Bempedoic Acid: A CLEAR Look into Cardiovascular Outcomes in Statin-Intolerant Patients

Casey LaBelle, PharmD., New Ulm Medical Center

Background: In current practice, statin intolerance due to muscle related adverse effects has limited the use of statins for both LDL-cholesterol reduction and cardiovascular benefits. According to the National Lipid Association, statin intolerance is defined as the inability to tolerate at least two statins either due to objectionable symptoms or abnormal laboratory analysis which is reversible by stopping the statin. Statin intolerance due to muscle related adverse events can be seen in 7% to 29% of patients reported by Stroes et al. In 2020, the FDA approved use of bempedoic acid for hyperlipidemia based on the results of the CLEAR Harmony trial. In the previous bempedoic acid trial, Ray et al. described the benefits that bempedoic acid had in reducing the LDL-cholesterol while showing similar incidences of muscle-related adverse events between treatment and control. It was hypothesized that the lower incidence of muscle-related adverse events compared to statins was due to bempedoic acid’s mechanism of action. This medication is a prodrug  requiring activation by the very-long-chain acyl-CoA synthetase-1 enzyme found in the liver instead of muscle or other tissues. Bempedoic acid acts by inhibiting adenosine triphosphate (ATP) citrate lyase, ultimately targeting the cholesterol synthesis upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the same enzyme inhibited by statins.This mechanism may be beneficial to avoid the muscle-related side effects that are commonly seen in patients receiving statins, prompting its use as an alternative for LDL-cholesterol lowering in patients unable or unwilling to be on statin therapy.

Purpose: To determine the cardiovascular outcomes of bempedoic acid in statin-intolerant patients.

Study Design: This study was a multicenter, double-blind, randomized, placebo-controlled trial. Participants were included if they were 18-75 years of age, had a reported statin intolerance, fasting LDL-cholesterol ≥100 mg/dL, and a history of cardiovascular disease or high-risk factors. The study excluded participants if they had a total fasting triglyceride of >500 mg/dL, renal dysfunction (eGFR <30 mL/min/1.73 m2), recent CVD event within the past 90 days, HbA1c ≥10%, uncontrolled hypothyroidism, or unexplained creatine kinase >3x the upper limit of normal. Despite statin-intolerance, participants were still included if they were currently tolerating very low doses of statin therapy. This included an average daily dose of <5 mg of rosuvastatin, <10 mg of atorvastatin, <10 mg of simvastatin, <20 mg of lovastatin, <40 mg of pravastatin, <40 mg of fluvastatin, or <2 mg of pitavastatin.  Those that were eligible underwent a 4-week, single-blind placebo run-in period. During this period participants were excluded if they were unable to receive placebo due to unacceptable adverse effects or if adherence was ≤ 80%. Adherence was assessed through tablet counts. The remaining 13,970 participants underwent randomization in a 1:1 ratio to receive either an oral dose of bempedoic acid 180 mg once daily or matching placebo. The primary efficacy endpoint of this study was the four-component composite of major adverse cardiovascular events (MACE) which includes death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, and coronary revascularization. The key secondary efficacy endpoints in this study were three-component composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction, and individually looking at fatal or nonfatal myocardial infarction, coronary revascularization, fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The study also looked at a selection of tertiary lipid endpoints including the mean percent change in mean LDL-cholesterol level at 6 months, median percent changes in high-sensitivity CRP level at 6 months, and mean percentage-point change in glycated hemoglobin level at 12 months in patients with inadequately controlled type 2 diabetes mellitus.

Results: The study was conducted between December 2016 and August 2019 which followed 13,970 participants that underwent randomization which were allocated into two groups: 6,992 were assigned to bempedoic acid and 6,978 were in the placebo group. The participants were then followed over a median follow-up of 40.6 months. The primary efficacy endpoint occurred in 819 (11.7%) patients in the bempedoic acid group and 927 (13.3%) patients in the placebo group (hazard ratio, 0.87; 95% CI, 0.79 to 0.96; P=0.004), concluding that there was a 13% lower risk in the bempedoic acid group over placebo. The key secondary endpoints noted a statistical difference in the three-component MACE which occurred in 575 patients (8.2%) in the bempedoic acid group and 663 (9.3%) patients in the placebo group (hazard ratio 0.85; 95% CI, 0.76 to 0.96; P=0.006). Fatal or nonfatal myocardial infarction occurred in 261 patients (3.7%) in the bempedoic acid group and 334 patients (4.8%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P=0.002). Coronary revascularization occurred in 435 patients (6.2%) in the bempedoic acid group and 529 patients (7.6%) in the placebo group (hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P=0.001). The other secondary endpoints including fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause did not show a statistically significant difference in incidences. The tertiary lipid endpoints after 6 months, showed that the mean LDL-cholesterol after treatment in the bempedoic acid group was 107.0 mg/dL compared to 136.0 mg/dL in the placebo group. This observed difference demonstrated a percentage reduction of 21.1% (95% CI, 20.3 to 21.9) in favor of the bempedoic acid group. Overall, the safety profile demonstrated no meaningful difference between the two groups in the incidences of adverse events. However, bempedoic acid versus placebo did show an increased number of incidences of elevation in alanine aminotransferase levels (1.2% vs 0.8), aspartate aminotransferase levels (1.1% vs. 0.6%),  hyperuricemia (10.9% vs 5.6%), gout (3.1% vs 2.1%), and cholelithiasis (2.2% vs 1.2%); without showing a difference in myalgias reported (5.6% vs. 6.8%).

Conclusions: After a 40.6 month follow-up, bempedoic acid 180 mg orally once daily showed a 13% lower incidence of the four-component composite MACE without causing an increased risk of myalgias.  Overall, the results showed an absolute risk reduction of 1.6% and the number needed to treat to prevent one event over a 40.6 month period was 63 patients. Despite not showing an increased risk of myalgias, bempedoic acid did have an increased number of incidences of elevated alanine and aspartate aminotransferase levels, hyperuricemia, gout, and chloelithiasis. The limitations of this study include the lack of head-to-head comparisons between other LDL cholesterol-lowering agents and the presence of confounding variables, as 23% of patients in each group were on a statin and being on other lipid-lowering therapies were permissible during the study duration.

Key Point: The benefits of statins exceed the need of just lowering LDL-cholesterol, they also reduce cardiovascular events, such as heart attack and stroke. Bempedoic acid was shown to have few adverse events of musculoskeletal effects that led to discontinuation of the trial. In patients with hypercholesterolemia and increased risk factors for ASCVD, statins are currently the preferred treatment;however, due to the increasing prevalence of statin intolerance, it may be beneficial for patients to have alternative lipid lowering therapy options that also reduce the risk of cardiovascular events to choose from.


  1. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy — European Atherosclerosis Society Consensus Panel statement on assessment, aetiology and management. Eur Heart J 2015;36:1012- 22
  2. Bytyçi, I., Penson, P. E., Mikhailidis, D. P., Wong, N. D., Hernandez, A. V., Sahebkar, A., Thompson, P. D., Mazidi, M., Rysz, J., Pella, D., Reiner, Ž., Toth, P. P., & Banach, M. (2022). Prevalence of statin intolerance: a meta-analysis. European Heart Journal, 43(34), 3213–3223.
  3. Ray KK, Phil M, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM. Safety and efficacy of bempedoic acid to reduce ldl cholesterol. N Engl J Med. 2019; 380:1022-1032.
  4. Nissen SE, Lincoff AM, Brennan KK, Ray KK, Mason D, Kastelein JJ, Thompson PD, Libby P, Cho L, Plutzky J, Bays HE, Moriarty PM, Menon V, Grobbee DE, Louie MJ, Chen C, Li N, Bloedon L, Robinson P, Horner M, Sasiela WJ, McCluskey J, Davey D, Fajardo-Campos P, Petrovic P, Fedacko J, Zmuda W, Lukyanov Y, Nicholls SJ. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023; DOI: 10.1056/NEJMoa2215024