Oral Presentation Australian and New Zealand Obesity Society Annual Scientific Conference 2024

Semaglutide improves cardiovascular outcomes in patients with high risk for metabolic dysfunction-associated steatohepatitis – a subgroup analysis from the SELECT trial (#30)

Melissa Leung 1 2 , Sebastian M Meyhöfer 3 4 , Bertrand Cariou 5 , Cintia Cercato 6 , Helen M Colhoun 7 , Anne Katrine Duun-Henriksen 8 , Iris Kliers 8 , Abraham M Lincoff 9 , Ildiko Lingvay 10 , Michelle T Long 8 11 , Philip Newsome 12 , Stephen J Nicholls 13 , Maria De Los Angeles Quiroga Pelaez 8 , Ferruccio Santini 14 , Arun J Sanyal 15 , Steven E Kahn 16
  1. Liverpool Hospital, Liverpool, Sydney, NSW, Australia
  2. School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
  3. Clinical, Medical & Regulatory, Novo Nordisk Pharma GmbH, Mainz, Germany
  4. Department of Internal Medicine 1 - Endocrinology & Diabetes, University Medical Centre Lübeck, Lübeck, Germany
  5. Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France
  6. Obesity Unit, Department of Endocrinology, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil
  7. Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
  8. Novo Nordisk A/S , Søborg, Denmark
  9. Department of Cardiovascular Medicine, Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
  10. Department of Internal Medicine/Endocrinology and Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
  11. Department of Medicine, Section of Gastroenterology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
  12. Institute of Hepatology, King’s College London and King’s College Hospital, London, UK
  13. Victorian Heart Institute, Monash University, Melbourne, Vic, Australia
  14. Obesity and Lipodystrophy Centre, University Hospital of Pisa, Pisa, Italy
  15. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
  16. Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA

Background and Aims: Cardiovascular (CV) risk is increased in people living with metabolic dysfunction-associated steatohepatitis (MASH). Non-invasive tests, such as Fibrosis-4 score (FIB-4), help stage patients with fibrotic MASH and predict overall CV- and liver-related mortality. In the SELECT CV outcome trial, patients treated with semaglutide had a 20% CV risk reduction versus placebo. We examined the CV benefits of semaglutide in a subgroup of participants at high risk of MASH.

Methods: In SELECT, 17,604 patients (≥45 years, BMI ≥27.0 kg/m2, with established CV disease, without diabetes) were enrolled. Patients were randomised 1:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo, plus standard-of-care recommendations for CV disease prevention. This subgroup analysis for 3-point major adverse CV event (MACE; non-fatal myocardial infarction, non-fatal stroke, CV death) was performed for patients with increased MASH risk (FIB-4 ≥1.3 for patients aged <65 years and FIB-4 ≥2.0 for patients ≥65 years), and for a second subgroup of patients of any age with advanced fibrosis (FIB-4 >2.67) and suspected MASH, respectively. Patients with medical history or co-medication for any non-MASH liver disease were excluded.

Results: Of the SELECT cohort, 3665 patients (20.8%) aged <65 years with FIB-4 ≥1.3 and aged ≥65 years with FIB-4 ≥2.0 were included in this analysis. A MACE occurred in 7.6% (n=140/1834) of semaglutide-treated patients (140/1834) and 9.6% (n=176/1831) of placebo-treated patients (hazard ratio [HR] 0.79; 95% confidence interval [CI]: 0.63;0.98; p<0.03). In the advanced fibrosis subgroup (n=475), 22 CV events occurred in 235 patients treated with semaglutide compared with 35 events in 240 placebo-treated patients (HR 0.64; 95% CI: 0.37;1.08; p=0.10).

Conclusions: Aligned with the SELECT trial primary analysis, use of semaglutide 2.4 mg in a subgroup of patients at high risk of fibrotic MASH as defined by FIB-4 produced a 21% reduction in MACE outcomes.