Efficacy and safety of inclisiran based on background lipid-lowering treatment

Abstract Aim To evaluate whether the effect of inclisiran to lower LDL-C varied by background lipid-lowering therapy (LLT). Methods In ORION-10 and ORION-11 Phase 3 trials, patients (N=3178) with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents were randomized 1:1 to receive inclisiran or placebo on Day 1, Day 90, and 6-monthly thereafter. In this pooled post hoc analysis, patients were stratified by baseline combination therapy (statin plus ezetimibe [n=214; 6.7%]), monotherapy (statin [n=2711; 85.3%] or ezetimibe [n=54; 1.7%]), or neither LLT (none [n=199; 6,3%]) into therapy groups with/without other LLT. Stratification by baseline statin intensity was also performed (N=3155). Relative and absolute changes in LDL-C were assessed. Results Mean (±SD) baseline LDL-C was 2.7 mmol/L (±1.0), 2.6 mmol/L (±0.9), 3.7 mmol/L (±1.7), and 4.1 mmol/L (±1.5) among patients receiving combination, statin, ezetimibe, or neither LLT, respectively. In these categories, mean (95% confidence interval [CI]) time-adjusted, placebo-corrected percentage change in LDL-C after Day 90 to Day 540 with inclisiran were −57.0% (−63.8, −50.1), −51.5.% (−53.4, −49.7), −50.5.% (−59.6, −41.5), and −43.1% (−48.7, −37.6); corresponding absolute changes were −1.5 mmol/L (−1.7, −1.3), −1.3 mmol/L (−1.4, −1.3), −1.7 mmol/L (−2.0, −1.4), and −1.7 mmol/L (−1.9, −1.5). Conclusion Sustained and effective LDL-C lowering with inclisiran was observed irrespective of background LLT treatment. Inclisiran was overall well tolerated with all background LLT treatments, consistent with its established safety profile.