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)?

Methods:

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.

Results:

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.

Conclusions:

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.

Perspective:

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


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