Efficacy and Safety of Moderate-Intensity Statin and Ezetimibe Combination Therapy Versus High-Intensity Statin Monotherapy in Patients With Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Statins represent the first-line therapy for cholesterol management. However, for patients prone to statin side effects, unable to tolerate higher doses, or requiring additional low-density lipoprotein cholesterol (LDL-C) reduction, ezetimibe alone or in combination with statins is recommended. This meta-analysis aimed to evaluate the safety and efficacy of combining low- or moderate-intensity statins with ezetimibe compared to high-intensity statin monotherapy, yielding reliable evidence to guide clinical decision-making and personalize treatment strategies. PubMed, Embase, and Scopus were systematically searched from inception until May 2023. All randomized controlled trials (RCTs) comparing a high-intensity statin with a low/moderate-intensity statin with ezetimibe were included. The outcomes of interest comprised changes in concentrations of lipids-LDL-C, high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TGs)-and apolipoprotein (Apo) A1, Apo B, and high-sensitivity C-reactive protein (hs-CRP), along with major adverse cardiovascular events (MACE). All data were analyzed using Review Manager version 5.4. p-values less than 0.05 were considered to indicate statistical significance. Overall, 20 RCTs, with 5,412 participants, were included. A low/moderate-intensity statin combined with ezetimibe yielded a significantly greater reduction in LDL-C levels than high-intensity statin monotherapy (mean difference [MD], -6.59; 95% confidence interval [CI], -10.95, -2.24; p=0.003; I²=84%). No significant differences were observed between combination and high-intensity statin monotherapy regarding TC, TG, or HDL-C levels. However, hs-CRP levels were significantly higher with combination therapy (MD, 0.32; 95% CI, 0.01, 0.64; p=0.04; I²=0%). Combination therapy involving a low/moderate-intensity statin with ezetimibe was significantly associated with lower LDL-C levels than high-intensity statin monotherapy. No significant differences were observed for TC, TGs, HDL-C, alanine transaminase, or MACE. However, creatine phosphokinase levels significantly increased with monotherapy.