Inclisiran Use in Patients with Cardiovascular Risk and High LDL Cholesterol

Long-term use of inclisiran was found to be safe and effective in patients with elevated LDL cholesterol at high risk for cardiovascular disease.

Inclisiran for patients with atherosclerotic cardiovascular disease can safely reduce their low-density lipoprotein (LDL) cholesterol and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, according to an extension study published in The Lancet Diabetes & Endocrinology.

High levels of LDL cholesterol increase the risk for atherosclerotic cardiovascular disease. Researchers have provided evidence that treatments reducing PCSK9 production can help control LDL cholesterol. The researchers tested the effectiveness of long-term dosing of small interfering ribonucleic (siRNA) inclisiran in reducing PCSK9 in patients with high LDL cholesterol and increased risk for atherosclerotic cardiovascular disease.

The current study is an extension of  a phase 2 clinical trial conducted across 5 countries from March 24, 2017 to December 17, 2021. Patients included in this investigation had already completed the clinical trial and had atherosclerotic cardiovascular disease or elevated LDL cholesterol levels despite receiving maximally tolerated statins or other LDL-lowering treatments. Participants in the intervention group received 300 mg inclisiran sodium subcutaneously twice per year (inclisiran-only arm, n=290). Control group participants initially received 140 mg evolocumab subcutaneously every 2 weeks until day 360; subsequently, they received a twice-yearly dose of inclisiran (switching arm, n=92) for the remainder of the trial.

Twice-yearly subcutaneous dosing of inclisiran was well tolerated and resulted in sustained and effective reductions in LDL cholesterol and PCSK9 concentrations over 4 years.

In the inclisiran-only arm, there was a 47.5% reduction in LDL cholesterol (95% CI, 50.7-44.3) after 210 days, sustained for 1440 days (4 years). The 4-year averaged mean reduction in LDL-C cholesterol was 44.2% (95% CI, 47.1-41.4). Reductions in PCSK9 ranged between 62.2% and 77.8%. Only 1% of participants in each of the inclisiran-only arm and switching arm (n=3 and n=1, respectively) experienced adverse effects from the treatment.

This investigation had certain limitations. As is typical in extension studies, participation was voluntary, making selection bias possible. The researchers hypothesize that patients who were more tolerant to the drug in the original randomized phase of the study were more likely to be adherent to treatment in the long term. In addition, the extension study did not include a placebo condition, which could limit the generalizability of the findings, especially with respect to conclusions regarding the drug’s safety.

According to the researchers, “Twice-yearly subcutaneous dosing of inclisiran was well tolerated and resulted in sustained and effective reductions in LDL cholesterol and PCSK9 concentrations over 4 years.” Investigators suggest that, in general, providers can safely prescribe inclisiran to help patients reduce their LDL cholesterol and PCSK levels. Researchers concluded that most patients managing their cardiovascular conditions will likely tolerate the treatment when taking it long-term.

Disclosure: This research was supported by Novartis Pharmaceuticals. Please see the original reference for a full list of disclosures.


Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023;11(2):109-119. doi: 10.1016/S2213-8587(22)00353-9