Inclisiran Safe, Effective in Dyslipidemia, ASCVD Regardless of BMI

Blood sample for lipid profile test
Using ORION 9, 10, and 11 data, investigators assessed inclisiran in patients with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk.

Regardless of body weight, after initial and 3-month doses, twice-yearly subcutaneous dosing with inclisiran, a small interfering RNA that targets PCSK9 hepatic mRNA, effectively lowered atherogenic lipids in patients with hypercholesterolemia or atherosclerotic cardiovascular disease (ASCVD), according to study findings presented at the American Heart Association (AHA) Scientific Sessions 2021, held virtually from November 13 to 15, 2021.

The investigators performed a post-hoc analysis of the ORION-9 ( Identifier: NCT03397121), ORION-10 ( Identifier: NCT03399370), and ORION-11 ( Identifier: NCT03400800) trials to analyze the efficacy and safety of inclisiran therapy in patients with heterozygous familial hypercholesterolemia, ASCVD, or risk of ASCVD. Participants were randomly assigned 1:1 to receive 300 mg inclisiran sodium or placebo at baseline, day 90, and every 6 months thereafter during a follow-up period of 540 days.

The primary study outcome was percentage change in atherogenic lipids from baseline to day 510. Investigators stratified analyses according to body mass index (BMI) at baseline (less than 25 kg/m2, 25 kg/m2 to less than 30 kg/m2, 30 kg/m2 to less than 35 kg/m2, and 35 kg/m2 or greater). Baseline clinical characteristics (including atherogenic lipid levels) and demographics were mostly balanced across the BMI strata and between treatment vs placebo arms.

At day 510, across all BMI strata, the percentage change in atherogenic lipids from baseline was significantly greater among patients who received inclisiran. The between-group difference for low-density lipoprotein cholesterol, or LDL-C, ranged from −48.8% to −50.5%; for total cholesterol, −30.1% to −33.9%; for non–high-density lipoprotein cholesterol, or non–HDL-C, −45.3% to −47.1%; for apolipoprotein B, −39.1% to −43.3%; and for triglycerides, −10.2% to −11.5%.

Treatment-emergent adverse events were similar between patients who received inclisiran vs placebo but were more frequent with increasing BMI. Injection-site adverse events were more common among patients treated with inclisiran but all were mild or moderate.

The investigators suggested that twice-yearly dosing with inclisiran following initiation is an effective lipid-lowering strategy and is well tolerated regardless of baseline BMI.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Leiter LA, Kallend DG, Koenig W, et al. Efficacy and safety of inclisiran by baseline body mass index: A post hoc pooled analysis of the ORION-9, ORION-10 and ORION-11 phase III randomized controlled trials. Presented at: AHA Scientific Sessions 2021; November 13-15, 2021. Poster 341.