Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials

J Am Coll Cardiol. 2023 Dec 12;82(24):2251-2261. doi: 10.1016/j.jacc.2023.10.007.


Background: Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol.

Objectives: The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran.

Methods: This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed.

Results: This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs.

Conclusions: Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.

Keywords: ASCVD; LDL-C; PCSK9; inclisiran; long-term safety.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents* / therapeutic use
  • Cholesterol, LDL
  • Dyslipidemias* / drug therapy
  • Humans
  • Hypercholesterolemia* / drug therapy
  • Proprotein Convertase 9
  • RNA, Small Interfering


  • Cholesterol, LDL
  • RNA, Small Interfering
  • Anticholesteremic Agents
  • Proprotein Convertase 9