Semaglutide was associated with significant reductions in worsening of kidney disease, cardiovascular events, and all-cause death compared to placebo for adults with type 2 diabetes (T2D) and chronic kidney disease (CKD) regardless of concomitant use of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), according to findings from the landmark FLOW clinical trial.¹

The new data from the first dedicated kidney outcomes trial with a glucagon-like peptide-1 receptor agonist (GLP-1RA) was presented at the American Diabetes Association’s (ADA) 84th Scientific Sessions, June 21-24, in Orlando, Florida, and simultaneously published in Nature Medicine.¹

CKD is common in adults with T2D, and GLP-1RAs and SGLT-2is have both been shown to reduce CV and kidney events. The effect of combining the 2 classes of medications, however, is unclear. In the new data from the FLOW trial, researchers analyzed the impact of semaglutide for trial participants who did and who did not receive SGLT-2is at baseline.¹

Launched in 2019, the FLOW clinical trial was a global randomized, double-blind, parallel-group, placebo-controlled, superiority trial comparing the safety and efficacy of once weekly injectable semaglutide 1.0 mg against placebo as an adjunct to standard of care on kidney outcomes in a cohort of 3533 individuals with T2D and CKD.

In March 2024, topline results were announced by the manufacturer, Novo Nordisk, which showed semaglutide reduced the risk of kidney disease progression and cardiovascular-and renal-related death by 24% compared with placebo in patients with T2D and CKD. Then in May 2024, a full readout of the data was presented at the 61st European Renal Association Congress in Stockholm, Sweden. Results showed that participants who received semaglutide experienced a reduction in progression of CKD as well as a 21% reduction in risk of renal-specific components of the primary composite outcome. Moreover, investigators reported an 18% lower risk of major adverse cardiovascular events in semaglutide-treated participants and a reduced risk of death from any cause of 20% vs placebo.

For the new analysis, researchers stratified participants by concomitant SGLT-2i use. Median follow up was 3.4 years. The primary outcome was a composite of kidney failure, at least 50% reduction in estimated glomerular filtration rate (eGFR), and kidney or CV death, according to the study abstract.¹

Findings

Among the 550 participants who received SGLT-2is at baseline, the primary outcome occurred in 14.4% of those in the semaglutide group compared to 13.9% of those in the placebo group (HR 1.07, 95% CI 0.69-1.67). Among the 2983 participants who did not receive SGLT-2is at baseline, the primary outcome occurred in 22.2% of those in the semaglutide arm and 24.9% of those in the placebo arm (HR 0.73, 95% CI 0.63-0.85; P < .001; P for interaction = .109), investigators reported.¹

Also, among participants in the SGLT-2i group, semaglutide was associated with decreased rate of declining eGFR compared with placebo, with a difference of 0.75 mL/min/1.73 m2 per year (95% CI –0.01 to 1.5). Researchers noted that this association was similar for participants in the non-SGLT-2i group, with a difference of 1.25 mL/min/1.73 m2 per year (95% CI 0.91-1.58; P for interaction = .237).¹

The benefits of semaglutide on major cardiovascular events and all-cause death were similar regardless of SGLT-2i use (P for interaction = .741 and .901, respectively). Moreover, the benefits of semaglutide in reducing kidney outcomes were consistent in participants with and without SGLT-2i use at baseline, according to the abstract.¹

“This is a patient population at high-risk of severe kidney outcomes. Despite existing treatment options, there is still a clear unmet need for this group,” presenting author Richard E. Pratley, MD, medical director of AdventHealth Diabetes Institute in Orlando, Florida, said in an ADA press release. “The findings from the FLOW trial have the potential to change the disease course of these high-risk patients and pave the way for new treatment strategies, offering hope to millions of patients globally.”²

Pratley and colleagues noted that new research will be conducted in 2024 and 2025 to assess clinically relevant areas to help address the unmet needs of patients with T2D and CKD, according to the ADA press release.²

References:

Pratley RE, Mann JFE, Rossing P, et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med. Published online June 24, 2024. doi:10.1038/s41591-024-03133-0

Semaglutide reduced risk for major kidney disease events by 24% for patients with type 2 diabetes and kidney disease. News item. American Diabetes Association. June 24, 2024. Accessed June 25, 2024. https://diabetes.org/newsroom/press-releases/semaglutide-reduced-risk-major-kidney-disease-events-24-patients-type-2