Statins are the standard first-line treatment for lowering cholesterol and the risk of cardiovascular (CV) diseases.¹ However, for statin-intolerant patients, discontinuation of therapy is often linked to an increased risk of adverse CV events.¹ Bempedoic acid, an adenosine triphosphate (ATP)-citrate lyase (ACL)-inhibiting regimen, targets the same biological pathway as statins, but it is a pro-drug activated in the liver rather than peripheral tissues, resulting in a lower incidence of muscle-related adverse events (AEs) than statins.¹ As a result, the United States (US) Food and Drug Administration (FDA) has approved it as a supplement for lowering low-density lipoprotein-cholesterol (LDL-C) in patients receiving maximally tolerated statin therapy.¹ However, the effects of bempedoic acid on CV outcomes have yet to be assessed.¹ To investigate the effects of bempedoic acid on CV outcomes, the progress of a large trial called CLEAR Outcomes has been recently presented at the American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023, which showed that bempedoic acid was able to reduce the combined rate of major adverse CV events (MACEs) by 13%, meeting its primary endpoint.¹ 

The CLEAR Outcomes trial enrolled approximately 14,000 primary or secondary prevention patients with statin intolerance, who are intolerant to ≥2 statins or 1 statin if patients only have I prior statin with baseline LDL levels ≥100mg/dL, from over 1,200 sites in 32 countries from December 2016 to August 2019.¹ Patients were randomized to receive bempedoic acid 180mg/day or a placebo daily, with a median duration follow-up of 40.6 months.¹ The primary endpoint was a 4-component composite of MACEs, including CV death, non-fatal myocardial infarction (MI), non-fatal stroke or coronary revascularization, while the key secondary endpoints were 3-component MACEs (i.e., MI, stroke or CV death), fatal and non-fatal MI, coronary revascularization, fatal and non-fatal stroke, CV death, and all-cause mortality.¹ Patient demographics were balanced, nearly half being women, in addition to around 30% in high-risk primary prevention and nearly half of patients having diabetes.¹ 

The findings revealed a statistically significant improvement in the primary and the first key secondary endpoint, i.e., 4-component MACEs (HR=0.87; 95% CI: 0.79-0.96; p=0.004) and 3-component MACEs (HR=0.85; 95% CI: 0.76-0.96; p=0.006).¹ For other secondary endpoints, bempedoic acid also reduced fatal and non-fatal MI by 23% (HR=0.77; 95% CI: 0.66-0.91; p=0.002), and coronary revascularizations by 19% (HR=0.81; 95% CI: 0.72-0.92; p=0.001).¹ The combined rate of CV death, heart attack, stroke or coronary revascularization occurred in 11.7% of participants taking bempedoic acid, and 13.3% of those taking a placebo, with no significant difference in the death rates.¹  

Additionally, the LDL-C and the high-sensitivity C-reactive protein (hsCRP) levels in those who received bempedoic acid dropped significantly in the 6-month time frame (LDL-C: -21.7% in the bempedoic acid arm vs. -0.6% in the placebo arm; hsCRP: -22.2% in the bempedoic acid arm vs. +2.4% in the placebo arm) and maintained over the course of the study.¹ With respect to safety, patients tolerated the bempedoic acid regimen very well, the AEs leading to drug discontinuation were the same between the 2 arms (bempedoic acid: 10.8 vs. placebo: 10.4).¹ Notably, there was no increase in new-onset diabetes due to the use of bempedoic acid when compared with placebo (16.1% vs. 17.1%). Only 1% absolute increase was shown in gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%) in the bempedoic acid arm when compared with the placebo arm.¹  

To conclude, bempedoic acid was well tolerated in the heterogeneous population of primary and secondary prevention patients with statin-intolerance.¹ Bempedoic acid also demonstrated significant improvement in the primary endpoint and the key secondary endpoints.1 Moreover, bempedoic acid lowered LDL-C by 21.7% and hsCRP by 22.2% in the 6-month time frame with only small increases in the incidence of gout and cholelithiasis.¹ These findings have established bempedoic acid as an effective approach to reducing MACEs in statin-intolerant patients.¹