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

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.

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.. 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.