Introduction
Cardiovascular (CV) risk is increased in people living with metabolic dysfunction-associated steatohepatitis (MASH). Although liver biopsy remains the gold standard to diagnose MASH, it is not practical to implement on a large scale. However, non-invasive tests, such as the Fibrosis-4 score (FIB-4), are useful for staging patients with fibrotic MASH and predict overall, CV- and liver-related mortality. In the SELECT CV outcome trial, which included patients with a body mass index ≥27.0 kg/m2 and established CV disease but without diabetes, those treated with the glucagon-like peptide-1 receptor agonist semaglutide had a 20% CV risk reduction compared with those receiving placebo. We examined the CV benefits of semaglutide in a subgroup of participants at high risk of MASH as defined by FIB-4.
Aims & Methods
SELECT was a multicentre, randomised, double-blind, placebo-controlled, event-driven trial that enrolled 17,604 patients aged ≥45 years. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo in addition to standard of care recommendations for CV disease prevention. This subgroup analysis for the primary composite endpoint of 3-point major adverse cardiovascular event (MACE; non-fatal myocardial infarction, non-fatal stroke, CV death) was performed for patients with increased MASH risk as indicated by FIB-4 ≥1.3 for patients aged <65 years and FIB-4 ≥2.0 for patients aged ≥65 years, and for a second subgroup of patients of any age with FIB-4 >2.67, respectively. As identified by review of medical history and co-medication, patients with a cause of liver disease other than MASH were not included in this analysis.
Results
From the SELECT cohort, 3,665 patients (20.8% of all) aged <65 years with FIB-4 ≥1.3 and aged ≥65 years with FIB-4 ≥2.0 were included in this analysis. The primary CV endpoint occurred in 140 of the 1,834 patients (7.6%) in the semaglutide group and in 176 of the 1,831 patients (9.6%) in the placebo group (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.63, 0.98; p < 0.03). In the subgroup of 475 patients with suspected MASH and advanced fibrosis (FIB-4 >2.67 irrespective of age), there were 22 CV events in 235 patients treated with semaglutide 2.4 mg compared with 35 events in 240 placebo-treated patients, yielding an HR of 0.64 (95% CI 0.37, 1.08; p = 0.10).
Conclusion
In line with the primary analysis of the SELECT trial, 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.
Disclosure
SM received consulting honoraria from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Daichii-Sankyo, esanum, Gilead, Ipsen, Lilly, Novartis, Novo Nordisk, Sandoz, Sanofi.
CB reports grants and personal fees from Amgen, Regeneron and Sanofi, and personal fees from Abbott, Akcea, AstraZeneca, Bristol Myers Squibb, Genfit, Gilead, Eli Lilly and Company, Merck (MSD) and Novo Nordisk.
CC served as advisory board for Novo Nordisk and reports having received research grants from Eli-Lilly, Novo Nordisk, Merck, Boehringer Ingelheim, Eurofarma, Fractyl, and EMS.
HC served on advisory panels for Novo Nordisk and Bayer; receiving research funding from Sanofi, Roche and IQVIA, and grants from Chief Scientist Office, Diabetes UK, European Commission, Juvenile Diabetes Research Foundation and Medical Research Council; serving on speaker’s bureau for Novo Nordisk; and holding stock in Roche Pharmaceuticals and Bayer.
AKDH, IK and ML are employees and stockholders of Novo Nordisk A/S.
ML declares having received honoraria from Akebia, Alnylam, Ardelyx, Becton Dickson, Brainstorm Cell, Eli Lilly, Endologix, FibroGen, GSK, Intarcia, Medtronic, Neovasc, Novo Nordisk, Provention Bio and ReCor, and for consulting activities and research funding to his institution from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion and Novartis.
IL declares having received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals Inc., Novo Nordisk, Pfizer and Sanofi US Services Inc., and has served as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Biomea Fusion, Boehringer Ingelheim, Carmot, Eli Lilly, Intarcia, Intercept Pharmaceuticals Inc., Janssen Global Services, LLC, Johnson & Johnson Medical Devices & Diagnostics Group - Latin America, L.L.C., MannKind Corporation, Merck, Novo Nordisk, Pfizer Inc., Sanofi US Services Inc., Shionogi Inc., Structure Therapeutics, Target pharma, Valeritas Inc., and Zealand Pharma A/S, and has received travel expenses from Boehringer Ingelheim, Eli Lilly and Company, Johnson & Johnson Medical Devices & Diagnostics Group - Latin America, L.L.C., Novo Nordisk, Sanofi US Services Inc. and Zealand Pharma A/S.
PN reports grants from Novo Nordisk, and has received consulting fees from Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol Myers Squibb (BMS), Pfizer, Sun Pharma, Madrigal and GSK. PNN also reports honoraria as a speaker for Novo Nordisk and AiCME; support for attending meetings for Novo Nordisk; and participation on an advisory board for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, BMS, Pfizer, Sun Pharma, Madrigal and GSK.
SN received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx and Sanofi-Regeneron and is also a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi- Regeneron, Vaxxinity, CSL Sequiris, and Novo Nordisk.
MQP is an employee and stockholder of Novo Nordisk A/S.
FS worked as a consultant, participated in studies, and/or received travel funds from the following companies that are involved with obesity, lipodystrophy and/or diabetes: Aegerion/Amryt, Novo Nordisk, Lilly, Bruno Pharma, Boehringer, Pfizer, BioItalia.
AJS consults for and advises Avant Santé and AstraZeneca. AJS also consults for and has received grants from Akero, BMS, Intercept, Eli Lilly, Madrigal and Novo Nordisk. AJS consults for and owns stock in Rivus, and also consults for AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelheim, 89Bio, Echosens, Genentech, Gilead, GSK, HistoIndex, Mallinckrodt , Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron, Salix, Siemens, Surrozen, Takeda, Terns and Zydus. AJS owns stock in Durect, Exalenz, Genfit, Indalo, Inversago and Tiziana, and has received royalties from Elsevier and Wolters Kluwer.
SK, for the period over which SELECT was conducted, declares receiving advisory board/consulting fees from AltPep, Bayer, Boehringer Ingelheim, Casma Therapeutics, Eli Lilly, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer and Third Rock Ventures.
