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Table of contents for the The CLEAR Trial summary:

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients

April 13, 2023

S.E. Nissen, A.M. Lincoff, D. Brennan, K.K. Ray, D. Mason, J.J.P. Kastelein, P.D. Thompson, P. Libby, L. Cho, J. Plutzky, H.E. Bays, P.M. Moriarty, V. Menon, D.E. Grobbee, M.J. Louie, C.-F. Chen, N. Li, L.A. Bloedon, P. Robinson, M. Horner, W.J. Sasiela, J. McCluskey, D. Davey, P. Fajardo-Campos, P. Petrovic, J. Fedacko, W. Zmuda, Y. Lukyanov, and S.J. Nicholls, for the CLEAR Outcomes Investigators

Link to Manuscript

  • What is Bempedoic acid?
    1. Bempedoic Acid: for Whom and When

Relevant literature

Relevant guidelines

2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee

2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)

Note that these guidelines are not included in the standard therapy protocol

Study Rationale

Recent data suggest that bempedoic acid has an LDL-lowering effect. However, cardiovascular outcome data related to this medication was missing. The CLEAR trial was conducted to determine the effect of bempedoic acid on cardiovascular events.


  1. Determine the safety and efficacy of bempedoic acid versus placebo in patients who are statin intolerant and either have cardiovascular disease or are at high-risk for cardiovascular disease.
    1. Statin-intolerance defined as being unable or unwilling to receive statins owing to an adverse effect that had started or increased during statin therapy and resolved or improved after statin therapy was discontinued

The CLEAR Outcomes Trial

  1. Patients assigned to oral bempedoic acid 180 mg daily or placebo
  2. Followed for a median of 40.6 months
  3. Of note, bempedoic acid has a similar end-goal to statins but is a prodrug activated in the liver and not in most peripheral tissues

Enrollment Criteria

Statistical Analysis

  1. Intention-to-treat analysis. Differences between the placebo and bempedoic acid groups for the primary outcome were assessed for statistical significance at p<0.05.
  2. Hierarchical statistical analysis. 
    • Sequential analysis was run for the primary end point and the six secondary endpoints
    • In order to progress, statistical significance was required at each step


  • 4-week run in period of a single-blind placebo
    • Those with unacceptable adverse effects or <80% adherence were then ineligible for randomization and excluded from trial
  • Randomized 1:1 bempedoic acid vs. placebo

Notable Baseline Characteristics (Intervention vs. Control)

  • Age: 65.5 vs. 65.5 years
  • Women: 48.1% vs. 48.4%
  • White race: 91.5% vs. 90.8%
  • LDL cholesterol: 139 vs. 139 mg/dL
  • HDL cholesterol: 49.6 vs. 49.4 mg/dL
  • TG: 159.5 vs. 158.5 mg/dL
  • CV risk category
    • Primary prevention: 30% vs. 30.2%
    • Secondary prevention: 70% vs. 69.8%
  • Statin use: 22.9% vs. 22.5%
  • Ezetimibe use: 11.5 vs. 11.6%
  • T2DM: 45% vs. 46.3%
  • Inadequately controlled DM*: 19.4% vs. 19.6%

* Defined as Diabetes Mellituswith an HbA1C greater than or equal to 7 at baseline.


*Of note, details of non-fatal myocardial infarction (e.g. spontaneous vs. Procedure-related) are not reported

Adverse Events (Intervention vs. Control)

The incidence of gout and cholelithiasis were higher with bempedoic acid than with placebo, as were the incidences of increases in serum creatinine, uric acid, and hepatic-enzyme levels.

  • Myalgias – 5.6% vs. 6.8%
  • Discontinuation of the trial regimen because of myalgia – 1.8% vs. 1.9%
  • Renal impairment – 11.5% vs. 8.6%
  • Hyperuricemia – 10.9% vs. 5.6%
  • Gout – 3.1% vs. 2.1%
  • Cholelithiasis – 2.2% vs. 1.2%

Change from baseline in lab results after 6 months

  • Uric acid – 0.76±1.2 vs. -0.03±1.0
  • Creatinine – 0.05±0.2 vs. 0.01± 0.2

There was no difference in the incidence of tendinopathy, as has been seen in prior trials.

  • Tendinopathy– 1.7% vs. 1.8%
  • Adjudicated tendon rupture– 1.2% vs. 0.9%

A difference in the rate of fatal and nonfatal hemorrhagic stroke was detected:

  • Fatal and nonfatal non-hemorrhagic stroke – 1.7% (bempedoic acid) vs. 2.1% (placebo)


  • The percent reduction in the LDL cholesterol was greater with bempedoic acid than placebo by 21%
  • The risk of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization was 13% lower with bempedoic acid than with placebo over a median of 3.4 years                             
  • Bempedoic acid was superior to placebo in reducing the risk of secondary end-point events, including the three-component composite endpoint of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke, along with, fatal or nonfatal myocardial infarction, and coronary revascularization
  • Similar effects of bempedoic acid were seen in patients using concomitant ezetimibe and very-low-dose statins
  • The percentage of patients with myalgias was similar in both groups, however incidences of gout, cholelithiasis, and serum elevations in creatinine, uric acid, and hepatic enzymes were higher with bempedoic acid than placebo                      
  • Limitations & Considerations
  • Only included patients who reported they were unable or unwilling to take statins. This resulted in elevated baseline mean LDL cholesterol level (139 and 139 mg/dL in each arm). The effects of bempedoic acid on CV events in populations with lower LDL cholesterol levels and in patients taking conventional therapeutic doses of statins were not studied.
  • Predominately White cohort (> 90%)
  • Use of composite outcomes.
  • Strength: randomized controlled trial, almost 50% women in each group
  1. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023;388(15):1353-1364. doi:10.1056/NEJMoa2215024
  2. Ray KK, Bays HE, Catapano AL, 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
  3. Alexander JH. Benefits of Bempedoic Acid – Clearer Now. N Engl J Med. 2023;388(15):1425-1426. doi:10.1056/NEJMe2301490
  4. Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, Stroes ES, MacDougall D, Zhao X, Catapano AL. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020 Apr;27(6):593-603. doi: 10.1177/2047487319864671. Epub 2019 Jul 29. PMID: 31357887; PMCID: PMC7153222.
  5. Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X, Leiter LA. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018 Oct;277:195-203. doi: 10.1016/j.atherosclerosis.2018.06.002. Epub 2018 Jun 12. PMID: 29910030.
  6. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM; CLEAR Harmony Trial. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022-1032. doi: 10.1056/NEJMoa1803917. PMID: 30865796.
  7. François Mach et. al, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), European Heart Journal, Volume 41, Issue 1, 1 January 2020, Pages 111–188,
  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

Trial summary by Christian Faaborg Andersen MD and Rachel Goodman, MD

Visual abstract by Cali Clark, DO, MBA

Trial tweets by Hamza Patel, MD

Promo by Apurva Bhavana Challa and Pacey Wetstein

House Chief:  Alaa Diab, MD

FIT experts: Paul Marano, MD , Kayla Riggs, MD , Usman Hasnie, MD , and Allison Bigeh, DO

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