke, non-fatal MI or cardiovascular death (MACE-3; HR, 0.85; 95% CI, 0.76–0.96; P=0.006);
- fatal or non-fatal MI (HR, 0.77; 95% CI, 0.66– 0.91; P=0.002);
- coronary revascularization (HR, 0.81; 95% CI, 0.72– 0.92; P=0.001).
Bempedoic acid had no significant effects on fatal or non-fatal stroke, cardiovascular death, or all-cause mortality. It was very well tolerated and did not increase the risk for diabetes. The incidence rates for gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs 2.1% and 2.2% vs 1.2%, respectively).
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue,” Dr. Nissen concluded. “Regardless of whether this problem represents the nocebo effect or actual intolerance, these high-risk patients need effective alternative therapies. The CLEAR Outcomes trial provides a sound rationale for the use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients who are intolerant to statins.”
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