Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial

• Published in: Diabetes care Vol. 42; no. 1; pp. 173 - 176
• Main Authors: Leiter, Lawrence A., Teoh, Hwee, Kallend, David, Wright, R. Scott, Landmesser, Ulf, Wijngaard, Peter L.J., Kastelein, John J.P., Ray, Kausik K.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.01.2019
• Subjects: Apolipoprotein B; Apolipoproteins B - blood; Arteriosclerosis; Atherosclerosis; Atherosclerosis - blood; Atherosclerosis - drug therapy; Cardiovascular disease; Cardiovascular diseases; Cholesterol; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Clinical trials; Diabetes; Diabetes mellitus; Diabetes Mellitus - blood; Diabetes Mellitus - drug therapy; Dose-Response Relationship, Drug; Dyslipidemia; Dyslipidemias - blood; Dyslipidemias - drug therapy; Evidence-based medicine; Female; Health risks; High density lipoprotein; Humans; Kexin; Lipids; Low density lipoprotein; Male; Metabolic disorders; Middle Aged; Proprotein Convertase 9 - blood; Research design; Risk Factors; RNA, Small Interfering - pharmacology; siRNA; Subtilisin
• DOI: 10.2337/dc18-1491
• ISSN: 0149-5992; 1935-5548

To evaluate the efficacy and safety of inclisiran by diabetes status. 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. Inclisiran was associated with marked declines in LDL-C (median -28% to -52%, < 0.0001 and -28% to -55%, < 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. PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option for managing dyslipidemia in the presence and absence of diabetes.