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Marx, N.* ; Deanfield, J.E.* ; Mann, J.F.E.* ; Arechavaleta, R.* ; Bain, S.C.* ; Bajaj, H.S.* ; Bayer Tanggaard, K.* ; Birkenfeld, A.L. ; Buse, J.B.* ; Davicevic-Elez, Z.* ; Desouza, C.* ; Emerson, S.S.* ; Engelmann, M.D.M.* ; Hovingh, G.K.* ; Inzucchi, S.E.* ; Jhund, P.S.* ; Mulvagh, S.L.* ; Pop-Busui, R.* ; Poulter, N.R.* ; Rasmussen, S.* ; Tu, S.T.* ; McGuire, D.K.*

Oral semaglutide and cardiovascular outcomes in persons with type 2 diabetes, according to SGLT2i use: Prespecified analyses of the SOUL randomized trial.

Circulation, DOI: 10.1161/CIRCULATIONAHA.125.074545 (2025)
DOI PMC
BACKGROUND: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) improve cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) and CV or chronic kidney disease (CKD). However, there are limited data about the effect of combining these agents on CV and safety outcomes. METHODS: The SOUL trial (NCT03914326) randomised 9650 participants with T2D and atherosclerotic CV disease and/or CKD to oral semaglutide or placebo. As prespecified, participants were analysed according to baseline use of SGLT2i (Yes: n=2596, No: n=7054) and, subsequently for any use of SGLT2i during the trial (Yes: n=4718, No: n=4932). The primary outcome was time to first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. Safety was evaluated by comparing the incidence of serious adverse events. RESULTS: Over a mean follow-up of 47.5±10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide vs placebo (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.77; 0.96). In those taking SGLT2i at baseline, there were 143/1296 (semaglutide) versus 158/1300 (placebo) primary outcome events (HR 0.89; 95% CI 0.71; 1.11); and 436/3529 versus 510/3525, respectively, in participants not taking SGLT2i at baseline (HR 0.84; 95% CI 0.74; 0.95; P-interaction 0.66). An analysis of MACE by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar. CONCLUSIONS: Oral semaglutide reduced MACE outcomes independently of concomitant SGLT2i treatment and this combination appeared to be safe.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0009-7322
e-ISSN 1524-4539
Journal Circulation
Publisher Lippincott Williams & Wilkins
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)