Inclisiran Lowers LDL Cholesterol Across Glycaemic and BMI Strata, suggests study

Inclisiran is a novel small interfering RNA (siRNA) therapeutic that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), leading to reduced LDL cholesterol levels. This study aimed to evaluate the efficacy and safety of inclisiran in diverse patient groups, stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) and BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m²).

Participants from multiple Phase 3 trials were randomized 1:1 to receive 300 mg inclisiran sodium or placebo biannually, following initial and 3-month doses for up to 18 months. All participants continued background oral lipid-lowering therapy. The primary endpoints were percentage and time-adjusted percentage changes in LDL cholesterol from baseline. The study also assessed safety across glycaemic and BMI strata.

Baseline characteristics were well-balanced between treatment groups and strata. Key findings include:

LDL Cholesterol Reduction:

• Percentage change in LDL cholesterol from baseline to Day 510 ranged from -47.6% to -51.9% across glycaemic strata and from -48.8% to -54.4% across BMI strata.

• Time-adjusted percentage changes after Day 90 up to Day 540 ranged from -46.8% to -52.0% across glycaemic strata and from -48.6% to -53.3% across BMI strata.

LDL Cholesterol Thresholds:

• The proportion of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with higher glycaemic and BMI strata.

Safety:

• Mild to moderate treatment-emergent adverse events (TEAEs) at the injection site were more common with inclisiran (2.8%-7.7%) compared to placebo (0.2%-2.1%).

Inclisiran consistently reduced LDL cholesterol levels across all examined patient groups, demonstrating substantial efficacy regardless of glycaemic status or BMI. The treatment also showed a significant reduction in PCSK9 and other atherogenic lipids. These findings highlight inclisiran's potential in managing dyslipidemia across diverse populations, offering a robust option for patients with varying metabolic profiles.

Inclisiran provides significant and sustained LDL cholesterol reduction across glycaemic and BMI strata, with a modest increase in transient mild-to-moderate injection site reactions. These results support the broader use of inclisiran in lipid management strategies, particularly for patients with higher cardiovascular risk due to diabetes or obesity.

Reference:

Leiter, L. A., Raal, F. J., Schwartz, G. G., Koenig, W., Ray, K. K., Landmesser, U., Han, J., Conde, L. G., & Wright, R. S. (2024). Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION‐9, ORION‐10 and ORION‐11 Phase 3 randomized trials. Diabetes, Obesity & Metabolism. https://doi.org/10.1111/dom.15650