Current guidelines recommend reducing LDL-C (low-density lipoprotein cholesterol) in patients at a high risk for a first major adverse cardiovascular (CV) event. Bempedoic acid, an ATP (adenosine triphosphate) citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of HMG-Co-A (β-Hydroxy β-methylglutaryl-coenzyme A) reductase. Bempedoic acid is a pro-drug that gets activated in the liver and not peripheral tissues, thus, resulting in a lower incidence of muscle-related adverse events.

The CLEAR Outcomes trial aimed to evaluate the CV outcomes with bempedoic acid administration in patients unable to tolerate the recommended statin dose. The study results were published in The New England Journal of Medicine on March 4.

Trial design and methodology: A mixed population of primary and secondary prevention patients with LDL-C ≥100 mg/dL unable or unwilling to take guideline-recommended doses of statins (N=13,970) were identified. A total of 4206 patients met high-risk primary prevention entry criteria* (66% with diabetes). They were randomized into two groups, one group received bempedoic acid 180 mg/day (N=2100) and the other received a matching placebo (N=2106). CV outcomes were assessed after 40.6 months of median follow-up.

High risk for cardiovascular event (Primary prevention) criteria: Reynolds Risk score >30% or SCORE risk >7.5% over 10 years or patients with type 1 or 2 diabetes; age >65 yrs for women and >60 yrs for men or coronary artery calcium (CAC) score >400 AU at any time in the past

The primary endpoint was a composite of major adverse cardiovascular events (MACE), death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.

Results: Mean reduction in LDL-C with bempedoic acid vs placebo were 22.7% vs 1.4%, respectively, with a difference of 21.3%. Bempedoic acid reduced hsCRP (high-sensitivity C-reactive protein) by 22% vs 0.5% with placebo. The 4-component and 3-component MACE were reduced by 30% [HR (hazard ratio) 0.70; 95% CI 0.55-0.89] and 36% (HR 0.64; 95% CI 0.48-0.84) with bempedoic acid. It reduced myocardial infarction (MI) by 39% (HR 0.61; 95% CI 0.39-0.98), stroke by 24% (HR 0.76; 95% CI 0.46-1.26), CV death by 39% (HR 0.61; 95% CI 0.41-0.92) and all-cause mortality by 27% ((HR 0.73; 95% CI 0.54-0.98).

Bempedoic acid was well-tolerated in primary prevention patients. Adverse events reported were small increases in gout (2.6%) and cholelithiasis (2.5%) incidences. Drug discontinuation due to adverse events was similar in both groups.

Limitations: This was a secondary analysis of a subpopulation in a larger randomized trial which can result in false positive findings. As the population included was at high risk of a first CV event, its results may not apply to a lower-risk populations.

Conclusion: The study findings suggest the benefits of treatment with bempedoic acid in lowering LDL-C, hsCRP and cardiovascular events among statin-intolerant patients.

American Diabetes Association (ADA) 83rd Scientific Sessions, 2023, 23- 25 June 2023, San Diego, CA.