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An analysis of the SOUL trial, the largest trial to date of oral semaglutide vs placebo, showed nonsignificant trends of kidney-related effects in contrast to the striking benefits observed with the injectable version of the drug seen in previous trials.

However, clearer benefits with the oral formulation may be masked by key trial limitations, said first author Johannes Mann, MD, of the KfH Kidney Center, in Munich, Germany, and the Friedrich Alexander University of Erlangen, Erlangen, Germany, who presented the findings at 62nd European Renal Association (ERA) Congress 2025.

The SOUL trial was primarily a cardiovascular outcomes trial, so albuminuria was not measured, and, overall, “we had a group of patients with a low kidney risk,” according to estimated glomerular filtration rates (eGFR), Mann explained. But we did see positive trends for kidney health associated with oral semaglutide, he added.

In the trial, 9650 patients with type 2 diabetes, atherosclerotic cardiovascular (CV) disease and/or chronic kidney disease were randomized 1:1 to treatment either with daily oral semaglutide 14 mg or placebo.

Of note, all patients also received standard of care medications, with 78.9% reporting baseline use of renin-angiotensin-aldosterone system blockers and 26.9% using SGLT2 inhibitors.

The study’s primary outcome focused on major adverse CV events, and with a median follow-up of 47.5 months, those treated with oral semaglutide had a significant 14% reduction in a composite of the CV outcomes compared with those treated with placebo (P = .006).

The drug’s effects on kidneys were evaluated as confirmatory secondary outcomes, with a 5-component composite outcome of major kidney disease events, which included a 50% or greater reduction in eGFR from baseline, persistent eGFR < 15 mL/min/1.73 m², initiation of chronic kidney replacement therapy, or death from kidney-related or CV causes.

For the composite outcome, an event occurred in 8.4% of patients receiving oral semaglutide and 9.0% of those receiving placebo, which was not a significant difference (hazard ratio [HR], 0.91; P = .19).

The analysis of a separate four-component, kidney-specific composite outcome that excluded the component of death from CV causes showed differences that were still not significant, with the four-component composite outcome occurring in 2.3% of the oral semaglutide group vs 2.7% of the placebo group (HR, 0.86; P = .23).

Higher Risk Subgroup Outcomes?

Importantly, patients in the SOUL trial overall had a mean baseline eGFR of 73.8 mL/min/1.73 m², reflecting relatively mild kidney impairment.

However, 29.2% of patients had more serious kidney disease, with an eGFR < 60 mL/min/1.73 m², indicative of moderate to severe kidney impairment.

Among those higher-risk patients, the main five-component kidney outcome occurred in 185 patients (13.2%) compared with 214 (15.2%) in the oral semaglutide and placebo groups, respectively, which, though still not significant, did suggest a notable trend of improvement with oral semaglutide (HR, 0.84; 95% CI, 0.69-1.02; P = .08).

For the four-point kidney specific outcomes among patients with impaired kidney function, rates of events were predictably higher and slightly more separated, occurring in 5.1% and 6.2% participants, respectively, however, also not significantly different (HR, 0.80; P = .16).

In looking at outcomes of specific components of the composites, the analysis showed that those treated with oral semaglutide generally had trends for greater improvement, including a lower mean annual decrease in eGFR vs placebo, with a -1.67 mL/min/1.73 m² reduction vs -2.06 mL/min/1.73 m² per year, for an estimated treatment difference of 0.40.

And fewer patients treated with oral semaglutide had an indication of kidney failure (eGFR < 15mL/min/1.73 m²) than those treated with placebo (HR, 0.69).

The oral semaglutide group further had a notable but nonsignificant difference in having a ≥ 50% reduction in eGFR (HR, 0.81) and a lower need for chronic kidney replacement therapy (HR, 0.82) than placebo.

In terms of safety, those treated with oral semaglutide had slightly fewer serious adverse events than those treated with placebo (47.9% vs 50.3%).

Comparisons With Injectable Semaglutide in FLOW Trial

Kidney benefits reported with the use of injectable semaglutide, administered once weekly, in the landmark FLOW trial, as reported by Medscape Medical News, were much more significant.

In that study, the relative risk reduction in the primary composite outcome, which included dialysis, transplantation, or an eGFR < 15 mL/min/1.73 m², along with at least a 50% reduction in the eGFR from baseline, or death from kidney-related or CV causes, was indeed significant, with a HR of 0.76 (P = .0003).

Importantly, the mean baseline eGFR in the FLOW trial was much lower than that in the SOUL trial (47.0 mL/min/1.73 m² vs 73.8 mL/min/1.73 m²).

And the data on patients’ median urinary albumin-to-creatinine ratio was not reported for the simple reason of cost, Mann explained.

“When you have more than 9000 patients, getting the samples, [etc.], amounts to a tremendous amount of money,” he said.

Results ‘Reassuring’ for Oral Semaglutide

Commenting on the study, Ronald T. Gansevoort, MD, PhD, a professor of medicine and nephrologist at the UMC Groningen, Groningen, the Netherlands, said the findings provide important insights on oral semaglutide, with the lack of albuminuria representing a notable limitation.

“The severity of chronic kidney disease as well as the speed of disease progression is normally assessed by eGFR and albuminuria,” he told Medscape Medical News.

“That in this cardiovascular outcome trial albuminuria was not measured is therefore a pity from a renal point of view,” Gansevoort said.

“Notwithstanding, the data obtained are reassuring,” he added.

“They also show that in the future, in all cardiovascular outcome trials, not only eGFR, but also albuminuria should be measured. Such information will give the public, and guidelines, important information.”

The SOUL and FLOW trials were each funded by Novo Nordisk. Mann’s disclosures include relationships with Novo Nordisk, AstraZeneca, Bayer, Boehringer, Hexal, and Sanofi. Gansevoort had no disclosures to report relating to the analysis.

Nancy A. Melville is a Maine-based medical and science journalist with more than 25 years of writing experience in specialties including endocrinology, oncology, hematology, psychiatry, and neurology.