https://doi.org/10.55788/88e583af
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 and its results were presented by Prof. Steven Nissen (Cleveland Clinic, OH, USA) [1,2].
The CLEAR Outcomes was a double-blind, randomised, 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 randomised 1:1 to bempedoic acid 180 mg/day or a matching placebo. The primary endpoint was a 4-component composite of MACE, defined as non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularisation, or cardiovascular death. The median follow-up was 40.6 months, and 48.1% were women. 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%). Addition of other therapies (including PCSK9 inhibitors) narrowed the LDL-C differences to 15.5% (-26.1% vs -10.6%) after 60 months. 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 in the bempedoic acid and placebo group, respectively (HR 0.87; 95% CI 0.79–0.96; P=0.004). Notably, the HR in women was the same in both groups: 0.86. The overall absolute risk reduction was 1.6% (number needed to treat 63).
The following key secondary endpoints also showed a significant difference:
- 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); and
- coronary revascularisation (HR 0.81; 95% CI 0.72–0.92; P=0.001).
Bempedoic acid was very well tolerated and did not increase the risk of diabetes. However, 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).
“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.”
- Nissen S, et al. Bempedoic acid and cardiovascular outcomes in statin intolerant patients at high cardiovascular risk. Session 402-06, ACC Scientific Session 2023, 4–6 March, New Orleans, USA.
- Nissen S, et al. N Engl J Med 2023; Mar 4. DOI:10.1056/NEJMoa2215024.
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