Oral Semaglutide Kidney Outcomes in SOUL

The SOUL randomized trial did not show a statistically significant reduction in either prespecified composite kidney outcome with oral semaglutide. It did find a slower annual decline in estimated glomerular filtration rate, or eGFR. Across 9,650 adults with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the mean annual eGFR change was -1.67 mL/min/1.73 m² with oral semaglutide and -2.06 with placebo. The estimated difference was 0.40 mL/min/1.73 m² per year^[2].

A November 2026 Diabetes Care letter framed the finding as a question of promise and limitations. PubMed identifies that item as a letter but exposes no abstract, so its detailed argument cannot be reconstructed from the record^[1]. This readout therefore rests on the accessible primary SOUL report rather than inferred claims from the letter.

What SOUL tested

SOUL was a double-blind, placebo-controlled cardiovascular outcomes trial. Participants were randomly assigned in equal numbers to once-daily oral semaglutide, at a dose up to 14 mg, or matching placebo alongside standard care. Mean follow-up was 47.5 months. The mean starting eGFR was 73.8 mL/min/1.73 m², and 29.2% of participants began below 60 mL/min/1.73 m²^[3]. Most participants therefore did not enter with advanced loss of kidney function.

The five-part composite counted a persistent fall of at least 50% in eGFR, persistent eGFR below 15, long-term kidney replacement therapy, kidney death, or cardiovascular death. A four-part kidney-specific composite removed cardiovascular death. Serum creatinine was measured at baseline, week 13, week 52, annually after that, and at the end of treatment. The eGFR thresholds needed confirmation at least four weeks apart^[3].

The composite outcomes were negative

The five-part outcome occurred in 403 of 4,825 participants assigned oral semaglutide and 435 of 4,825 assigned placebo. That produced a hazard ratio of 0.91, with a 95% confidence interval from 0.80 to 1.05 and a P value of 0.19. The interval includes no difference, so the result does not establish a reduction in the composite outcome^[2].

The four-part kidney-specific outcome occurred in 112 participants receiving oral semaglutide and 129 receiving placebo. Its hazard ratio was 0.86, with a 95% confidence interval from 0.66 to 1.10 and a P value of 0.22. This result was also not statistically significant. The full report says cardiovascular death made up 71% of events in the broader five-part composite, which matters when interpreting that endpoint as a kidney result^[3].

The eGFR slope signal

The annual eGFR slope favored oral semaglutide. The estimated between-group difference of 0.40 mL/min/1.73 m² per year had a 95% confidence interval from 0.27 to 0.53 and a P value below 0.0001. Among participants who began with eGFR below 60, the estimated difference was 0.55. It was 0.34 among those starting at or above 60. The interaction P value was 0.15, so the trial did not establish that baseline eGFR changed the treatment effect^[3].

A slower change in a laboratory estimate is not the same finding as fewer cases of kidney failure or less need for dialysis in practice. It may matter over a longer period, but SOUL did not demonstrate that progression from slope to hard kidney benefit in this population. The distinction is central: one continuous marker favored treatment while both event composites remained inconclusive.

Safety and study context

Serious adverse events were reported in 47.9% of participants assigned oral semaglutide and 50.3% assigned placebo. Reported serious kidney adverse-event rates were 1.19 and 1.45 per 100 patient-years, respectively, while acute kidney injury rates were 0.76 and 0.93. These adverse-event observations are useful for this trial population, but they do not prove that kidney harm is impossible for an individual patient^[3].

Novo Nordisk funded SOUL, maintained the clinical database, and performed the statistical analyses. Several authors were employees and shareholders, and many investigators reported industry relationships^[2]. Funding does not invalidate randomization or the reported results. It does make the prespecified endpoints, statistical hierarchy, confidence intervals, and independent replication especially important.

What we don't yet know

SOUL was sized around its cardiovascular outcome rather than kidney events. Once the five-part kidney composite failed in the hierarchical testing sequence, further secondary analyses were exploratory. The study also did not measure urine albumin, which limits assessment of baseline kidney risk and treatment effects on albuminuria. The trial population had mostly preserved eGFR, so this readout should not be treated as a dedicated advanced-CKD trial^[3].

The clean reading is narrow. Oral semaglutide slowed average eGFR decline over about four years in SOUL, but it did not significantly reduce either composite kidney outcome. Readers considering the medicine need an individual review of diabetes, cardiovascular risk, kidney status, and other treatment options with a qualified clinician. Our semaglutide regulation overview covers broader status information, not personal treatment advice.

Medical disclaimer: This article is for educational and journalistic purposes only and does not constitute medical advice. Peptides discussed may be classified as prescription medicines or research chemicals depending on your jurisdiction. Always consult a qualified healthcare professional before using any peptide product. PeptideMethods.com does not sell, distribute, or facilitate the sale of any peptide product.