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.