Inclisiran and cardiovascular events: a patient-level analysis of phase III trials

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Genetics

Background:

• Inclisiran, an siRNA therapy, effectively lowers LDL cholesterol (LDL-C) with twice-yearly administration.
• The impact of inclisiran-induced LDL-C reduction on cardiovascular (CV) event risk remains to be established.

Purpose of the Study:

• To evaluate the effect of inclisiran on major adverse cardiovascular events (MACE) in patients with high CV risk.
• To assess the safety and efficacy of inclisiran in reducing LDL-C and its association with CV outcomes.

Main Methods:

• Patient-level pooled analysis of ORION-9, -10, and -11 trials.
• Inclusion of patients with heterozygous familial hypercholesterolemia or atherosclerotic CV disease (ASCVD) on maximally tolerated statins.
• Randomized, double-blind, placebo-controlled trial with inclisiran (284 mg) or placebo at specified intervals for 18 months. Exploratory MACE endpoint analysis.

Main Results:

• Inclisiran achieved a 50.6% placebo-corrected LDL-C reduction by Day 90 (P < 0.0001).
• Over 18 months, inclisiran significantly reduced composite MACE (OR 0.74; 95% CI: 0.58-0.94).
• No significant reduction was observed for fatal/non-fatal myocardial infarction or stroke individually.

Conclusions:

• This analysis provides early evidence for potential CV benefits of inclisiran, including MACE reduction.
• Findings suggest inclisiran may contribute to lowering CV risk beyond LDL-C reduction.
• Further confirmation is required from ongoing, larger cardiovascular outcomes trials.