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Goldberg AC, Leiter LA, Stroes ESG, et al. 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. JAMA. 2019;322(18):1780–1788. doi:10.1001/jama.2019.16585
To what extent does bempedoic acid lower low-density lipoprotein cholesterol (LDL-C) levels in patients at high cardiovascular risk who have ongoing hypercholesterolemia, despite the use of maximally tolerated lipid-lowering therapy?
In this clinical trial that included 779 randomized patients, the addition to stable background lipid-lowering therapy of bempedoic acid compared with placebo resulted in mean LDL-C levels of 97.6 mg/dL vs 122.8 mg/dL at 12 weeks, a difference that was statistically significant.
Bempedoic acid provided additional LDL-C lowering in patients who did not achieve an adequate response to lipid-lowering therapy when compared with placebo.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT02991118
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