FLOW Trial Fortifies Semaglutide's Role in Chronic Kidney Disease and Type 2 Diabetes

Helen Colhoun, MD
Credit: University of Edinburgh

Use of semaglutide 1.0 mg (Ozempic) not only reduced a composite of kidney outcomes and cardiovascular death by 24%, but full data presented at the European Renal Association (ERA) 2024 congress suggest use of the GLP-1 receptor agonist was also associated with a slower decline in eGFR and a 21% reduction in risk of kidney-specific components of the primary composite endpoint.

The latest landmark trial evaluating use of the GLP-1 receptor agonist from Novo Nordisk, the FLOW trial offers an overview of a potential role for the 1.0 mg dose of semaglutide on renal and cardiovascular endpoints among patients with type 2 diabetes and chronic kidney disease.

“These findings offer great promise in reshaping treatment strategies for individuals at high risk of diabetes-related complications, offering a new avenue for kidney and cardiovascular protection,” said lead investigator Helen M. Colhoun, MD, chair of Medical Informatics and Epidemiology at the University of Edinburgh.

Semaglutide’s meteoric ascent from antihyperglycemic agent to the spotlight has taken the medical community and general public by storm. Stopped early following a prespecified interim analysis concluded the trial could be halted due to overwhelming efficacy, the FLOW trial comes on the heels of several major trials assessing semaglutide in recent years, including the STEP trials, SELECT, STEP HFpEF, and STEP HFpEF DM. Of note, the STEP Program and subsequent SELECT, STEP HFpEF, and STEP HFpEF DM trials examined use of the 2.4 mg dose of semaglutide.

For inclusion in the FLOW trial, patients needed an eGFR of 50 to 75 ml/min/1.73m2 of body-surface area and a urinary albumin-to-creatinine ratio (UACR) of greater than 300 and less than 5000 or an eGFR of 25 to less than 50 ml/min/1.73m2 and a UACR greater than 100 and less than 5000.

The primary outcome of interest for the trial was major kidney disease events, which investigators defined as dialysis, transplantation, an eGFR decline to less than 15 ml/min/1.73m2, a reduction of 50% or greater in eGFR from baseline, or death from kidney-related or cardiovascular causes. Investigators also included a bevy of secondary outcomes of interest, which were tested hierarchically.

In total, 3553 patients were recruited from 387 sites in 28 countries. This cohort had a mean age of 66.6 (SD, 9.0) years, 69.7% were male, 65.8% were non-Hispanic White patients, and the median follow-up time was 3.4 years when the trial was stopped. Among the 3553 patients included in the trial, 1767 were randomized to semaglutide and 1766 were randomized to placebo therapy.

As previously described the prespecified interim analysis revealed use of semaglutide was associated with a 24% relative risk reduction for the trial’s primary outcome of major kidney disease events compared to placebo therapy (Hazard Ratio [HR], 0.76; 95% Confidence Interval [CI], 0.66 to 0.88; P = .0003). Further analysis leveraging kidney-specific components of the primary outcome suggested semaglutide use was associated with a 21% reduction in risk relative to placebo therapy (HR, 0.79; 95% CI, 0.66 to 0.94). Additionally, analysis of death from cardiovascular causes revealed a 29% reduction in risk relative to placebo therapy (HR, 0.71; 95% CI, 0.56 to 0.89).

When assessing secondary outcomes of interest, results demonstrated each of the confirmatory outcomes favored the semaglutide arm of the trial, including a slower decline of eGFR (difference, 1.16 ml/min/1.73m2; P <.001), reduced risk of major cardiovascular events (HR, 0.82; 95% CI, 0.68 to 0.98; P = .029), and all-cause mortality (HR, 0.80; 95% CI, 0.67 to 0.95; P = .01). In safety analyses, results suggested the adverse events were reported in a lower percentage of participants in the semaglutide group than among the placebo group (49.6% vs 53.8%).

“The use of semaglutide in people with type 2 diabetes and chronic kidney disease can lower the risk of major kidney outcomes and reduce the risk of cardiovascular events, cardiovascular death and all-cause death," Colhoun added. "These benefits signify a profound clinical impact saving kidneys, hearts and lives, for patients with type 2 diabetes and chronic kidney disease. Additionally, the reassuring safety findings further support the strong potential value of semaglutide in this population.”