Analysis of Inclisiran Trials on Hypercholesterolemia or Atherosclerosis

Quick Takes

  • Inclisiran administered as a twice-yearly subcutaneous injection is associated with a mean LDL-C change of -50%.
  • Self-limited mild-to-moderate injection-site adverse events were associated with inclisiran injection.
  • Inclisiran was similar in safety to placebo for other outcomes including liver and kidney function.

Study Questions:

Is inclisiran, a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin–kexin type 9 (PCSK9) translation in the liver, effective for low-density lipoprotein cholesterol (LDL-C)?


Inclisiran is a double-stranded small interfering RNA that suppresses PCSK9 translation in the liver. Participants with elevated LDL-C levels despite receiving statin therapy at the maximum tolerated dose with or without other LDL-C–lowering agents were included in this patient-level pooled analysis of three studies. The trials included in this analysis were ORION-9 (Trial to Evaluate the Effect of Inclisiran Treatment on LDL-C in Subjects With Heterozygous Familial Hypercholesterolemia [HeFH]), ORION-10 (Inclisiran for Participants With Atherosclerotic Cardiovascular Disease [ASCVD] and Elevated LDL-C), and ORION-11 (Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated LDL-C). All participants in each trial were randomly assigned to either inclisiran or placebo, administered by injection on day 1, day 90, and every 6 months thereafter. Outcomes of interest included percentage change in LDL-C from baseline, change in other lipid parameters (total cholesterol, apolipoprotein B, and non–high-density lipoprotein cholesterol), and adverse events.


A total of 3,660 adults from ORION-9 (n = 482), ORION-10 (n = 1,561), and ORION-11 (n = 1,617) were included in the present analysis. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval [CI], -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% CI, -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups.


The investigators concluded that these pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with HeFH, ASCVD, or ASCVD risk equivalents.


Inclisiran injection was associated with a significant reduction in LDL-C among participants at high risk for ASCVD, including those with familial hypercholesterolemia. With the exception of injection site reactions, inclisiran had a similar safety profile to placebo. These pooled data support the use of inclisiran for LDL-C among groups at high ASCVD risk.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Apolipoproteins B, Atherosclerosis, Cholesterol, Cholesterol, LDL, Creatine Kinase, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Kidney Function Tests, Lipids, Liver Function Tests, PCSK9 protein, human, Platelet Count, Primary Prevention, Proprotein Convertase 9, RNA, Double-Stranded, RNA, Small Interfering, Subtilisins

< Back to Listings