Physicians' Academy for Cardiovascular Education

PCSK9-targeted siRNA therapy: effective, safe and durable lipid-lowering irrespective of diabetes status

Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial

Literature - Leiter LA, Teoh H, Kallend D et al. - Diabetes Care 2018: published online ahead of print

Introduction and methods

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is associated with CV benefit in individuals with stable CVD [1,2] and recent acute coronary syndromes [3,4] independent of whether they have diabetes [2,3]. Inclisiran, a synthetic siRNA that drives PCSK9-specific mRNA degradation in the liver, has been reported to significantly lower LDL-c levels in individuals with ASCVD or ASCVD risk and high LDL-c levels in the ORION-1 trial [5,6].

The phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose ORION-1 trial randomized eligible subjects (n=501) to either one dose of placebo or inclisiran (200, 300, or 500 mg on day 1) or two doses of placebo or inclisiran (100, 200 or 300 mg on day 1 and 90) on top of standard care and stratified participants based on the presence (n=67) or absence (n=415) of diabetes at baseline.

This post-hoc analysis of the ORION-1 trial assessed whether individuals with and without diabetes at baseline respond differently to inclisiran with regard to changes in lipid profiles, safety, and glycemic control. The primary efficacy endpoint was the percent change from baseline LDL-c at day 180. Secondary efficacy endpoint included the percent change in lipid measure. Adverse events were documented up to day 210.

Main results

Inclisiran and LDL-c levels

Inclisiran and lipid profiles and glycemic control

Inclisiran and adverse events

PCSK9-targeted siRNA therapy: effective, safe and durable lipid-lowering irrespective of diabetes status


Regardless of diabetes status and dose regimen, one or two doses of inclisiran on top of standard care not only yielded extended reduction of LDL-c levels, but this siRNA treatment also improved atherogenic lipid and lipoprotein profiles. Inclisiran treatment was found to be safe and well tolerated. These data suggest that inclisiran may be a viable lipid-lowering alternative in both people with and without diabetes.


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