New data from the landmark FLOW trial, which linked the glucagon peptide 1 (GLP-1) receptor agonist semaglutide with significant kidney outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), suggests that these benefits are consistent whether patients are or are not also treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors.
The results come with the important caveat, however, that the number of patients on SGLT2 inhibitors in the study was very low.
"For now, my conclusion is that the FLOW trial had limited power to test [kidney outcomes] effects among those on SGLT2 inhibitors," senior author Johannes F.E. Mann, MD, a professor of medicine at the KfH Kidney Centre, Munich, and the University of Erlangen-Nuremberg, Germany, told Medscape Medical News.
"No clear differences were found for kidney, cardiovascular, and mortality benefits of semaglutide with or without SGLT2i use, and similar benefits of semaglutide were found for the estimated glomerular filtration rate (eGFR)," he said.
The new analysis was presented this week at the American Diabetes Association (ADA) 84th Scientific Sessions and published concurrently in Nature Medicine.
The FLOW trial, published last month in The New England Journal of Medicine, was the first dedicated kidney outcomes trial to demonstrate that a GLP-1 receptor agonist (in this case, semaglutide 1 mg) had a clear benefit on kidney as well as cardiovascular and survival outcomes in T2D and CKD.
However, one of the most pressing questions the initial study left open was how the use of SGLT2 inhibitors, which is the standard treatment for patients with T2D and CKD, affect those outcomes.
To further investigate that issue, Mann and his colleagues conducted an analysis of the trial, in which patients with T2D and CKD were randomly assigned to treatment with either semaglutide or placebo. The patients were also stratified at baseline according to SGLT2 inhibitor use (n = 550) vs nonuse (n = 2983).
As previously reported by Medscape Medical News, the trial's primary composite outcome of kidney failure, ≥ 50% eGFR reduction, and kidney or cardiovascular death was 24% lower in participants treated with semaglutide vs placebo (18.7% vs 23.2%, respectively; hazard ratio [HR], 0.76; P = .0003), at a mean follow-up of 3.4 years.
For the new analysis, among the participants receiving SGLT2 inhibitors at baseline, 41 of 277 (14.8%) treated with semaglutide experienced the primary composite outcome compared with 38 of 273 (13.9%) who received placebo, with no significant difference between the groups (HR, 1.07; P = .755).
Of those who were not using SGLT2 inhibitors at baseline, 290 of 1490 (19.5%) treated with semaglutide vs 372 of 1493 (24.9%) receiving placebo had the kidney composite outcome (HR, 0.73; P< .001). The difference between the SGLT2 inhibitor–use and –nonuse groups was not significant (P-interaction = .109).
For the rates of change in total eGFR slope, which showed a slower decline in the semaglutide-treated patients, there were again no significant differences between the SGLT2 inhibitor–use and –nonuse groups (0.75 vs 1.25 mL/min/1.73 m2/yr; P-interaction = .237).
Those treated with semaglutide also had significant benefits in terms of major cardiovascular events and all-cause death, with no significant interaction based on SGLT2 inhibitor use (P-interaction =.741 vs .901, respectively).
Regarding the low percentage of patients on SGLT2 inhibitors, Richard E. Pratley, MD, medical director at the AdventHealth Diabetes Institute, Orlando, Florida, and co-chair of the FLOW trial, explained at the meeting that the rates represent the timeframe of the trial.
"The FLOW trial was initiated in 2019, which is when guidelines on SGLT2 inhibitors only began to evolve, so at the time when we enrolled patients, this was still not common practice in our patient population," he said.
Mann noted that more than 80% of patients in the study on SGLT2 inhibitors at baseline remained on the drugs throughout the trial, and by the end of the trial, the percentage of patients on SGLT2 inhibitors had increased to 33%.
Overall, the results show "no consistent evidence of heterogeneity of semaglutide's benefits in participants with T2D/CKD with or without baseline SGLT2 inhibitor use." Mann told Medscape Medical News.
"Given the substantial benefits of both semaglutide and SGLT2 inhibitors, concurrent use may be considered with T2D and CKD," he added.
Staying Tuned
Commenting on the research, Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA and associate professor at Harvard Medical School, agreed that studies with larger cohorts of patients on SGLT2 inhibitors will be needed to better understand kidney outcomes and other effects seen with GLP-1 receptor agonists.
"It's going to be interesting to see [those outcomes] in a larger study that's looking specifically at that question," he told Medscape Medical News.
"This study was really aimed at really understanding whether GLP-1s can be effective in improving kidney disease or in preventing progression," he noted.
"The benefit of a GLP-1 receptor agonist on top of that probably needs another study to really drill a bit deeper on the issue."
Gabbay noted that the uniquely different mechanisms of SGLT2 and GLP-1 drugs suggest the potential for benefits in combination.
As previously reported by Medscape Medical News, results of a major meta-analysis of nearly 73,000 patients support that suggestion, illustrating the various improved cardiovascular and CKD outcomes with the combination of the drugs.
Other new data presented at ADA included adding obstructive sleep apnea to the ever-growing list of apparent GLP-1 benefits; so far, the data bode well for improving treatment for T2D and CKD, said Gabbay.
"I think the that the potential benefits of these classes of drugs are expanding rapidly, and I'm looking forward to seeing more data on all of that," he said.
Mann's disclosures include research support from the European Union, Canadian Institutes of Health Research, AstraZeneca, Bayer, Boehringer Ingelheim, Idorsia, Novo Nordisk, and Sanofi and honoraria from AstraZeneca, Bayer, Hexal, MedUpdate, Novartis, Novo Nordisk, and UpToDate. Gabbay had no disclosures to report.
