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

Diabetes Care. 2019 Jan;42(1):173-176. doi: 10.2337/dc18-1491. Epub 2018 Nov 28.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoproteins B / blood
  • Atherosclerosis / blood
  • Atherosclerosis / drug therapy
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood*
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / drug therapy
  • Dose-Response Relationship, Drug
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Proprotein Convertase 9 / blood*
  • RNA, Small Interfering / pharmacology*
  • Risk Factors

Substances

  • ALN-PCS
  • Apolipoproteins B
  • Cholesterol, HDL
  • Cholesterol, LDL
  • RNA, Small Interfering
  • PCSK9 protein, human
  • Proprotein Convertase 9

Associated data

  • ClinicalTrials.gov/NCT02597127