Key takeaways:
Semaglutide benefits were observed for adults with type 2 diabetes and chronic kidney disease whether or not they used SGLT2 inhibitors.
The FLOW trial was not powered to observe effects for those on SGLT2s.
ORLANDO — Semaglutide use was associated with significant reductions in worsening of kidney disease, cardiovascular events and all-cause death vs. placebo for adults with type 2 diabetes regardless of concomitant use of SGLT2 inhibitors.

GLP-1 receptor agonists and SGLT2 inhibitors both reduce CV and kidney events. In new data from the FLOW trial presented at the American Diabetes Association Scientific Sessions, Johannes F. E. Mann, MD, director of the KfH Kidney Center in Munich, presented analysis of semaglutide (Ozempic, Novo Nordisk) effects for trial participants who did and who did not take SGLT2 inhibitors at baseline.

Johannes F. E. Mann
Johannes F. E. Mann, MD, discusses new data from the FLOW trial at the American Diabetes Association Scientific Sessions.
As Healio previously reported, top-line data from the FLOW trial, published in The New England Journal of Medicine in May, showed adults with type 2 diabetes and chronic kidney disease treated with semaglutide had significantly reduced risks for major kidney disease events, CV outcomes and all-cause mortality vs. placebo. During a median follow-up of 3.4 years, semaglutide was associated with a 24% reduction in the composite kidney endpoint, an 18% reduction in major adverse CV outcomes and a 20% reduction in all-cause death. Semaglutide was well tolerated with fewer serious adverse events than in the placebo group. The most common adverse events were gastrointestinal.

The new analysis of outcomes broken out by concomitant SGLT2 inhibitor use was simultaneously published in Nature Medicine.

FLOW, the first dedicated kidney outcomes trial with a GLP-1 receptor agonist, started in 2019 with more than 400 investigator sites in 28 countries.

In the trial, researchers randomly assigned 3,533 adults with type 2 diabetes who were prescribed a stable dose of renin-angiotensin system inhibitors, 1:1, to weekly 1 mg semaglutide injection or placebo. The primary outcome was a composite of kidney failure, at least 50% reduction in estimated glomerular filtration rate and kidney or CV death.

Richard E. Pratley
“About 15% of people [enrolled in the trial] were on SGLT2 inhibitors at the time, because that was about the time that we were getting results from the SGLT2 trials, and the guidelines were changing,” Richard E. Pratley, MD, the Samuel E. Crockett Chair in Diabetes Research, medical director of AdventHealth Diabetes Institute and a Healio | Endocrine Today Co-editor, said during a press briefing about the findings. “So, it wasn’t yet standard of care, and access to SGLT2 inhibitors was still limited. … We asked whether or not that made any difference in outcomes.”

Among participants taking SGLT2 inhibitors at baseline, the primary outcome occurred in 14.4% of the semaglutide group vs. 13.9% of the placebo group, which was not statistically significant (HR = 1.07; 95% CI, 0.69-1.67). Among participants not taking SGLT2 inhibitors at baseline, the primary outcome occurred in 22.2% of the semaglutide group and 24.9% of the placebo group, which was significant (HR = 0.73; 95% CI, 0.63-0.85; P < .001; P for interaction = .109).

“So, does that mean that [semaglutide] doesn’t work on top of an SGLT inhibitor?” Pratley said. “I don’t think we can conclude that with the small number of patients, and we have other evidence to suggest that the two are useful in combination.”

At 2 years, in the SGLT2 group, semaglutide was associated with decreased rate of declining eGFR compared with placebo whether calculated by serum creatinine or by cystatin C, with a difference of 0.75 mL/min/1.73 m2 per year (95% CI, –0.01 to 1.5). This association was similar for participants not taking an SGLT2 inhibitor, with a difference of 1.25 mL/min/1.73 m2 per year (95% CI, 0.91-1.58; P for interaction = .237).

For participants taking SGLT2 inhibitors, there were nonsignificant reductions in CV endpoints and all-cause death for the semaglutide vs. placebo groups (P for interaction = .741 and .901, respectively).

“FLOW had limited power to test effects in those on SGLT2 inhibitors. No heterogeneity in benefits of semaglutide were found for kidney, CV and mortality outcomes,” Mann said during the presentation. “Given the substantial benefits of semaglutide and SGLT2 inhibitors, concurrent use may be considered in type 2 diabetes with chronic kidney disease.”

References:
Mann JFE, et al. Nat Med. 2024;doi:10.1038/s41591-024-03133-0.
Perkovic V, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2403347.