Highlights
- In the SOUL trial, oral semaglutide demonstrated a statistically significant reduction in the rate of estimated glomerular filtration rate (eGFR) decline compared to placebo.
- The treatment slowed the annual eGFR loss by 0.40 mL/min/1.73 m², a finding with potential long-term clinical implications for renal preservation.
- Despite the benefit in eGFR slope, the trial did not find a statistically significant reduction in a five-point composite kidney outcome, likely due to the relatively preserved baseline renal function of the study cohort.
- Safety profiles were consistent with the known class effects of GLP-1 receptor agonists, with no new safety signals observed regarding renal or cardiovascular health.
Background: The Interplay of Diabetes, Cardiovascular Disease, and the Kidney
Chronic kidney disease (CKD) remains one of the most debilitating complications of type 2 diabetes (T2D), significantly increasing the risk of end-stage renal disease (ESRD), cardiovascular events, and premature death. For decades, the therapeutic landscape for diabetic kidney disease was limited to glycemic control and renin-angiotensin system (RAS) inhibition. However, the emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has revolutionized the management of these patients.
While injectable semaglutide has shown robust cardiovascular and renal benefits in trials such as SUSTAIN-6 and the more recent FLOW trial, the impact of the oral formulation of semaglutide on hard kidney outcomes remained an area of active investigation. The SOUL trial (Semaglutide Cardiovascular Outcomes Trial) was designed to address this gap, specifically looking at patients with T2D and high cardiovascular risk.
Study Design and Participant Characteristics
The SOUL trial (NCT03914326) was a randomized, double-blind, placebo-controlled, multicenter trial. It enrolled 9,650 participants with type 2 diabetes who also had established atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (defined as an eGFR < 60 mL/min/1.73 m²). Participants were randomized 1:1 to receive either oral semaglutide (up-titrated to 14 mg once daily) or a matching placebo, in addition to standard of care.
The baseline characteristics revealed a mean age of 66.1 years and a mean duration of diabetes of 15.4 years. Crucially for the interpretation of kidney outcomes, the mean baseline eGFR was 73.8 mL/min/1.73 m², indicating a population with relatively preserved kidney function compared to trials specifically targeting advanced CKD. The median follow-up period was 47.5 months.
Analysis of Primary and Secondary Kidney Outcomes
The investigators prespecified several kidney-related endpoints to evaluate the nephroprotective potential of oral semaglutide. The primary kidney outcome was a five-point composite including: a persistent ≥50% reduction in eGFR from baseline, persistent eGFR < 15 mL/min/1.73 m², initiation of chronic kidney replacement therapy (dialysis or transplantation), death from kidney-related causes, or death from cardiovascular causes.
The results showed that the five-point composite outcome occurred in 403 participants (8.4%) in the oral semaglutide group compared to 435 participants (9.0%) in the placebo group. This resulted in a hazard ratio (HR) of 0.91 (95% CI 0.80, 1.05; P = 0.19). Similarly, a four-point composite outcome—which excluded cardiovascular death to focus more specifically on renal events—occurred in 112 (2.3%) and 129 (2.7%) participants, respectively (HR 0.86; 95% CI 0.66, 1.10; P = 0.22).
While these composite outcomes did not reach statistical significance, it is essential to consider the “event-driven” nature of these endpoints. In a population with a mean eGFR of nearly 74 mL/min/1.73 m², the progression to a 50% decline or ESRD over a four-year period is relatively infrequent, which may have limited the statistical power to detect a difference in these specific hard endpoints.
The eGFR Slope: A Significant Signal of Preservation
Perhaps the most clinically relevant finding from the SOUL trial regarding kidney health was the change in eGFR over time. The trial measured the mean annual eGFR decline (the eGFR slope) as a prespecified secondary endpoint. This metric is increasingly recognized by regulatory bodies and clinicians as a valid surrogate for long-term renal health.
The annual decline in eGFR was significantly slower in the oral semaglutide group compared to the placebo group. Specifically, the eGFR decreased by 1.67 mL/min/1.73 m² per year in the semaglutide arm versus 2.06 mL/min/1.73 m² per year in the placebo arm. This represents an estimated treatment difference of 0.40 mL/min/1.73 m² per year (95% CI 0.27, 0.53; P < 0.0001). This benefit was consistent across various subgroups, including those who already had an eGFR below 60 mL/min/1.73 m² at baseline.
Safety and Tolerability
Safety is a paramount concern in chronic management. In the SOUL trial, serious adverse events were reported at similar rates between the oral semaglutide and placebo groups. The gastrointestinal side effects typically associated with GLP-1 RAs—such as nausea and vomiting—were the most common reasons for treatment discontinuation, but these did not translate into an increased risk of serious renal adverse events. There was no evidence of an increased risk of acute kidney injury (AKI), which has historically been a concern when initiating therapies that affect intrarenal hemodynamics.
Expert Commentary: Interpreting the Data
The SOUL trial provides a nuanced view of GLP-1 RA therapy in renal protection. While the trial did not replicate the dramatic reduction in hard kidney events seen in the FLOW trial (which used injectable semaglutide in a much higher-risk CKD population), the slowing of eGFR decline is a vital finding. In clinical practice, preserving 0.4 mL/min/1.73 m² of filtration every year can delay the need for dialysis by several years over the course of a patient’s lifetime.
Mechanistically, semaglutide is thought to protect the kidney through multiple pathways: reducing systemic inflammation, improving glycemic control, lowering blood pressure, and potentially exerting direct effects on the GLP-1 receptors within the kidney vasculature and tubules. The SOUL data suggests that these benefits are accessible through the oral formulation, providing a more convenient option for patients who are hesitant about injections.
One limitation to note is the study population. Because SOUL primarily targeted cardiovascular outcomes, the inclusion of many patients with normal kidney function meant that the “hard” renal events were rare. Future meta-analyses combining SOUL data with other GLP-1 RA trials may provide more definitive evidence on these composite endpoints.
Conclusion
The SOUL trial reinforces the role of oral semaglutide as a multi-organ protective agent in type 2 diabetes. While it did not significantly reduce the primary composite kidney endpoint in this specific cohort, the significant slowing of eGFR decline provides clear evidence of a nephroprotective effect. For clinicians, these results support the early use of GLP-1 RAs not just for glycemic and cardiovascular management, but as a strategy to preserve long-term renal function in patients with T2D and established vascular disease.
Funding and ClinicalTrials.gov
The SOUL trial was funded by Novo Nordisk. ClinicalTrials.gov Identifier: NCT03914326.
References
- Mann JFE, Marx N, Deanfield JE, et al. Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial. Diabetes Care. 2026;49(2):257-265. doi:10.2337/dc25-1080.
- Perkovic V, Wanner C, Toutain P, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Chronic Kidney Disease (FLOW). N Engl J Med. 2024.
- Heerspink HJL, Sattar N, Pavo I, et al. Effects of Tirzepatide on Kidney Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the SURPASS-4 Randomized Clinical Trial. Lancet Diabetes Endocrinol. 2022;10(11):774-785.
