Cardiovascular Outcomes in Patients Intolerant to Statins Treated with Bempedoic Acid


In December 2023, the FDA granted expanded indications for bempedoic acid and bempedoic acid plus ezetimibe in the treatment of primary hyperlipidemia.

Bempedoic acid (Nexletol; Esperion) is a pioneering adenosine triphosphate-citrate lyase (ACL) which received FDA approval in 2020.1 Additionally, a combination product of bempedoic acid and ezetimibe (Nexlizet; Esperion) gained FDA approval for providing enhanced control over low-density lipoprotein cholesterol (LDL-C) levels in patients facing persistent elevations despite prior statin treatment.2 In December 2023, the FDA granted expanded indications for bempedoic acid and bempedoic acid plus ezetimibe in the treatment of primary hyperlipidemia. The requirement for patients to already be on maximally tolerated statins has been eliminated.3

3d rendered medically accurate illustration of the human heart

Image credit: SciePro |

Bempedoic acid was previously recommended as a supplementary treatment alongside diet and maximally tolerated statin therapy for adults diagnosed with heterozygous familial hypercholesterolemia or those with existing atherosclerotic cardiovascular disease that necessitates additional reduction of LDL-C. Additionally, the combination of bempedoic acid and ezetimibe was recommended, along with dietary management and maximally tolerated statin therapy, for adults with heterozygous familial hypercholesterolemia or pre-existing atherosclerotic cardiovascular disease requiring further reduction of LDL-C levels.1,2

Bempedoic acid works by inhibiting cholesterol synthesis in the liver, leading to a reduction in LDL-C levels. This, in turn, diminishes the formation of atherosclerotic plaques, mitigating the risk of cardiovascular events. Earlier clinical trials examining bempedoic acid demonstrated a dose-dependent decrease in LDL-C levels, accompanied by a reduction in LDL particle number, lowered levels of apolipoprotein B, decreased non-high-density lipoprotein cholesterol, and reduced high-sensitivity C-reactive protein. Notably, bempedoic acid's unique mechanism of action sets it apart because it is not associated with myositis, a common adverse effect linked to statin therapy. Statin intolerance may cause non-adherence and therapy discontinuation.4,5

In the CLEAR trial, the impact of bempedoic acid was assessed in high-risk patients with statin intolerance. Bempedoic acid was investigated for its ability to lower LDL synthesis and enhance LDL clearance, with a focus on evaluating its influence on cardiovascular events.6

The CLEAR study was a double-blind, randomized, placebo-controlled trial which enrolled patients unable or unwilling to take statins due to unacceptable adverse effects (referred to as statin-intolerant patients) who either had or were at high risk for cardiovascular disease. Participants were randomly assigned to receive either oral bempedoic acid at a daily dose of 180 mg or a placebo. The primary endpoint was a 4-component composite of major adverse cardiovascular events, encompassing death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.6

The 13,970 participants had an average age of 65.5 years. Approximately half of the tested population were female and 69.9% had a prior cardiovascular event (indicating secondary prevention). Among the tested population there were 45.6% patients with diabetes and 42.8% had an HbA1c of 7% or higher. The mean LDL was 139 mg/dL, with 44% having an LDL level below 130 mg/dL. Approximately 23% were taking a statin and 11.5% were taking ezetimibe.6

Bempedoic acid demonstrated a greater reduction in LDL levels compared to the placebo at 6 months (21.1% reduction) and at the end of the trial (15.9% reduction). High-sensitivity C-reactive protein also experienced a greater reduction with bempedoic acid at 6 months. Following a median follow-up of 40.6 months, the primary endpoint of major adverse cardiovascular events (MACE) occurred in 11.7% of those on bempedoic acid and 13.5% of those on placebo (hazard ratio 0.87; 95% confidence interval 0.79-0.96; p=0.004).6

Bempedoic acid therapy was linked to significant reductions in fatal or nonfatal myocardial infarction and coronary revascularization. However, no difference was observed in cardiovascular death or death from any cause. Adverse events did not vary between the groups, but notably, the bempedoic acid arm had a higher percentage of patients with elevated liver enzymes (4.5% vs. 3.0% with placebo), renal impairment (11.5% vs. 8.6% with placebo), and hyperuricemia (10.9% vs. 5.6% with placebo).6

The CLEAR trial demonstrated that when administered to statin-intolerant patients, bempedoic acid resulted in a lower risk of MACE, particularly myocardial infarction and coronary revascularization. The treatment was well-tolerated in both primary and secondary prevention patients.6,7

Bempedoic acid influences the identical biological pathway targeted by statins but remains inactive until it reaches the liver. This restricted activation minimizes the drug's impact on muscles, the brain, and other tissues or organs, elucidating why it lacks the same adverse effects associated with statins. Bempedoic acid holds promise, especially for statin-intolerant patients, although further studies targeting specific patient risk groups are needed.7,8


1. Nexletol (bempedoic acid) [prescribing information]. Ann Arbor, MI: Esperion Therapeutics Inc; February 2020.

2. Nexlizet (bempedoic acid and ezetimibe) [prescribing information]. Ann Arbor, MI: Esperion Therapeutics Inc; February 2020.

3. U.S. FDA Updates LDL-C Lowering Indication for Esperion’s NEXLETOL (bempedoic acid) Tablet and NEXLIZET (bempedoic acid and ezetimibe) Tablet. News release. Esperion. December 13, 2023. Accessed January 21, 2024.

4. Zagelbaum NK, Yandrapalli S, Nabors C, Frishman WH. Bempedoic Acid (ETC-1002): ATP Citrate Lyase Inhibitor: Review of a First-in-Class Medication with Potential Benefit in Statin-Refractory Cases. Cardiol Rev. 2019;27(1):49-56. doi:10.1097/CRD.0000000000000218

5. Jia X, Virani SS. CLEAR Serenity Trial: More Clarity for the Future of Bempedoic Acid in Patients Unable to Take Statins? J Am Heart Assoc. 2019;8(7):e012352. doi:10.1161/JAHA.119.012352

6. Ray KK, Bays HE, Catapano AL, Lalwani ND, et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019;380(11):1022-1032. doi:10.1056/NEJMoa1803917

7. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353-1364. doi:10.1056/NEJMoa2215024

8. Ruscica M, Sirtori CR, Carugo S, Banach M, Corsini A. Bempedoic Acid: for Whom and When. Curr Atheroscler Rep. 2022;24(10):791-801. doi:10.1007/s11883-022-01054-2

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