Semaglutide and Kidney Outcomes in Type 2 Diabetes Patients at Low to Moderate Kidney Risk: A Retrospective Active-Comparator Cohort Study

Abstract Background Semaglutide has demonstrated kidney benefits in advanced chronic kidney disease (CKD), but evidence in adults with type 2 diabetes at low-to-moderate kidney risk remains limited. We compared kidney outcomes after semaglutide or dipeptidyl peptidase-4 inhibitor (DPP4i) initiation in this population. Methods This retrospective active-comparator, new-user cohort study used data from August 1, 2019 to February 28, 2025 from Maccabi Healthcare Services (MHS), Israel. Adults with type 2 diabetes and low-to-moderate risk according to Kidney Disease: Improving Global Outcomes (KDIGO) who initiated semaglutide (oral or subcutaneous) or DPP4i were propensity score-matched 1:1 and stratified by baseline sodium‒glucose cotransporter-2 inhibitor (SGLT2i) use. The primary endpoint was the first occurrence of a composite of confirmed ≥ 30% decline in the estimated glomerular filtration rate (eGFR), new-onset or worsening albuminuria, end-stage kidney disease, or all-cause death. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated via Cox proportional hazards regression. Results The final matched cohort comprised 6,705 participants per group. Among the matched semaglutide initiators, 6,230 (92.9%) received subcutaneous semaglutide and 475 (7.1%) received oral semaglutide. Over 36 months, the primary composite outcome occurred in 581 (8.7%) semaglutide- and 844 (12.6%) DPP4i-treated participants (HR 0.69; 95% CI 0.60–0.78; p < 0.001). Rates were lower with semaglutide for ≥ 30% eGFR decline [125 (1.9%) vs 191 (2.8%); p = 0.004], albuminuria progression [399 (6.0%) vs 545 (8.1%); p < 0.001], and all-cause death [61 (0.9%) vs 114 (1.7%); p < 0.001]; kidney failure was rare in both groups. The composite was driven mainly by albuminuria and, to a lesser extent, by eGFR decline and all-cause death. Associations were consistent across KDIGO risk categories and regardless of baseline SGLT2i use. Conclusions Among adults with type 2 diabetes at low-to-moderate KDIGO risk, semaglutide initiation was associated with a lower risk of adverse kidney outcomes than DPP4i initiation was, extending evidence regarding semaglutide and kidney outcomes beyond advanced CKD.