Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Weight-independent benefits of semaglutide on histology and non-invasive tests in participants with biopsy-defined MASH: Post hoc analysis of the ESSENCE trial part 1 (127990)

Leon A Adams 1 2 , Phillip N Newsome 3 4 , Matthew J Armstrong 5 , Igor Bakulin 6 , Adel Belloum 7 , Anna MG Cali 7 , Anja Geerts 8 9 , Jacob George 10 , Ewa Janczewska 11 , Niels Krarup 7 , Chun-Jen Liu 12 13 , Havard Midgard 14 , Vlad Ratziu 15 , Mary Rinella 16 , Michael Roden 17 18 19 , Arun Sanyal 20 , Jorn Schattenberg 21 , Mohammed Tawfik 7 , Thea Vestergaard 7 , Elisabetta Bugianesi 22
  1. Department of Hepatology, Sir Charles Gairdner Hospital, Perth , WA, Australia
  2. Internal Medicine Division, Medical School, University of Western Australia , Perth , WA, Australia
  3. Roger WIlliams Institute of Liver Studies, Faculty of Life Sciences & Medicine, King's College London, Foundation for Liver Reserarch & Kings College Hospital, London UK, London, UK
  4. College of Medical and Health , University of Birmingham, Birmingham, UK
  5. Liver Unit, Queen Elizabeth Hospital Birmingham and NIHR Biomedical Research Centre, University of Birmingham, Birmingham, UK
  6. Mechnikov North-Western State Medical University, Saint Petersburg, Russia
  7. Novo Nordisk A/S, Bagsvaerd, Denmark
  8. Department of Gastroenterology & Hepatology Ghent, University Hospital Ghent, Ghent, Belgium
  9. Faculty of Medicine and Health Sciences, University of Ghent, Ghent, Belgium
  10. Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital, Sydney, NSW, Australia
  11. Hepatology Outpatient Clinic, ID Clinic, Mysłowice, Poland
  12. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
  13. Hepatitis Research Center and Clinical Trial Center, National Taiwan University Hospital, Taipei, Taiwan
  14. Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
  15. Institute of Cardiometabolism and Nutrition, INSERM UMRS 1138 CRC, Hospital Pitié Salpêtrière (ICAN), Sorbonne Université, Paris, France
  16. Division of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, USA
  17. Department of Endocrinology and Diabetology, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University of Düsseldorf, Dusseldorf, Germany
  18. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Dusseldorf, Germany
  19. German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Dusseldorf, Germany
  20. Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, USA
  21. Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany
  22. Department of Medical Sciences, University of Turin, Turin, Italy

Aim: The phase 3 ESSENCE trial (NCT04822181) reported positive interim results in 800 randomised participants with F2/F3 MASH receiving once-weekly semaglutide 2.4 mg vs placebo. In this post hoc analysis, we assessed the weight dependency of the effects of semaglutide 2.4 mg on non-invasive tests (NIT)s & histology after 72 weeks, using weight loss-independent & -dependent pathways as covariates.

Methods: NITs & biopsies were assessed at baseline & week 72. MASH-related NIT responder endpoints were change in ALT( ≥17-unit reduction) & FibroScan-AST (FAST) score (≥0.22 reduction). Fibrosis-related NIT responder endpoints were change in liver stiffness measurement (VCTE -30%) & Enhanced Liver Fibrosis (ELF) score (≥0.5-unit reduction). Histologic endpoints included MASH resolution & improvement in fibrosis. All endpoints were assessed using logistic regression at week 72 with treatment as exposure, % weight loss from baseline to w72 as mediator, baseline T2D status, fibrosis stage, & body weight as covariates. The total & weight loss-independent & -dependent effect sizes were calculated as odds ratios (ORs), & missing data were omitted. Data are based on the full analysis set from the on-treatment observation period.

Results: 

 

68705f624ce6f-Figure+1.+MASH+related+endpoints.jpg

68705f624ce6f-Figure+2.+Fibrotic+related+endpoints+.jpg

Conclusion: Semaglutide 2.4 mg improved MASH-related histological & NIT endpoints & fibrosis-related NIT endpoints through equal contributions of weight loss-independent & -dependent metabolic mechanisms, with effects beyond weight loss.