Bempedoic Acid for High-Risk Primary Prevention of Cardiovascular Disease

Abstract

Statin therapy is the mainstay of lipid-lowering therapy for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). 1 But 5% to 10% of patients are unable to tolerate a statin at any dose or at a dose high enough to achieve patient-specific target levels of low-density lipoprotein cholesterol (LDL-C), most commonly due to musclerelated symptoms. Statinintolerant patients have historically had few therapeutic options: ezetimibe produces only modest reductions in LDL-C levels, and proprotein convertase subtilisin/kexin type 9 inhibitors are indicated for primary prevention only if the patient is diagnosed with heterozygous familial hypercholesterolemia. Therefore, the recent approval of bempedoic acid, a new lipid-lowering agent associated with fewer muscle-related symptoms compared with statins, was an exciting development. Bempedoic acid inhibits cholesterol synthesis by blocking ATP citrate lyase, upstream of the hydroxymethylglutaryl-CoA reductase enzyme that is blocked by statins. The resulting upregulation of LDL receptors on the surface of hepatocytes enhances clearance of LDL particles from the bloodstream and lowers the level of circulating LDL-C. 2 Bempedoic acid is associated with fewer muscle-related symptoms than statins, presumably because the enzyme responsible for activating bempedoic acid is present in hepatocytes but not in myocytes. But whether lipid lowering with bempedoic acid improves cardiovascular outcomes in statin-intolerant patients at risk of developing ASCVD was, until recently, uncertain. 3 In this issue of JAMA, Nissen and colleagues 4 present new evidence of the effectiveness and safety of bempedoic acid for the primary prevention of ASCVD based on a prespecified subgroup analysis of the CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial. Of the 13 970 patients enrolled in the trial, 4206 (30%) did not have ASCVD at baseline and were included in this analysis. This primary prevention subpopulation comprised statin-intolerant adults aged 18 to 85 years with an LDL-C level of 100 mg/dL or greater who had an elevated predicted risk of adverse cardiovascular outcomes based on a clinical risk score, presence of high levels of coronary calcium, or the co-occurrence of diabetes. Patients receiving bempedoic acid had a timeaveraged LDL-C reduction of 23.2 mg/dL (16.3% reduction from a mean baseline level of 142.2 mg/dL) over the course of the trial and a reduction of 0.6 mg/L in levels of high-sensitivity Multimedia Related article page 131Opinion EDITORIAL

The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: Lower for longer is better

“…A subgroup analysis of CLEAR Outcomes was published focusing on the primary prevention group, and in this analysis, a striking 39% and 27% RRR was seen for cardiovascular and all-cause mortality, respectively [60] . While these associations did meet significance, this subgroup analysis should be interpreted with some level of caution and considered hypothesis-generating [61] . CLEAR Outcomes was not powered to detect differences in subgroups, and these findings may represent chance.…”