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Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients
Open accessAbstract
BACKGROUND: Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. RESULTS: A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. CONCLUSIONS: Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).
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“The CLEAR Outcomes trial randomized 13,970 patients with established or high risk for CVD, intolerance to statins, and LDL-C level ≥ 100 mg/dL to receive bempedoic acid (180 mg daily) or placebo [131]. Bempedoic acid reduced the risk of MACE by − 13% (HR 0.87, 95% CI 0.79–0.96, p = 0.004) and resulted in a − 21.1% greater reduction in LDL-C levels”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [133]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It is important to note that ∼19% of individuals were on very-low-dose statin therapy at baseline (135).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [135]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This substantially exceeded other oral non-statin therapies, as ezetimibe lowers LDL-C by 18–25%, bempedoic acid by 17–21%, and their combination by ∼36–40% [[21], [22], [23], [24]]”
From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [23]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In the CLEAR-Outcomes trial, an intriguing observation was that BA’s relative risk reduction for the primary composite outcome differed significantly between the primary and secondary prevention groups (with hazard ratios of 0.68 versus 0.91 respectively) [7].”
From The Clinical Efficacy and Safety of Bempedoic Acid in Patients at Elevated Risk of Cardiovascular Disease: A Meta-Analysis of Randomized Clinical Trials (2024) · cites this paper as [7]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“A higher frequency of gout (3.1% versus 2.1%) and cholelithiasis (2.2% versus 1.2%) was observed with bempedoic acid than with placebo [133].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [133]
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In the citing paper
“The Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid or Placebo (CLEAR Outcomes) trial found a reduction in four-point major adverse cardiovascular events by 13% compared with placebo for individuals with established ASCVD (70% of population) or at high risk for ASCVD (30% of population) a”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [141]
The cited source says what the claim attributes to it.
In the citing paper
“Clinical trials have shown bempedoic acid reduces LDL-C levels and the CLEAR Outcomes trial demonstrated a significant reduction in MACE compared with placebo in patients who are statin intolerant [[12], [13], [14], [15],17].”
From Systematic literature review on the real-world effectiveness and safety of bempedoic acid (2026) · cites this paper as [17]
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In the citing paper
“The CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial reported cardiovascular outcomes in a mixed population of primary and secondary prevention patients unable or unwilling to take guideline-recommended doses of statins.11”
From Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“This primary prevention cohort was a prespecified subgroup that represented 30% of the total enrolled within a larger trial that included a mixed population of primary and secondary prevention patients.11”
From Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“This was followed by recent data from the CLEAR Outcomes trial showing reductions in clinical events [7].”
From The Clinical Efficacy and Safety of Bempedoic Acid in Patients at Elevated Risk of Cardiovascular Disease: A Meta-Analysis of Randomized Clinical Trials (2024) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“These differences are likely attributable to a lack of statistical power and imprecise estimates as the largest outcomes-based trial, CLEAR Outcomes, had not yet been published at the time of the previous meta-analyses but is included in our meta-analysis [7].”
From The Clinical Efficacy and Safety of Bempedoic Acid in Patients at Elevated Risk of Cardiovascular Disease: A Meta-Analysis of Randomized Clinical Trials (2024) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, most of the trials included in this analysis had relatively short follow-up durations with the exception of CLEAR Outcomes [7] and CLEAR Harmony [12].”
From The Clinical Efficacy and Safety of Bempedoic Acid in Patients at Elevated Risk of Cardiovascular Disease: A Meta-Analysis of Randomized Clinical Trials (2024) · cites this paper as [7]
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In the citing paper
“The overall risk of bias was low 7 of 11 trials [7, 9–12, 15, 16], with 4 trials being assessed as having a moderate risk of bias [8, 13, 14, 17].”
From The Clinical Efficacy and Safety of Bempedoic Acid in Patients at Elevated Risk of Cardiovascular Disease: A Meta-Analysis of Randomized Clinical Trials (2024) · cites this paper as [7]
Experimental — accuracy not yet measuredIn the citing paper
“Among the 6992 patients assigned to the active arm of the study 45% had T2DM.Bempedoic acid was associated with a significantly lower incidence of the four-component composite primary endpoint of CV death, non-fatal MI, non-fatal stroke, or coronary revascularization and a higher incidence of some adverse events (gout and cholelithiasis) at the 40.6 month follow-up.”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [282]
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Citations
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Metadata
- Authors
- Nissen, S. E., Lincoff, A. M., Brennan, D., Ray, K. K., Mason, D., Kastelein, J. J. P., Thompson, P. D., Libby, P., Cho, L., Plutzky, J., Bays, H. E., Moriarty, P. M., Menon, V., Grobbee, D. E., Louie, M. J., Chen, C.-F., Li, N., Bloedon, L., Robinson, P., Horner, M., Sasiela, W. J., McCluskey, J., Davey, D., Fajardo-Campos, P., Petrovic, P., Fedacko, J., Zmuda, W., Lukyanov, Y., & Nicholls, S. J.
- Affiliations
- Brigham and Women's Hospital (US)
- From the Cleveland Clinic, Cleveland (S.E.N., A.M.L., D.B., D.M., L.C., V.M., J.M., D.D.); Imperial College London, London (K.K.R.); University of Amsterdam Academic Medical Center, Amsterdam (J.J.P.K.), and University Medical Center Utrecht, Utrecht (D.E.G.) — both in the Netherlands; Hartford Hospital, Hartford, CT (P.D.T.); Brigham and Women’s Hospital, Harvard Medical School, Boston (P.L., J.P.); Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); University of Kansas Medical Center, Kansas City (P.M.M.); Esperion Therapeutics, Ann Arbor, MI (M.J.L., C.-F.C., N.L., L.B., P.R., M.H., W.J.S.); Centro de Investigación Cardiovascular y Metabólica, Tijuana, Mexico (P.F.-C.); General Hospital Sveti Luka, Smederevo, Serbia (P.P.); Center of Clinical and Preclinical Research Medipark, Pavol Jozef Šafárik University, Košice, Slovakia (J.F.); Medicome, Oświęcim, Poland (W.Z.); Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia (Y.L.); and Victorian Heart I...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2023-04-13
- Volume
- 388
- Issue
- 15
- Pages
- 1353-1364
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W4323075797
- Semantic Scholar
- 33b876475ba15ddd5ffc66ad5046afe4cb9173b0
- Cited by
- 988
- References
- 21
- Citations by year
- 2026: 266 · 2025: 261 · 2024: 270 · 2023: 189
- FWCI
- 263.23
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Esperion Therapeutics
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- bempedoic acid, statin intolerance, ATP-citrate lyase inhibitor, LDL cholesterol lowering, major adverse cardiovascular events, cardiovascular disease prevention, LDL cholesterol targets, cardiovascular mortality, myocardial infarction, stroke, coronary revascularization, hypercholesterolemia, lipid-lowering therapy, statin adverse effects
- MeSH terms
- Administration, Oral, Hypolipidemic Agents, Cardiovascular Diseases, Dicarboxylic Acids, Double-Blind Method, Fatty Acids, Humans, Myocardial Infarction, Myocardial Revascularization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Stroke
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