Abstract Body (Do not enter title and authors here): Introduction: One third of patients with high and very high-risk of dyslipidemia reach their low-density lipoprotein cholesterol (LDL-C) targets (<55 mg/dL). Contemporary guidelines recommend initial high-intensity statin and adding ezetimibe (EZ) if the targets are not met.
Hypothesis: We assessed the efficacy and safety of early addition of EZ to atorvastatin (AS) in patients with very high cardiovascular risk prior to reaching the maximally tolerated statin dose.
Methods: This phase 4 (NCT05761444), multicenter, randomized, open-label, active-controlled study in Korea included patients at very high-risk who failed to achieve LDL-C <70 mg/dL with low/moderate intensity statin monotherapy, were statin-naive or not on a stable statin regimen for 4 weeks prior to enrollment. Patients were randomized 1:1 to EZ/AS (10/40 mg) or AS (40 mg) for 12 weeks. Primary endpoint was the percentage change in LDL-C from baseline (BL) to week 6. Secondary endpoints were the percentage change in LDL-C from BL to week 12 and proportion of patients achieving LDL-C goal of <55 mg/dL after 6 and 12 weeks. The LDL-C change from BL was compared using ANCOVA. Between group differences were tested using Fisher's exact test at 0.05 significance.
Results: A total of 137 patients received EZ/AS (n=67) or AS (n=70). Mean (SD) age was 65.0 (10.35) years and 54.5% were aged ≥65 years. Statin history of low/moderate intensity statin monotherapy was 65.2%. Lipid-lowering efficacy was significantly greater with EZ/AS compared with AS monotherapy at Week 6 (LS mean difference [LSMD]: -21.22; 95% CI: -29.26, -13.19; P <0.0001) and Week 12 (LSMD: -15.96; 95% CI: -23.56, -8.36; P <0.0001). The mean (SD) LDL-C levels at 6 weeks were 58.4 (16.6) mg/dL and 75.6 (18.5) mg/dL in EZ/AS and AS groups, at weeks 12: 54.8 (15.2) mg/dL and 70.1 (16.7) mg/dL, respectively. Significantly higher proportions of patients achieved target LDL-C levels <55 mg/dL in EZ/AS group compared with AS group at week 6 (46.2% vs. 9.0%; P <0.0001) and week 12 (55.0% vs. 15.4%; P <0.0001). The safety profile was comparable between the groups at week 6 and week 12.
Conclusions: Early combination with EZ/AS versus AS monotherapy, significantly reduced the plasma LDL-C levels and showed greater LDL-C target achievement without safety concerns in patients with dyslipidemia at very high-risk.