Physicians' Academy for Cardiovascular Education

In high-risk primary prevention individuals, RNAi against PCKS9 reduces LDL-c

News - Oct. 6, 2020

Effect of inclisiran on atherogenic lipoproteins in high-risk primary prevention populations

Presented at the virtual EAS 2020 by Kausik Ray (Imperial College, London, UK)

Introduction and methods

High-risk primary prevention refers to subjects without existing atherosclerotic CVD, but have a single high risk condition, such as T2DM or FH, or a combination of risk factors. Many of these patients fail to achieve LDL-c targets despite recommendations for diet and lifestyle changes and use of maximally tolerated statins. There is therefore a need for additional lipid-lowering therapies.

This analysis examined the effect of inclisiran on LDL-c levels and other atherogenic lipids in the primary prevention cohort of the ORION-11 trial.

The ORION-11 trial was a randomized, double-blind, parallel-group phase III trial. Enrolled patients received either inclisiran 300 mg or placebo (1:1 ratio) at day 1, day 90 and then every 6 months until day 540. The primary endpoint was the percentage change in LDL-c at day 510. Because of the infrequent dosing regiment, the co-primary endpoint of time-averaged change from baseline after day 90 to day 540 was assessed.

For this analysis, those in the primary prevention cohort were included (n=203). These subjects had either T2DM (65%), FH (11.3%) or a 10-year CV risk ≥20% (23.6%) with LDL-c ≥2.6 mmol/L.

Main results


In a high-risk primary prevention cohort in the ORION-11 trial, 6-monthly injections with inclisiran resulted in reductions of LDL-c (42% reduction over 15 months) compared to placebo. In addition, inclisiran reduced total cholesterol, non-HDL-c, ApoB and Lp(a) compared to placebo in this cohort of primary prevention subjects.


In response to the question which specific patient type would be included in the label of inclisiran, Ray answered that this includes all patient populations studied (with high CV risk), and in those in whom maximally tolerated statins do not provide sufficient LDL-c reduction.

Our reporting is based on the information provided at the EAS 2019 congress.

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