Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy

Abstract

Aims: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy.

Methods: This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol.

Results: Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P < 0.001), ezetimibe alone (-23.2%; P < 0.001) or bempedoic acid alone (-17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo.

Conclusion: The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk.

Trial registration: ClinicalTrials.gov identifier: NCT03337308.

Keywords: Bempedoic acid; LDL-cholesterol; ezetimibe; hydroxymethylglutaryl-CoA reductase inhibitors; hypercholesterolemia; hyperlipidemias; hypolipidemic agents; lipid-regulating agents.

Figure 1.

Patient disposition. ^aOne patient randomly assigned to the bempedoic acid and ezetimibe fixed-dose combination (FDC) treatment group did not receive any dose of study drug and was therefore excluded from the safety analyses.

Figure 2.

Change from baseline to week 12 in low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (hsCRP), post hoc population. (a) Percentage change from baseline in LDL-cholesterol was analysed using analysis of covariance with treatment group and random assignment stratification as factors and baseline LDL-cholesterol as a covariate. Baseline was defined as the mean of the values from week –2 and pre-dose on day 1. Missing values were imputed using a multiple imputation method, taking into account adherence to treatment. Bars represent least-squares means ± standard errors. (b) Percentage change from baseline in hsCRP was analysed using a non-parametric (Wilcoxon rank sum test) analysis with Hodges–Lehmann estimates and confidence intervals. Baseline was defined as the value recorded pre-dose on day 1. Bars represent medians. Data are as observed, without imputation for missing values. Between-group differences are shown with 95% confidence intervals for LDL-cholesterol and (1 – alpha) percentage confidence intervals for hsCRP. The BA + EZE FDC versus placebo comparison used alpha = 0.01, and the BA + EZE FDC versus ezetimibe and BA + EZE FDC versus bempedoic acid comparisons used alpha = 0.02. BA + EZE FDC: bempedoic acid and ezetimibe fixed-dose combination; NS: not significant.