AbstractAimThis study evaluated the safety and efficacy of a moderate‐intensity statin with ezetimibe combination therapy versus high‐intensity statin monotherapy in patients with metabolic syndrome (MetS) and atherosclerotic cardiovascular disease.Materials and MethodsIn this post‐hoc subgroup analysis of the RACING trial, patients were analysed based on the presence of MetS. MetS was defined as meeting at least three of the five following criteria: (a) elevated waist circumference; (b) elevated triglycerides; (c) reduced high‐density lipoprotein cholesterol; (d) elevated blood pressure; and (e) elevated fasting glucose. The primary outcome was a 3‐year composite of cardiovascular death, major cardiovascular events, or non‐fatal stroke.ResultsOf the 3780 patients enrolled in the RACING trial, 1703 (45.1%) had MetS at baseline. The primary outcome rate was 10.1% and 10.3% in patients with MetS receiving ezetimibe combination therapy versus high‐intensity statin monotherapy (hazard ratio = 0.97; 95% confidence interval = 0.72‐1.32; p = .868). Lower rates of intolerance‐related drug discontinuation or dose reduction (3.9% vs. 8.0%; p < .001) and lower low‐density lipoprotein cholesterol levels (57 vs. 65 mg/dl; p < .001) were observed with ezetimibe combination therapy versus high‐intensity statin monotherapy. Furthermore, the rate of new‐onset diabetes was 18.5% and 19.1% in each group (p = .822). There were no significant interactions between MetS and therapy regarding study outcomes in the total population.ConclusionsIn patients with MetS and atherosclerotic cardiovascular disease, a moderate‐intensity statin with ezetimibe combination therapy had comparable cardiovascular benefits with those of high‐intensity statin monotherapy. Meanwhile, ezetimibe combination therapy was associated with lower drug intolerance and low‐density lipoprotein cholesterol levels, but there was no apparent between‐group difference in new‐onset diabetes.