Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status: The ORION-1 randomized clinical trial

Abstract

OBJECTIVE To evaluate the efficacy and safety of inclisiran by diabetes status. RESEARCH DESIGN AND METHODS ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C–lowering therapies, to one or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared. RESULTS Inclisiran was associated with marked declines in LDL-C (median −28% to −52%, P < 0.0001 and −28% to −55%, P < 0.005 for all doses in the without- and with-diabetes groups, respectively) and PCSK9. The inclisiran-treated groups also had lower apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL cholesterol. Inclisiran had an adverse profile similar to that of placebo, and adverse events were proportionally balanced in the baseline with- and without-diabetes groups. CONCLUSIONS PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option for managing dyslipidemia in the presence and absence of diabetes.