Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2019 Nov 12;322(18):1780-1788.
doi: 10.1001/jama.2019.16585.

Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial

Anne C Goldberg  1 , Lawrence A Leiter  2 , Erik S G Stroes  3 , Seth J Baum  4 , Jeffrey C Hanselman  5 , LeAnne T Bloedon  5 , Narendra D Lalwani  5 , Pragna M Patel  5 , Xin Zhao  5   6 , P Barton Duell  7
Affiliations
Clinical Trial

Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial

Anne C Goldberg et al. JAMA. .

Erratum in

  • Incorrect Value in Results.
    [No authors listed] [No authors listed] JAMA. 2020 Jan 21;323(3):282. doi: 10.1001/jama.2019.20661. JAMA. 2020. PMID: 31961396 No abstract available.

Abstract

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies.

Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy.

Design, setting, and participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy.

Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks.

Main outcomes and measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers.

Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%).

Conclusions and relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety.

Trial registration: ClinicalTrials.gov Identifier: NCT02991118.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Goldberg reported receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck. Dr Leiter reported receiving research grants/support from AstraZeneca, Amgen, Kowa, The Medicines Company, and Sanofi/Regeneron and serving as a consultant for AstraZeneca, Amgen, Esperion, HLS, Kowa, Merck, The Medicines Company, and Sanofi/Regeneron. Dr Stroes reported receiving research grants/support to his institution from Amgen, Sanofi, Resverlogix, and Athera and serving as a consultant for Amgen, Sanofi, Esperion, Novartis, and Ionis Pharmaceuticals. Dr Baum reported serving as a consultant/speaker for Akcea, Amgen, Aralez, Boehringer Ingelheim, Cleveland Heart Labs, Gerson Lehrman Group, Guidepoint Global, Novartis, Novo Nordisk, Regeneron, and Sanofi. Dr Duell reported receiving institutional research grants/support from Retrophin, Regeneron, and Regenxbio and serving as a consultant for Akcea, AstraZeneca, Esperion, Retrophin, Regeneron, and Regenxbio. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in the CLEAR Wisdom Randomized Clinical Trial
Discontinuations are categorized by the primary reason for discontinuation. If a patient had a fatal adverse event and the death occurred at the end of treatment or study, then “death” was reported as the primary reason for both discontinuation of study treatment and discontinuation from the study. If a patient had a fatal adverse event and the death occurred after the end of treatment, “adverse event” was reported as the primary reason for discontinuation of study treatment, and “death” as the primary reason for discontinuation from the study. aComprising patients who discontinued study drug but continued with study visits and assessments. bFour patients (3 bempedoic acid, 1 placebo) discontinued study drug after implementation of a protocol amendment that made them no longer eligible for study treatment because of use of simvastatin at an average daily dose of 40 mg or greater.
Figure 2.
Figure 2.. Effect of Bempedoic Acid on Low-Density Lipoprotein Cholesterol (LDL-C) Level
A, Error bars indicate 95% CIs. Numbers of patients at each time point are those with evaluable data per treatment group; no imputation was performed for missing data. See eTable 1 in Supplement 3 for data. B, Boxes indicate 25th and 75th percentiles; horizontal lines within boxes indicate median LDL-C values; error bars indicate Tukey-style upper and lower bounds; points beyond the error bars indicate individual patient values outside of this range.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Grundy SM, Stone NJ, Bailey AL, et al. . 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003 - DOI - PubMed
    1. Boekholdt SM, Hovingh GK, Mora S, et al. . Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64(5):485-494. doi:10.1016/j.jacc.2014.02.615 - DOI - PMC - PubMed
    1. deGoma EM, Ahmad ZS, O’Brien EC, et al. . Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH registry. Circ Cardiovasc Genet. 2016;9(3):240-249. doi:10.1161/CIRCGENETICS.116.001381 - DOI - PMC - PubMed
    1. Gitt AK, Lautsch D, Ferrieres J, et al. . Low-density lipoprotein cholesterol in a global cohort of 57,885 statin-treated patients. Atherosclerosis. 2016;255:200-209. doi:10.1016/j.atherosclerosis.2016.09.004 - DOI - PubMed
    1. Menzin J, Aggarwal J, Boatman B, et al. . Ezetimibe use and LDL-C goal achievement: a retrospective database analysis of patients with clinical atherosclerotic cardiovascular disease or probable heterozygous familial hypercholesterolemia. J Manag Care Spec Pharm. 2017;23(12):1270-1276. doi:10.18553/jmcp.2017.16414 - DOI - PMC - PubMed

MeSH terms

Substances

Associated data

-