Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION‐9, ORION‐10 and ORION‐11 Phase 3 randomized trials

Abstract

AbstractAimsTo conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata.Materials and MethodsParticipants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3‐month doses up to 18 months, with background oral lipid‐lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co‐primary endpoints were percentage and time‐adjusted percentage change in low‐density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed.ResultsBaseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo‐corrected) with inclisiran from baseline to Day 510 ranged from −47.6% to −51.9% and from −48.8% to −54.4% across glycaemic/BMI strata, respectively. Similarly, time‐adjusted percentage changes after Day 90 and up to Day 540 ranged from −46.8% to −52.0% and from −48.6% to −53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment‐emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%–7.7%) versus placebo (0.2%–2.1%).ConclusionInclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild‐to‐moderate TEAEs at the injection site.