Oral Semaglutide and the Kidney: Promise, Limitations, and the Road Ahead

Chronic kidney disease (CKD) remains a leading cause of morbidity in people with type 2 diabetes (T2D). While sodium–glucose cotransporter 2 inhibitors (SGLT2is) and nonsteroidal mineralocorticoid receptor antagonists have established nephroprotective roles, the contribution of glucagon-like peptide 1 receptor agonists (GLP-1RAs) to kidney protection is still being defined. In a recent issue of Diabetes Care, Mann et al. (1) report a prespecified kidney analysis of the Semaglutide Cardiovascular Outcomes Trial in Patients With Type 2 Diabetes (SOUL), examining whether oral semaglutide can reduce adverse kidney outcomes in 9,650 participants with T2D and atherosclerotic cardiovascular (CV) disease and/or CKD.

The principal findings are instructive yet sobering. Oral semaglutide did not significantly reduce either the five-point composite kidney outcome (hazard ratio [HR] 0.91; 95% CI 0.80, 1.05) or the four-point kidney-specific composite excluding CV death (HR 0.86; 95% CI 0.66, 1.10). Notably, however, oral semaglutide did slow the annual decline in estimated glomerular filtration rate (eGFR) compared with placebo (−1.67 vs. −2.06 mL/min/1.73 m²; P < 0.0001), an effect that was numerically more pronounced in the subgroup with baseline eGFR <60 mL/min/1.73 m². These eGFR preservation findings are consistent with those observed in the Evaluate Renal Function With Semaglutide Once Weekly (FLOW) trial with subcutaneous semaglutide (2) and in meta-analyses of GLP-1RA trials (3).

Several design features of SOUL limit interpretation of kidney outcomes. First, the study population had mostly preserved kidney function (mean eGFR 73.8 mL/min/1.73 m²), and urinary albumin was not measured, precluding identification of those at highest risk for CKD progression. Second, CV death dominated the five-point composite (71% of events), substantially diluting the kidney-specific signal. Third, the trial was not powered for kidney end points, with only 43% power to detect a 20% risk reduction for the four-point composite. The contrast with the FLOW trial (2), which enrolled a population with established CKD and heavy albuminuria and yielded an event rate more than threefold higher, underscores the critical role of baseline kidney risk in determining trial outcomes.

The interaction between oral semaglutide and concomitant SGLT2i use deserves particular attention. While the eGFR benefit of oral semaglutide appeared attenuated in participants already receiving SGLT2is (estimated treatment difference 0.17 vs. 0.48 mL/min/1.73 m²/year; P_interaction = 0.03), statistical power was limited. Large meta-analyses have not detected heterogeneity in kidney benefits of GLP-1RAs based on SGLT2i use (4), and observational data support additive benefits of the combination (5). Ultimately, dedicated randomized trials comparing combination therapy with monotherapy are needed to resolve this important clinical question.

In summary, SOUL adds important long-term data that confirm the kidney safety and potential eGFR-preserving benefit of oral semaglutide. However, the absence of a significant effect on hard kidney outcomes highlights the need for dedicated kidney trials that enroll populations with more advanced CKD and albuminuria. The ongoing Renal Mode of Action of Semaglutide in Patients With Type 2 Diabetes and Chronic Kidney Disease (REMODEL) trial, which incorporates functional MRI and kidney biopsies, may illuminate the direct renal mechanisms of semaglutide, informing future trial designs. Until such evidence is available, clinicians should recognize oral semaglutide as a CV risk–reducing agent with encouraging, but unproven, kidney benefits.