Long-Term Safety of Inclisiran for Treatment of Hypercholesterolemia

Quick Takes

  • Long-term inclisiran appears safe and generally well tolerated in a diverse population of patients with dyslipidemia treated for as long as 6 years.
  • Treatment-induced antidrug antibodies were uncommon among participants taking inclisiran.

Study Questions:

What is the evidence on the long-term safety profile of inclisiran for treatment of hypercholesterolemia?


The investigators examined the safety of inclisiran in a post hoc analysis which was comprised of patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, ORION-3, ORION-5, ORION-9, ORION-10, and ORION-11) and ongoing (ORION-8) trials. A total of 5,544 participants were included in the present analysis (3,576 receiving inclisiran and 1,968 receiving placebo). Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events, abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed.


The study population examined 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. The majority of participants had a diagnosis of atherosclerotic cardiovascular disease and were taking a statin. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that treatment-emergent adverse events 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. Fewer major cardiovascular events reported as treatment-emergent adverse events 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 treatment-emergent adverse events leading to study drug discontinuation or serious treatment-emergent adverse events.


The authors concluded that 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.


Inclisiran, a small interfering ribonucleic acid (siRNA) taken twice yearly (after initial and 3-month doses) via subcutaneous injection, results in decreased production of PCSK9 with significant lowering of plasma low-density lipoprotein cholesterol. This post hoc analysis brings important information on the long-term safety profile of this medication used for cholesterol management.

Clinical Topics: Dyslipidemia, Homozygous Familial Hypercholesterolemia, Prevention

Keywords: Hypercholesterolemia, PCSK9 Inhibitors

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