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

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.

Graphical abstract

Figure 1

Composite kidney outcomes in the overall population and participants with eGFR <60 mL/min/1.73 m² at baseline. A–D: Data are from the in-trial period from the full analysis set. Cumulative incidence estimates were based on time from randomization to first composite kidney event with non–CV-related and non–kidney-related death modeled as competing risks using the Aalen-Johansen estimator. Participants without events of interest were censored at the end of their in-trial observation period. Events not related to eGFR were confirmed by the events adjudication committee. eGFR was calculated using the CKD-EPI equation. Time from randomization to first composite kidney event was analyzed using a Cox proportional hazards model with treatment as a categorical fixed factor and based on the available number of events for analysis. Numbers under each graph represent the number of participants at risk. sema, semaglutide.

Figure 2

Mean eGFR (mL/min/1.73 m²) over time. A: Overall population. B: Participants with eGFR ≥60 mL/min/1.73 m² at baseline. C: Participants with eGFR <60 mL/min/1.73 m² at baseline. Observed data from the in-trial period were from the full analysis set. Error bars are ± standard error of the mean. Numbers under each panel represent the number of participants contributing to the means. sema, semaglutide.

Figure 3

Subgroup analysis of the five-point composite kidney outcome. Data are from the in-trial period. For the subgroup analyses, estimated HRs and corresponding 95% CIs were calculated using a Cox proportional hazards model with interaction between treatment group and the relevant subgroup as fixed factors. HbA_1c level of 8% corresponds to 64 mmol/mol. P value for test of no interaction effect. MI, myocardial infarction; sema, semaglutide.