Ezetimibe Plus Atorvastatin Versus Double-Dose Atorvastatin for Hypercholesterolemia

Background: The combination of ezetimibe with a lower dose of atorvastatin may enhance LDL-C lowering while avoiding statin toxicity. Prior meta-analyses (Ai et al., 2018) showed ezetimibe/atorvastatin’s benefit versus double-dose atorvastatin, but new trials emerged since 2017. We updated the meta-analysis with all recent randomized trials to assess efficacy and safety. Methods: We searched PubMed, Cochrane, and Embase (inception to April 2025) for randomized, double-blind trials comparing ezetimibe (10 mg) plus atorvastatin (any dose) versus double-dose atorvastatin. Primary endpoint was LDL-C change at 8 weeks. Secondary endpoints included TC, TG, HDL-C, non-HDL-C, ApoB, and adverse events. Data were pooled using random-effects models, and heterogeneity was assessed (I 2 ). We added three new trials (Qian 2022, Lee 2023, Ki 2025) to the prior (Ai et al., 17 studies). Results: Twenty trials (5,924 patients) were analyzed. Baseline characteristics were similar (mean age 60.8, 56% male, LDL-C 142 mg/dL). At 8 weeks, combination therapy reduced LDL-C more (-14.6%; p<0.001; I 2 =28%). Significant reductions in TC (-9.5%), non-HDL-C (-12.9%), ApoB (-11.5%), and TG (-6.8%) were also observed. HDL-C increased (+0.9%; p=0.004). LDL-C goal attainment (per 2016 ESC/EAS) was higher (72% vs. 48%; RR 1.50). Safety outcomes were similar (18.2% vs. 17.5% adverse events; p=0.56). Alanine aminotransferase, creatine kinase, and drug discontinuation rates were not different. Conclusions: This updated meta-analysis confirms that ezetimibe plus half-dose atorvastatin is more effective than double-dose statin, with better LDL-C reduction, goal attainment, and similar safety. Ezetimibe adds ~14-15% LDL-C reduction without extra adverse events. Clinical Implication: For hypercholesterolemia patients who need more LDL-C lowering but can't tolerate high-intensity statins, this fixed-dose combination is a superior, well-tolerated option. This approach should be considered in clinical practice, especially for primary prevention, statin-sensitive individuals, and Asian populations.