Diabetes CareKidney & RenalRCTDecember 4, 2025

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

Mann JFE, Marx N, Deanfield JE, Emerson SS, Inzucchi SE, McGuire DK, Mulvagh SL, Pop-Busui R, Poulter NR, Engelmann MDM, 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, SOUL Study Group*

View on PubMed DOI: pii: dc251080. 10.2337/dc25-1080

Key Finding

Oral semaglutide slowed kidney function decline by about 0.4 mL/min/1.73m² per year compared to placebo in people with type 2 diabetes, but didn't significantly reduce major kidney complications over 4 years.

What This Study Found

Imagine your kidneys as sophisticated water filters that gradually lose efficiency over time - this study tracked how fast that decline happens. Researchers followed 9,650 people with type 2 diabetes who also had heart disease or existing kidney problems for nearly 4 years (47.5 months). Think of kidney function like a car's speedometer - it's measured by estimated glomerular filtration rate (eGFR), where higher numbers mean better filtering. The average person in this study started with an eGFR of 73.8, which is like having a car that can still cruise at decent speeds but isn't brand new. The key finding was like comparing two groups of cars going down a long hill - both groups' engines gradually lost power (kidney function declined), but the semaglutide group's engines degraded more slowly. While the semaglutide group lost 1.67 units of filtering power per year, the placebo group lost 2.06 units - a meaningful difference of 0.4 units annually. However, when researchers looked at major kidney emergencies (like needing dialysis, severe kidney failure, or kidney-related death), both groups had similar rates - about 8-9% experienced these serious outcomes.

Statistics Decoded

HR 0.91 for the five-point kidney outcome means semaglutide reduced risk by 9%, but the confidence interval (0.80-1.05) crosses 1.0, meaning this could be due to chance - like getting heads 19 out of 20 coin flips, impressive but not quite proof. The P-value of 0.19 means there's a 19% chance this was just luck - much higher than the 5% threshold scientists usually want. The eGFR decline difference of 0.40 mL/min/1.73m² per year had P < 0.0001, meaning this slower decline was almost certainly real - like flipping heads 50 times in a row. In practical terms, over 10 years, semaglutide users might retain 4 extra units of kidney function compared to placebo.

Why This Matters

While semaglutide didn't prevent major kidney disasters, slowing the gradual decline of kidney function could mean people maintain healthier kidneys longer - potentially delaying the eventual need for dialysis or transplant by months or years.

Original Abstract

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). 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. 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. 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.