Hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, better known as "statins," are a foundational therapy in primary and secondary atherosclerotic cardiovascular (CV) disease risk reduction.¹ However, intolerance to statins, most commonly in the form of muscle-related symptoms, is seen in up to 20% of patients and remains a vexing problem for clinicians because it is a major reason for patients discontinuing therapy and increases the risk of CV events, including in those who stop taking statins because of the "nocebo" effect.^1,2

Bempedoic acid (BA) is a prodrug that is converted to its active metabolite by an enzyme very-long-chain acyl-CoA synthetase 1, which is expressed abundantly in the liver but not in the muscle. It produces an active metabolite that inhibits adenosine triphosphate citrate lyase.³ This enzyme is in the cholesterol biosynthetic pathway upstream of HMG-CoA reductase, the target enzyme for statins. BA reduces low-density lipoprotein cholesterol (LDL-C) levels by approximately 18-20% and can be useful in patients with statin intolerance because the prodrug is converted into its active metabolite only in the liver and not in muscle.

The CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen - CLEAR Outcomes) trial was a randomized, double-blind, placebo-controlled trial evaluating the efficacy of BA in patients who could not tolerate more than a very low dose of any statin.⁴ There were 13,970 patients randomized to receive either BA 180 mg daily or placebo. Approximately 70% of patients required secondary-prevention therapy and 30% required primary-prevention therapy, with mean baseline LDL-C level 139 mg/dL. In a refreshing departure from similar lipid trials conducted previously, more women and minorities were represented: 48% of enrolled patients were women and 17% were Hispanic. Patients could continue secondary therapies in combination with BA, with the most common adjunct therapy continued being ezetimibe (~11% in each group). The primary endpoint was a four-component major adverse cardiac event (MACE), defined as death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.

After 6 months of therapy, there was a significant drop in LDL-C levels in the BA arm compared with the placebo arm (by 29 mg/dL [~21%]). At a median follow-up of 40.6 months, this drop translated into a significant 13% reduction in MACE, with hazard ratio (HR) 0.87 (95% confidence interval, 0.79-0.96; p = 0.004), which is in line with the benefit previously seen with statin therapy in other large meta-analyses. This benefit was largely driven by a decrease in MI and coronary revascularization rates. BA was generally well tolerated, with discontinuation rates (including for musculoskeletal adverse effects) being comparable to placebo at approximately 10%. There was a slightly higher incidence of gout and cholelithiasis with BA than with placebo; similarly, there were small increases in serum creatinine, uric acid, and hepatic-enzyme levels with BA compared with placebo. Additionally, the medication resulted in a 22% reduction in high-sensitivity C-reactive protein levels and a 0.03% reduction in glycated hemoglobin levels compared with placebo; whether these will impact additional CV benefits in the long run will be a topic for further study. A subgroup analysis identified that the benefit of BA favored the primary-prevention cohort (HR, 0.68 [0.53-0.87]) but not the secondary-prevention cohort (HR, 0.91 [0.82-1.01]), with a p-value of 0.03.

Whether this difference is a play of chance or a real finding is still a matter of debate and will need to be explored further. Similarly, whether BA can provide additional benefit in those who can tolerate high-dose statin therapy or can be used instead of statin therapy in such patients were not questions posed in this trial; the answers to these questions are thus yet unknown. This medication is commercially available alone or in conjunction with ezetimibe; the combination pill can lower LDL-C levels by up to 38%.⁵

In summary, BA reduces CV events in patients intolerant of statins and offers a CLEAR glimmer of hope for this challenging clinical scenario.

References

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.
2. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res 2019;124:328-50.
3. Keaney JF Jr. Bempedoic acid and the prevention of cardiovascular disease. N Engl J Med 2023;388:1427-30.
4. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388:1353-64.
5. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol 2016;10:556-67.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Prevention, Stable Ischemic Heart Disease

Keywords: ACC Annual Scientific Session, ACC23, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ezetimibe, Prodrugs, Creatinine, Glycated Hemoglobin A, Nocebo Effect, Adenosine Triphosphate, Acyl Coenzyme A, Cholelithiasis, Lipoproteins, Infarction

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