Novo Nordisk Stops FLOW Trial Early Due to Renoprotective Benefits of Semaglutide

This week, Novo Nordisk announced the early stop of the FLOW trial, a Phase 3 trial comparing kidney outcomes for injectable semaglutide 1.0 mg vs. placebo in T2D and CKD. The stop was prompted because, “results from an interim analysis met certain pre-specified criteria for stopping the trial early for efficacy.” As a nephrologist, who established his early academic career with a focus on hypertension, I speculate on the mechanisms behind these apparent renoprotective benefits of semaglutide. Improved glycemic control is part of the story, but hardly enough. Weight loss, in part the reason for improved glycemic control, is likewise a possible factor. Given the abundance of GLP-1 receptors throughout the kidney, it is reasonable to suspect that specific renal actions of semaglutide may contribute to its benefits. GLP-1 analogues can inhibit the sodium-proton exchanger located in the proximal tubule, thereby increasing natriuresis. This would reduce blood pressure and hyperfiltration. I previously noted that the blood-pressure lowering effects of GLP-1 analogues are underappreciated. There is also evidence suggesting that GLP-1RA may inhibit mesangial expansion, reduce endothelial expression of profibrotic molecules, increase intraglomerular nitric oxide availability, and reduce free oxygen species, all of which would slow the progression of chronic kidney disease. While awaiting further details from the FLOW trial, it may be worth considering whether the renal benefits of semaglutide will extend to non-diabetic CKD, as has been demonstrated for SGLT-2 inhibitors.