CLEAR Outcomes

Jules Hickey, PharmD, MSPH

Citation 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
Previous o Bempedoic acid is an ATP citrate lyase inhibitor – inhibits cholesterol synthesis at a target upstream of
Literature and HMG-CoA reductase (statin MOA). Also increases LDL receptor expression
Background o Previous studies have found that bempedoic acid reduces LDL by 17 to 28%
o Approved by the FDA in 2020 as adjunct to maximally tolerated statin therapy in adults with HeFH
or established ASCVD who require additional LDL-lowering
o Effects of bempedoic acid on cardiovascular outcomes remain uncertain
o Statins are a cornerstone of medication therapy to reduce the risk of major adverse cardiovascular
events in patients who are indicated for primary or secondary prevention. However, 7 to 29% of
patients report adverse musculoskeletal effects from statins that prevent their use at guideline-
recommended doses
o Trials that have explored monotherapy with other LDL-lowering drugs have shown varying benefits in CV
risk reduction (PCSK9i: 15% reduction; ezetimibe: 6% reduction)
Funding and Designed and sponsored by Esperion Therapeutics in collaboration with the Cleveland Clinic.
Sponsorship
Primary Objective Determine the adverse cardiovascular outcomes of bempedoic acid in patients who are unable or unwilling
to take statins due to unacceptable adverse effects but for whom primary or secondary prevention is
clinically indicated.
Methods
Study Design o Double-blind, randomized, placebo-controlled trial
o 1250 sites in 32 countries
o Estimated sample size of 14,000 patients to provide 90% power to detect a 15% reduction in relative risk
of the primary endpoint
o Estimated median duration to be 42 months
Inclusion and Inclusion Exclusion
Exclusion Criteria o 18 to 85 years of age o Fasting TG > 500 mg/dL
o Either of 2 CV criteria: o Renal dysfunction (eGFR < 30
o Previous CV event (secondary prevention) o mL/min/1.73 m2)
o High risk for CV event (primary prevention) o Recent (within 90 days) acute CVD event,
o Written confirmation from patient of inability unstable or symptomatic arrhythmia,
or unwillingness to take a statin at a guideline- placement of pacemaker
recommended dose due to an AE despite o NYHA Class IV HF
confirmed knowledge of the benefits of statins o Uncontrolled hypertension > 180/110 mmHg
o Vey low dose statin therapy o A1c > 10%
(e.g., atorvastatin <10mg) were considered o Uncontrolled hypothyroidism
to be intolerant o Liver diseases or dysfunction, including AST or
o Fasting LDL > 100 mg/dL while on stable LDL- ALT > 2.0x ULN
lowering therapies, including very low dose o Nonadherence to 4-week run-in period with
statin placebo
Treatment Plan o Patients were permitted to remain on other lipid-lowering therapies so long as they were stable at least
4 weeks prior (12 weeks prior for PCSK9i)
o 4-week run-in period with single-blind placebo to assess placebo tolerability and adherence
o Randomization 1:1 to receive bempedoic acid 180mg daily or placebo daily
Primary Endpoint Four-component composite of major adverse cardiovascular events (MACE) assessed in time-to-first-event
analysis:
o Death from CV causes
o Nonfatal MI
o Nonfatal stroke
o Coronary revascularization
Secondary Assessed in time-to-first-event analysis and tested in a hierarchical order
Endpoints o Three-component composite: death from CV causes, nonfatal stroke, nonfatal MI

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 o Fatal or nonfatal MI
o Coronary revascularization
o Fatal or nonfatal stroke
o Death from CV causes
o Death from any cause
Statistical Tests o Endpoints were evaluated sequentially using a hierarchical approach
o All efficacy analyses were based on the intention-to-treat principle with the use of a Cox proportional-
hazards model
Results
Enrollment o 13,970 patients underwent randomization between December 2016 and August 2019
o 6992 patients in the bempedoic acid group
o 6978 patients in the placebo group
Baseline Age Mean: 65.5 + 9.0
Characteristics Sex 48.2% Female
Race 91% White
LDL-C Mean: 139.0 mg/dL
High-Sensitivity CRP Median: 2.3 mg/L
CV Risk Category Primary Prevention: 30.1% Secondary Prevention: 69.9%
LDL-Lowering Therapy Statin: 22.7% Ezetimibe: 11.5% Fibrates: 5.5% Others: <1%
Baseline characteristics were similar in the trial groups.

Outcomes and Median duration of follow-up was 40.6 months

Efficacy Analyses Primary Endpoint:
 The incidence of four-component MACE was significantly lower with bempedoic acid than with
placebo (11.7% vs 13.3%; HR 0.87; 95% CI 0.79-0.96; p=0.004); NNT = 63
 Bempedoic acid lowered the risk of four-component MACE by 13% compared to placebo
Secondary Endpoint:
 The results of the first three secondary endpoints (three-component MACE, fatal or nonfatal MI,
coronary revascularization) found a statistically significant difference in favor of bempedoic acid
 No significant differences on fatal or nonfatal stroke, death from CV causes, and death from any
cause
Observed Efficacy Endpoints:
 At 6 months, the mean percent reduction in mean LDL level in the bempedoic acid group was 21.1%
 At 6 months, the median percent reduction in median CRP level in the bempedoic acid group was
22.2%
 LDL- and CRP-lowering were sustained through the end of the trial
 Similar findings to previous trials
Safety-Related Findings:
 The safety population included all patients who underwent randomization and received at least one
dose of bempedoic acid or placebo
 Adverse events did not differ meaningfully between the two groups, except for changes in LFTs,
creatinine levels, uric acid levels, and incidences of gout and cholelithiasis, which were greater or
occurred more frequently in the bempedoic acid group
 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)
 Incidences of discontinuation for any reason, including adverse musculoskeletal effects, were similar
in both groups
Author’s For patients who clinically require primary or secondary prevention of cardiovascular disease but are unable
Conclusion or unwilling to take guideline-recommended doses of statins, bempedoic acid significantly lowered the risk
of a composite endpoint event (death from CV causes, nonfatal MI, nonfatal stroke, and revascularization)
compared to placebo. Additionally, bempedoic acid reduced LDL and CRP levels more than placebo at 6
months, with few adverse events. Bempedoic acid is among the medications that lower LDL cholesterol and
have clinically meaningful cardiovascular benefits, similarly to statins. Because the incidence of muscle-
related adverse effects was similar in the bempedoic acid group and placebo group, bempedoic acid may be
an alternative LDL- and CV risk-lowering therapy in patients who cannot take statins.

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 Critique
Strengths and Strengths Limitations
Limitations o Randomized, double-blind design o Manufacturer sponsored study,
across multiple sites designed by manufacturer (with
o Primary endpoint is a composite of efforts to mitigate bias)
clinically meaningful endpoints o Many patients were on other LDL-
o Appropriate statistical tests with lowering therapies, including 22.7%
independent biostatistician on a statin
o Ethical inclusion criteria; appropriate o Predominantly White cohort
exclusion criteria to limit variables
that may affect CV outcomes

o
Clinical Application and Statins are Still the Drugs of Choice
Overall Conclusion The ACC/AHA guidelines recommend statins at moderate to high intensity as first-line therapy for
both primary prevention and secondary prevention to decrease ASCVD risk. However, many patients
taking statins do experience adverse effects related to muscle pain and muscle damage, which can
develop at any time while taking the drug.
Steps in Clinically Managing Statin Intolerance
Because of the clear and abundant evidence of LDL-lowering and ASCVD risk reduction from statin
therapy, a second statin or a dose reduction should be attempted first in patients who are
experiencing intolerable muscle pain, as well as counseling on the benefits of statin therapy. Based on
this trial, switching to bempedoic acid can be a potential next step over other non-statin therapies to
replace statins and achieve reductions in both LDL levels and risk of ASCVD.
Future Considerations
PCKS9 inhibitors have demonstrated CV benefits but are more expensive and are injectables. It would
be more interesting to see head-to-head trials of PCSK9 inhibitors, ezetimibe, and bempedoic acid to
compare CV benefits in patients who cannot/will not take statins.

References

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

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