The role of early ezetimibe combination with atorvastatin in patients with atherosclerotic cardiovascular disease

Background Despite statin therapy, achieving target low-density lipoprotein cholesterol (LDL-C) levels remain suboptimal in high-risk patients with atherosclerotic cardiovascular disease (ASCVD). This study evaluated efficacy and safety of early addition of ezetimibe (EZ) with atorvastatin (AS), prior to reaching the maximally tolerated dose of statin, in very high-risk patients. Methods This phase 4 (NCT05761444), multicenter, randomized, open-label, active-controlled study enrolled patients (≥ 30 years) with very high-risk of ASCVD. Eligible patients had LDL-C ≥ 70 mg/dL with low/moderate intensity statin monotherapy or statin-naïve or not been on stable statin regimen prior to enrollment. Patients were randomized 1:1 to EZ10/AS40 mg combination therapy or AS40 mg statin alone for 12 weeks. Primary endpoint was percentage change in LDL-C from baseline to week 6. Results Patients ( N = 137) received EZ/AS ( n = 67) or AS ( n = 70) once a day. The EZ/AS lipid-lowering effect was statistically greater than AS monotherapy at week 6 (LSMD: ˗21.2; P < 0.0001) and week 12 (LSMD: ˗16.0; P < 0.0001). At week 12, higher proportions of patients who received EZ/AS achieved target LDL-C < 55 mg/dL (55.0% vs. 15.4%; P < 0.0001) and LDL-C < 70 mg/dL (85.0% vs. 58.5%; P = 0.0009) than in AS group. Higher reduction from baseline was observed for lipid parameters in EZ/AS group than AS monotherapy. Incidence of adverse events were comparable between EZ/AS and AS groups. Conclusions Early combination of EZ with AS, rather than a stepwise approach, significantly reduced LDL-C levels and improved LDL-C reduction target achievement compared to AS monotherapy in very high-risk patients with dyslipidemia with no new safety issues. Trial registration NCT05761444; Registration date: March 9, 2023.