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

Lawrence A Leiter; Frederick J Raal; Gregory G Schwartz; Wolfgang Koenig; Kausik K Ray; Ulf Landmesser; Jackie Han; Lorena Garcia Conde; R Scott Wright

doi:10.1111/dom.15650

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 Obes Metab. 2024 May 17. doi: 10.1111/dom.15650. Online ahead of print.

Authors

Lawrence A Leiter¹, Frederick J Raal², Gregory G Schwartz³, Wolfgang Koenig^{4

5

6}, Kausik K Ray⁷, Ulf Landmesser⁸, Jackie Han⁹, Lorena Garcia Conde¹⁰, R Scott Wright¹¹

Affiliations

¹ Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada.
² Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³ Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁴ Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
⁵ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
⁶ Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
⁷ Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK.
⁸ Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Charité University Medicine Berlin, Friede Springer Cardiovascular Prevention Center od Charité, Berlin Institute of Health, DZHK, Partner Site Berlin, Berlin, Germany.
⁹ Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
¹⁰ Novartis Pharma AG, Basel, Switzerland.
¹¹ Division of Preventive Cardiology and Department of Cardiology, Mayo Clinic, Rochester, Minnesota, USA.

PMID: 38757725
DOI: 10.1111/dom.15650

Abstract

Aims: To 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 methods: Participants 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.

Results: Baseline 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%).

Conclusion: Inclisiran 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.

Keywords: clinical trial; dyslipidaemia; glycaemic control; lipid‐lowering therapy; randomized trial; type 2 diabetes.

Grants and funding

Novartis Pharma AG, Basel, Switzerland