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Clinical Trial
. 2025 Jun 10;151(23):1639-1650.
doi: 10.1161/CIRCULATIONAHA.125.074545. Epub 2025 Mar 29.

Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial

Nikolaus Marx  1 , John E Deanfield  2 , Johannes F E Mann  3   4 , Rosario Arechavaleta  5 , Stephen C Bain  6 , Harpreet S Bajaj  7 , Katrine Bayer Tanggaard  8 , Andreas L Birkenfeld  9   10 , John B Buse  11 , Zaklina Davicevic-Elez  8 , Cyrus Desouza  12 , Scott S Emerson  13 , Mads D M Engelmann  8 , G Kees Hovingh  8 , Silvio E Inzucchi  14 , Pardeep S Jhund  15 , Sharon L Mulvagh  16 , Rodica Pop-Busui  17 , Neil R Poulter  18 , Søren Rasmussen  8 , Shih-Te Tu  19 , Darren K McGuire  20 ; SOUL Study Group
Affiliations
Clinical Trial

Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial

Nikolaus Marx et al. Circulation. .

Abstract

Background: Both GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter-2) inhibitors (SGLT2i) improve cardiovascular outcomes in people with type 2 diabetes and cardiovascular or chronic kidney disease. However, there are limited data about the effect of combining these agents on cardiovascular and safety outcomes.

Methods: The SOUL trial (Semaglutide Cardiovascular Outcomes Trial; NCT03914326) randomized 9650 participants with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease to oral semaglutide or placebo. As prespecified, participants were analyzed 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, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal 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 versus placebo (hazard ratio, 0.86; 95% CI, 0.77-0.96). In those taking SGLT2i at baseline, there were 143 of 1296 (semaglutide) versus 158 of 1300 (placebo) primary outcome events (hazard ratio, 0.89; 95% CI, 0.71-1.11); and 436 of 3529 versus 510 of 3525, respectively, in participants not taking SGLT2i at baseline (hazard ratio, 0.84; 95% CI, 0.74-0.95; P-interaction, 0.66). An analysis of major adverse cardiovascular events 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 major adverse cardiovascular event outcomes independently of concomitant SGLT2i treatment, and this combination appeared to be safe.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03914326.

Keywords: cardiovascular diseases; cardiovascular system; diabetes mellitus, type 2; glucagon-like peptide-1 receptor agonists; renal insufficiency, chronic; semaglutide; sodium-glucose transporter 2 inhibitors.

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Conflict of interest statement

Dr Marx is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TRR 219; project ID, 322900939 [M03, M05]); has given lectures for Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, and Novo Nordisk; has received unrestricted research grants from Boehringer Ingelheim; and has served as an advisor for Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, and Novo Nordisk. In addition, Dr Marx served in trial leadership for Boehringer Ingelheim and Novo Nordisk. Dr Marx declines all personal compensation from pharma or device companies. Dr Deanfield reports grants or contracts from 2022 to 2025 from Alzheimer’s Research UK and from 2019 to 2022 from the British Heart Foundation. He received consulting fees/honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer. Dr Mann reports grants from Novo Nordisk, the European Union, and McMaster University, Hamilton, Canada; consulting fees from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim; and honoraria from Novo Nordisk, AstraZeneca, Bayer, and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi, and Boehringer Ingelheim. He is an author for UpToDate and has a leadership role in the KDIGO group. Dr Arechavaleta has given lectures for Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim, and Sanofi. She has received advisory board fees and honoraria for clinical trials from Novo Nordisk and Eli Lilly. Dr Bain reports grants and honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Menarini, and Novo Nordisk. He has provided expert advice to the All-Wales Medicines Strategy Group and the National Institute for Health and Care Excellence (United Kingdom). Dr Bajaj reports trial fees paid to his institution by Abbott, Amgen, Anji Pharmaceuticals, Arrowhead Pharmaceuticals, AstraZeneca, Biomea, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Novo Nordisk, and Pfizer. Dr Tanggaard is an employee at Novo Nordisk. Dr Birkenfeld is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; GRK2816; BI1292/12-1; 10-1; 9-1) and the German Federal Ministry for Education and Research (01GI0925) through the German Center for Diabetes Research (DZD e.V.). Dr Birkenfeld has given lectures for Novo Nordisk and Daiichi Sankyo, has received unrestricted research grants from Boehringer Ingelheim and AstraZeneca, and has served as an advisor for Bayer and Novo Nordisk. In addition, Dr Birkenfeld served in trial leadership for Boehringer Ingelheim, Novo Nordisk, and Eli Lilly. Dr Birkenfeld declines all personal compensation from pharma or device companies. Dr Buse reports research support from Corcept, Dexcom, and Novo Nordisk; consulting fees from Altimmune, Antag, Amgen, ApStem, Aqua Medical, AstraZeneca, Boehringer Ingelheim, CeQur, Corcept Therapeutics, Dexcom, Eli Lilly, embecta, GentiBio, Glyscend, Insulet, Medtronic MiniMed, Mellitus Health, Metsera, Novo Nordisk, Pendulum Therapeutics, Praetego, Stability Health, Tandem, Terns Inc, Vertex, and Zealand; and stock options from Glyscend, Mellitus Health, Metsera, Pendulum Therapeutics, Praetego, and Stability Health. Dr Davicevic-Elez is an employee of and holds shares in Novo Nordisk. Dr Desouza reports Novo Nordisk research grants (payments to institution) and has personally received consulting fees from Eli Lilly and consulting fees and support for attending meetings or travel from Novo Nordisk. Dr Emerson declares consulting fees from Novo Nordisk for steering committee participation and from Boehringer Ingelheim for consulting regarding veterinary congestive heart failure; received support for attending meetings or travel from Novo Nordisk for attendance at steering committee and scientific meetings; and declares participation on an advisory board for Novo Nordisk, AstraZeneca, Daiichi Sankyo, Vertex, Roche, GlaxoSmithKline, Lilly, Novartis, Bristol Myers, and Sanofi. Dr Engelmann is a full-time employee of Novo Nordisk and has stocks in the company. Dr Hovingh has received funding from the Klinkerpadfonds, paid to his former academic institute (Amsterdam UMC, The Netherlands). He is also an employee and shareholder of Novo Nordisk. Dr Inzucchi has served as a consultant or on advisory boards for Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, and Bayer. He has given lectures sponsored by AstraZeneca and Boehringer Ingelheim/Lilly. He declares royalties from McGraw Hill and Wolters Kluwer Health and support for attending meetings or travel from Novo Nordisk, AstraZeneca, Boehringer Ingelheim/Lilly, and Bayer. Dr Jhund reports speaker fees from AstraZeneca, Novartis, and ProAdWise Communications; advisory board fees from AstraZeneca; research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics. Dr Jhund reports other financial interests, including as Director of GCTP Ltd. His employer, the University of Glasgow, has been remunerated for his time working on clinical trials by AstraZeneca, Novartis, Novo Nordisk, and Bayer AG. Dr Mulvagh has served as a consultant or on advisory boards for Novo Nordisk and Merck. Dr Pop-Busui received research grant support to her institutions from NIDDK, Breakthrough T1D (formerly JDRF), Bayer, Lexicon Pharmaceuticals, and Novo Nordisk, and consulting fees from Averitas Pharma, Biogen, Lexicon Pharmaceuticals, Nevro Inc, Novo Nordisk, and Roche Diagnostic; received support for attending meetings or travel from Roche; participated on an advisory board for Biogen/Reata; and is a member of the board of directors of the American Diabetes Association. Dr Poulter received financial support from several pharmaceutical companies that manufacture blood pressure–lowering, lipid-lowering, and glucose-lowering agents for consultancy fees, research projects, and staff and for arranging and speaking at educational meetings including Servier, Pfizer, AstraZeneca, Amgen, Sanofi, and Novo Nordisk. He holds no stocks or shares in any such companies. Dr Rasmussen is an employee and shareholder in Novo Nordisk. Dr Tu has given lectures for Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim, and Sanofi; received advisory board fees from Novo Nordisk and Eli Lilly; and received honoraria for clinical trials from Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr McGuire has received consulting fees from Novo Nordisk, AstraZeneca, Pfizer, Altimmune, Ventyx Pharmaceuticals, Bayer, Lexicon, Applied Therapeutics, Intercept Pharmaceuticals, Esperion, Lilly USA, Boehringer Ingelheim, New Amsterdam, CSL Behring, Amgen, Neurotronics, Metsera, Kailera, and Alveus Pharma.

Figures

Figure 1.
Figure 1.
Cumulative incidence plots of outcomes for oral semaglutide vs placebo in subgroups with or without SGLT2i use at baseline. A, Time to first occurrence of MACE. B, Time to cardiovascular death. C, Time to first nonfatal myocardial infarction event. D, Time to first nonfatal stroke event. E, Time to all-cause death. The cumulative incidence rate is calculated using the Aalen-Johansen method with noncardiovascular death (A and B)/all-cause death (C and D) as a competing risk. CV indicates cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; and SGLT2i, sodium-glucose cotransporter-2 inhibitor
Figure 2.
Figure 2.
Forest plot: primary outcomes, components and all-cause death according to SGLT2i use at baseline. Data from the in-trial period. Time from randomization to relevant end point was analyzed using a Cox proportional hazards model with treatment as categorical fixed factor. Participants without events of interest were censored at the end of their in-trial period. For the subgroup analyses, estimated HRs and corresponding CIs are calculated in a Cox proportional hazards model with interaction between treatment group and subgroup as fixed factor. P-value, P value for the test of no interaction effect. CV indicates cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; and SGLT2i, sodium-glucose cotransporter-2 inhibitor.
Figure 3.
Figure 3.
Forest plot: cardiovascular outcomes according to SGLT2i use at baseline, by cardiovascular and kidney subgroups. A, ASCVD. B, CKD. C, ASCVD and CKD. Each plot shows data from the in-trial period. Time from randomization to relevant end point was analyzed using a Cox proportional hazards model with treatment as a fixed factor. Participants without events of interest were censored at the end of their in-trial period. For the subgroup analyses, estimated HRs and corresponding CIs are calculated in a Cox proportional hazards model with interaction between treatment group and subgroup as fixed factor. P-value, P value for the test of no interaction effect. ASCVD indicates atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; and SGLT2i, sodium-glucose cotransporter-2 inhibitor.
See this image and copyright information in PMC

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