Efficacy and safety of low-dose atorvastatin plus ezetimibe for primary hypercholesterolemia: A randomized, double-blind, multicenter phase 3 trial

Abstract

Studies have suggested that low-dose statin monotherapy may be insufficient for target LDL-C levels. In this randomized, double-blind, multicenter phase 3 trial, we evaluated the efficacy of combined ezetimibe and low-dose atorvastatin in 222 Korean patients with primary hypercholesterolemia. Participants received either 10-mg ezetimibe/5-mg atorvastatin (EZE10/ATV5), 10-mg ezetimibe (EZE10), 5-mg atorvastatin (ATV5), or 10-mg atorvastatin (ATV10). At 8 weeks, EZE10/ATV5 achieved the greatest LDL-C reduction (-44.8%) compared with EZE10 (-12.7%, p < 0.0001), ATV5 (-27.3%, p < 0.0001), and ATV10 (-32.0%, p = 0.0012). The combination therapy showed the highest LDL-C goal achievement rate (41.1% vs. EZE10 8.9%, p < 0.0001; ATV5 10.9%, p < 0.0001; ATV10 27.3%, p = 0.0342), particularly in moderate to high-risk patients. Additionally, EZE10/ATV5 had the lowest adverse events among all groups (6.9% vs. 15.0%, 12.3%, and 27.6%, p = 0.017), with most events being mild. These findings suggest that the combination of ezetimibe and low-dose atorvastatin provides superior lipid-lowering efficacy with an improved safety profile, offering an effective treatment for primary hypercholesterolemia in Korean patients.

Keywords: LDL; atorvastatin; clinical trial; ezetimibe; hypercholesterolemia; lipoprotein; phase III.

FIGURE 1

Study flow diagram. This figure shows the flow of participants in this study, which evaluated different doses and combinations of ezetimibe and atorvastatin. Starting with 316 individuals, 81 were excluded at screening due to not meeting inclusion criteria or meeting exclusion criteria. The remaining 235 participants were divided into four groups: EZE10/ATV5, EZE10, ATV5, and ATV10. The numbers of participants who completed the safety and efficacy evaluations are shown for each group. ATV5, atorvastatin 5 mg monotherapy; ATV10, atorvastatin 10 mg monotherapy; EZE10, ezetimibe 10 mg monotherapy; EZE10/ATV5, combination therapy of ezetimibe 10 mg and atorvastatin 5 mg.

FIGURE 2

Changes in lipid levels by treatment group. This figure illustrates the percentage change from baseline in lipid levels in different ezetimibe and atorvastatin treatment groups: (a) LDL‐C, (b) TC, (c) non‐HDL‐C, and (d) Apo B. Each bar represents the mean percent change (± standard deviation), with p‐values indicating statistical significance between groups, highlighting the effect of each treatment on lipid levels. Apo B, apolipoprotein B; ATV, atorvastatin; EZE, ezetimibe; LDL‐C, low‐density lipoprotein cholesterol; non‐HDL‐C, non‐high‐density lipoprotein cholesterol; TC, total cholesterol.

FIGURE 3

Target LDL‐C achievement by treatment group. Each bar shows the percentage of patients that achieved their risk‐based LDL‐C goals (<55 mg/dL for very high‐risk, <70 mg/dL for high‐risk, <100 mg/dL for moderate‐risk patients, and <116 mg/dL for low‐risk patients) in the different treatment groups. Statistical significance between treatments is indicated by the p‐values above the parentheses connecting the bars. ATV5, atorvastatin 5 mg monotherapy; ATV10, atorvastatin 10 mg monotherapy; EZE10, ezetimibe 10 mg monotherapy; EZE10/ATV5, combination therapy of ezetimibe 10 mg and atorvastatin 5 mg.

FIGURE 4

Target LDL‐C achievement by SCORE2 risk and treatment group. Each bar chart shows target LDL‐C achievement percentages for patients categorized by SCORE2 risk levels (low to moderate, high, and very high). The treatments are represented by different colored bars: EZE10/ATV5 (blue), EZE10 (black), ATV5 (red), and ATV10 (green). Each bar represents the percentage of patients within each risk category that achieved their LDL‐C goals (<116 mg/dL for low‐risk, <100 mg/dL for moderate‐risk, <70 mg/dL for high‐risk, and <55 mg/dL for very high‐risk patients). Statistical significance is indicated by the p‐values above the parentheses comparing treatments. ATV5, atorvastatin 5 mg monotherapy; ATV10, atorvastatin 10 mg monotherapy; EZE10, ezetimibe 10 mg monotherapy; EZE10/ATV5, combination therapy of ezetimibe 10 mg and atorvastatin 5 mg; SCORE2, Systematic COronary Risk Evaluation2.