Impact of Inclisiran on LDL-C Over 18 months in Patients With ASCVD or Risk-Equivalent - ORION-11

Contribution To Literature:

Highlighted text has been updated as of November 14, 2022.

The ORION-11 trial showed that twice yearly inclisiran injection reduced LDL-C by 50%.


The goal of the trial was to evaluate inclisiran compared with placebo among patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk-equivalents. Inclisiran is a small interfering double-stranded RNA that inhibits PCSK9 production.

Study Design

  • Randomized
  • Parallel
  • Double-blind

Patients with ASCVD or ASCVD risk-equivalents were randomized to inclisiran 300 mg injection administered on day 1, day 90, day 270, and day 450 versus placebo.

  • Total number of enrollees: 1,617
  • Duration of follow-up: 18 months
  • Mean patient age: 65 years
  • Percentage female: 28%
  • Percentage with diabetes: 35%

Inclusion criteria:

  • ≥18 years of age
  • Stable ASCVD or ASCVD risk-equivalent (type 2 diabetes, familial hypercholesterolemia, ≥20% ASCVD risk)
  • Elevated low-density lipoprotein cholesterol (LDL-C) (≥70 mg/dl if ASCVD and 100 mg/dl if risk-equivalents) despite maximum tolerated statin therapy

Exclusion criteria:

  • Prior or planned use of PCSK9 inhibitor
  • Major adverse cardiac event within the last 3 months
  • Left ventricular ejection fraction ≤30% or New York Heart Association class III-IV symptoms
  • Uncontrolled hypertension
  • Severe concomitant noncardiovascular disease
  • Use of another investigational drug
  • Fasting triglyceride >400 mg/ml

Other salient features/characteristics:

  • 87.6% had established ASCVD
  • 12.4% had ASCVD risk-equivalents
  • Mean baseline LDL-C was 112 mg/dl
  • 96.2% were on statin therapy at baseline

Principal Findings:

The primary outcome, mean percent change in LDL-C at 510 days, was -49 in the inclisiran group compared with 4 in the placebo group (p < 0.0001). This was a time-averaged 50% reduction in LDL-C for inclisiran versus placebo.

Secondary outcomes:

  • Exploratory cardiovascular endpoint: 7.8% with inclisiran vs. 10.3% with placebo
  • Treatment-emergent adverse event: 83% with inclisiran vs. 82% with placebo
  • Serious adverse event: 22% with inclisiran vs. 23% with placebo
  • Protocol defined skin event: 4.7% with inclisiran vs. 0.5% with placebo
  • No sign of liver, kidney, or muscle toxicity

Primary prevention cohort of ORION-11 (n = 203):

  • Mean percent change in LDL-C at 510 days: −41.9 in the inclisiran group compared with +1.8 in the placebo group (p < 0.0001). This was a time-averaged −41.0% reduction in LDL-C for inclisiran vs. placebo (p < 0.0001).

Pooled analysis of ORION-9, ORION-10, and ORION-11:

  • Mean percent change in LDL-C at 510 days: -51 in the inclisiran group compared with 4 in the placebo group (p < 0.0001). This was a time-averaged 52% reduction in LDL-C for inclisiran vs. placebo.
  • At least one treatment-emergent adverse event: 78.0% with inclisiran vs. 77.3% with placebo
  • At least one serious treatment-emergent adverse event: 20.4% with inclisiran vs. 23.0% with placebo
  • Prespecified exploratory cardiovascular event: 7.1% with inclisiran vs. 9.4% with placebo


Among patients with ASCVD or ASCVD risk-equivalents, twice yearly inclisiran injection resulted in a significant reduction in LDL-C. This was well tolerated with no sign of liver, muscle, or kidney toxicity. The use of a small interfering double-stranded RNA is a novel approach to management of LDL-C. Clinical event-powered randomized trials are needed.


Ray KK, Kallend D, Leiter LA, et al. Effect of inclisiran on lipids in primary prevention: the ORION-11 trial. Eur Heart J 2022;Nov 4:[Epub ahead of print].

Ray KK, Wright RS, Kallend D, et al., on behalf of the ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients With Elevated LDL Cholesterol. N Engl J Med 2020;382:1507-19.

Presented by Dr. R. Scott Wright at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 28, 2020.

Presented by Dr. Kausik K. Ray at the European Society of Cardiology Congress, Paris, France, September 2, 2019.

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

Keywords: acc20, ACC Annual Scientific Session, ESC Congress, ESC 19, Atherosclerosis, Cholesterol, LDL, Diabetes Mellitus, Type 2, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Metabolic Syndrome, Proprotein Convertases, Primary Prevention, RNA, Double-Stranded, RNA, Small Interfering

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