The New England Journal of Medicine April 13, 2023

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients

Steven E. Nissen, A. Michael Lincoff, Danielle Brennan, Kausik K. Ray, Denise Mason, John J.P. Kastelein, Paul D. Thompson, Peter Libby, Leslie Cho, Jorge Plutzky, et al.

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Bottom Line

In statin-intolerant patients with or at high risk for cardiovascular disease, bempedoic acid significantly lowered the risk of a composite of major adverse cardiovascular events compared to placebo.

Key Findings

1. Treatment with bempedoic acid significantly reduced the primary 4-point MACE endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization), occurring in 11.7% of patients versus 13.3% in the placebo group (HR 0.87; 95% CI, 0.79-0.96; P=0.004) [1.3].

2. The reduction in the primary outcome was driven largely by a 23% relative risk reduction in fatal or nonfatal myocardial infarction (3.7% vs. 4.8%; HR 0.77; 95% CI, 0.66-0.91; P=0.002) and a 19% reduction in coronary revascularization (6.2% vs. 7.6%; HR 0.81; 95% CI, 0.72-0.92; P=0.001).

3. At 6 months, patients taking bempedoic acid achieved an LDL cholesterol reduction that was 21.1% (29.2 mg/dL) greater than the placebo group.

4. Bempedoic acid had no significant impact on fatal or nonfatal stroke, cardiovascular death, or all-cause mortality.

5. Adverse events were generally balanced, but bempedoic acid was associated with a higher incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%) compared with placebo.

Study Design

Design

RCT

Double-Blind

Sample

13,970

Patients

Duration

40.6 mo

Median

Setting

Multinational, multicenter

Population Patients with, or at high risk for, cardiovascular disease who reported being unable or unwilling to take statins due to unacceptable adverse effects (statin-intolerant).

Intervention Bempedoic acid 180 mg daily orally.

Comparator Matching oral placebo.

Outcome Four-component composite of major adverse cardiovascular events (MACE-4), defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

Study Limitations

• The study population lacked racial and ethnic diversity, with 91% of participants identifying as White, which limits the generalizability of the results [1.6].

• The median follow-up of 40.6 months may have been too short to observe significant differences in cardiovascular or all-cause mortality endpoints.

• The magnitude of the absolute LDL-C reduction (approximately 29 mg/dL) and the absolute risk reduction for the primary MACE endpoint (1.6%) were relatively modest compared to those seen with more potent lipid-lowering therapies like PCSK9 inhibitors.

• The diagnosis of statin intolerance was based largely on patient-reported previous adverse effects rather than a formal placebo-controlled re-challenge to verify physiological intolerance.

Clinical Significance

The CLEAR Outcomes trial established bempedoic acid as an effective, evidence-based pharmacological alternative for lipid lowering and cardiovascular risk reduction in patients unable to tolerate statins. By proving that ATP citrate lyase inhibition safely reduces hard cardiovascular endpoints, it provided clinicians with a robust oral non-statin option to mitigate MACE risk. This fills a critical therapeutic gap for statin-intolerant patients who may be unsuited for or hesitant to use injectable PCSK9 inhibitors.

Historical Context

Statins remain the foundational pharmacological therapy for the prevention of atherosclerotic cardiovascular disease. However, up to 10-30% of patients report statin-associated muscle symptoms (SAMS) or other intolerances in real-world settings, leading to treatment nonadherence and persistently elevated cardiovascular risk. Bempedoic acid is an ATP citrate lyase inhibitor that decreases hepatic cholesterol synthesis. Because it requires activation by the enzyme ACSVL1, which is present in the liver but absent in skeletal muscle, it biologically circumvents the myotoxicity pathway associated with statins. Prior to the CLEAR Outcomes trial, bempedoic acid had been approved by regulatory agencies based solely on its LDL-lowering capability. CLEAR Outcomes was a landmark trial because it provided the first definitive evidence that targeting this upstream cholesterol synthesis pathway with an oral agent successfully translates into the reduction of hard major adverse cardiovascular events.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of bempedoic acid specifically address the pathophysiological basis of statin intolerance in skeletal muscle?

Key Response

Bempedoic acid is an ATP-citrate lyase inhibitor and a prodrug that requires activation by very-long-chain acyl-CoA synthetase-1 (ACSVL1). This activating enzyme is present in the liver but absent in skeletal muscle. Therefore, unlike statins, bempedoic acid does not inhibit the cholesterol biosynthesis pathway in muscle tissue, theoretically preventing the myopathy and myalgias that are the primary drivers of statin intolerance.

Resident

For a patient with established ASCVD who refuses statins due to severe myalgias, how do you decide between prescribing bempedoic acid, a PCSK9 inhibitor, or ezetimibe?

Key Response

The decision depends on the required LDL reduction, cost, route of administration, and proven cardiovascular benefit. PCSK9 inhibitors offer the greatest LDL reduction (around 60 percent) and proven MACE reduction but are injectable. Ezetimibe is oral, lowers LDL by roughly 18 percent, and has modest CV benefit. Bempedoic acid lowers LDL by about 21 percent and, based on CLEAR Outcomes, now has proven MACE reduction, making it a strong oral alternative or add-on for patients averse to injections.

Fellow

The CLEAR Outcomes trial noted increased incidences of hyperuricemia, gout, and tendon rupture in the bempedoic acid group. How should these adverse effects influence patient selection and monitoring in a lipid clinic?

Key Response

Bempedoic acid and its metabolite compete with uric acid for the renal OAT2 transporter, decreasing uric acid excretion and potentially triggering gout. Tendon rupture, while rare, is another distinct risk. Fellows must weigh these risks carefully, especially in patients with a history of gout or concurrent use of medications that increase tendon rupture risk like fluoroquinolones or corticosteroids, necessitating baseline uric acid checks and targeted patient counseling.

Attending

Given that statin intolerance is often subjective, how does the validation of bempedoic acid as an effective MACE-reducing therapy risk inadvertently decreasing the rates of statin rechallenge, and how can we mitigate this in primary care?

Key Response

Statins remain the cornerstone of ASCVD prevention with robust mortality data. Having a validated, easy-to-prescribe oral alternative might lead clinicians to readily accept a patient's label of statin intolerance rather than attempting a rechallenge, which is successful in over 70 percent of cases. Clinicians must continue to use evidence-based algorithms for statin rechallenge before abandoning first-line therapy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The CLEAR Outcomes trial required patients to provide written confirmation of their statin intolerance rather than undergo a structured biochemical or clinical rechallenge protocol. How does this pragmatic inclusion criterion affect the internal validity and generalizability of the trial's estimates?

Key Response

Relying on patient confirmation maximizes real-world generalizability by capturing the clinical phenotype of statin intolerance seen in practice. However, it introduces heterogeneity by including both true biological intolerance and nocebo effects, which dilutes the internal validity of studying a pure muscle-sparing biological mechanism, potentially underestimating the drug's effect size if nocebo patients have different adherence patterns.

Journal Editor

The primary endpoint was a composite of four major adverse cardiovascular events (MACE), but the benefit was largely driven by reductions in nonfatal MI and coronary revascularization, with no significant difference in cardiovascular or all-cause mortality. As a reviewer, how does this component-driven outcome influence your appraisal of the drug's overall impact?

Key Response

A rigorous reviewer would flag that while the composite MACE was significantly reduced, the lack of a mortality benefit requires careful framing. Positive results driven by softer or less fatal components like revascularization mean the manuscript's conclusions must be strictly limited to morbidity reduction rather than life-saving claims, ensuring the abstract does not overstate the clinical impact compared to therapies with proven mortality benefits.

Guideline Committee

Based on the CLEAR Outcomes data, what class of recommendation and level of evidence should bempedoic acid receive for secondary prevention in statin-intolerant patients, and how does this update the 2018 AHA/ACC cholesterol guidelines?

Key Response

With a large, randomized, placebo-controlled RCT demonstrating CV outcome benefits, bempedoic acid merits a Class 1 or 2a (Level of Evidence: A or B-R) recommendation for secondary prevention in truly statin-intolerant patients. The 2018 AHA/ACC guidelines currently position ezetimibe and PCSK9 inhibitors as the primary non-statin options. This new evidence necessitates an update to position bempedoic acid alongside or immediately after ezetimibe, particularly for patients needing oral therapy.

Clinical Landscape

Noteworthy Related Trials

2015

IMPROVE-IT Trial

n = 18,144 · NEJM

Tested

Ezetimibe 10 mg daily added to simvastatin

Population

Patients stabilized after acute coronary syndrome

Comparator

Simvastatin plus placebo

Endpoint

Cardiovascular death, nonfatal myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke

Key result: Adding ezetimibe to statin therapy resulted in a significant additional lowering of LDL cholesterol and improved cardiovascular outcomes.

2017

FOURIER Trial

n = 27,564 · NEJM

Tested

Evolocumab (PCSK9 inhibitor)

Population

Patients with atherosclerotic cardiovascular disease on statin therapy

Comparator

Placebo

Endpoint

Cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization

Key result: Evolocumab significantly reduced the risk of major adverse cardiovascular events by 15% compared to placebo.

2018

ODYSSEY OUTCOMES Trial

n = 18,924 · NEJM

Tested

Alirocumab (PCSK9 inhibitor)

Population

Patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite high-intensity statin

Comparator

Placebo

Endpoint

Coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization

Key result: Alirocumab significantly reduced the risk of major adverse cardiovascular events and was associated with a lower rate of death from any cause.

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