Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial

Mann JF, Marx N, Deanfield JE, Emerson SS, Inzucchi SE, McGuire DK, Mulvagh SL, Pop-Busui R, Poulter NR, Engelmann MD, Hovingh GK, Belmar N, Idorn T, Jeppesen OK, Birkenfeld AL, Amod A, Mankovsky B, Desouza C, Gorgojo-Martinez JJ, Arechavaleta R, Tu ST, Buse JB (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 49

Pages Range: 257-265

Journal Issue: 2

DOI: 10.2337/dc25-1080

Abstract

OBJECTIVE: To examine the effects of oral semaglutide on kidney outcomes in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: SOUL (NCT03914326), a double-blind randomized controlled trial, compared oral semaglutide with placebo in people with T2D, ASCVD, and/or CKD, showing a 14% reduction in risk of major adverse cardiovascular (CV) events. Prespecified kidney outcomes included a five-point composite (≥50% decrease in estimated glomerular filtration rate [eGFR], persistent eGFR <15 mL/min/1.73 m2, initiation of chronic kidney replacement therapy, or death from kidney or CV causes); a four-point composite (excluding CV death); and eGFR decline. Prespecified subgroups were also assessed, including those with eGFR <60 mL/min/1.73 m2 at baseline. RESULTS: Among 9,650 participants, mean eGFR was 73.8 mL/min/1.73 m2, and follow-up was 47.5 months. The five-point outcome occurred in 403 (8.4%) and 435 (9.0%) participants taking oral semaglutide versus placebo, respectively (hazard ratio [HR] 0.91; 95% CI 0.80, 1.05; P = 0.19). The four-point outcome occurred in 112 (2.3%) and 129 (2.7%) participants, respectively (HR 0.86; 95% CI 0.66, 1.10; P = 0.22). Mean annual eGFR decline was less with oral semaglutide than placebo (-1.67 vs. -2.06 mL/min/1.73 m2; estimated treatment difference 0.40 [95% CI 0.27, 0.53; P < 0.0001). These effects were similar across most subgroups, including those with eGFR <60 mL/min/1.73 m2. Serious adverse events occurred at similar rates in both groups. CONCLUSIONS: In people with T2D and ASCVD and/or CKD but with overall mostly preserved eGFR, orally administered semaglutide, compared with placebo, did not significantly reduce adverse kidney outcomes but did slow the decline in eGFR.

Involved external institutions

University of KwaZulu-Natal (UKZN) South Africa (ZA) National Academy of Medical Sciences of Ukraine (NAMS) / NAMS Ukraine Ukraine (UA) Hospital Universitario Fundación Alcorcón (HUFA) Spain (ES) Universidad Autónoma de Guadalajara Mexico (MX) Changhua Christian Hospital Taiwan (TW) University of North Carolina at Chapel Hill United States (USA) (US) Novo Nordisk A/S Denmark (DK) Universitätsklinikum Tübingen Germany (DE) Universitätsklinikum Aachen (UKA) Germany (DE) University College London (UCL) United Kingdom (GB) University of Washington United States (USA) (US) Yale University United States (USA) (US) University of Texas Southwestern Medical Center (UT Southwestern) United States (USA) (US) Dalhousie University Canada (CA) Oregon Health and Science University (OSHU) United States (USA) (US) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) KfH Kuratorium für Dialyse und Nierentransplantation e.V. Germany (DE)

How to cite

APA:

Mann, J.F., Marx, N., Deanfield, J.E., Emerson, S.S., Inzucchi, S.E., McGuire, D.K.,... Buse, J.B. (2026). Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial. Diabetes Care, 49(2), 257-265. https://doi.org/10.2337/dc25-1080

MLA:

Mann, Johannes F.E., et al. "Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial." Diabetes Care 49.2 (2026): 257-265.

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