Going With The FLOW?Thursday, October 12, 2023
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 cannot help but speculate on the mechanisms behind these apparent renoprotective benefits of semaglutide.
Obviously, 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.
But clearly, given the abundance of GLP-1 receptors throughout the kidney, it is only reasonable to suspect that specific renal actions of semaglutide may contribute to its benefits.
For one, GLP-1 analogues can inhibit the sodium-proton exchanger located in the proximal tubule, thereby increasing natriuresis. Increased sodium reaching the macula densa would in turn suppress overactivation of the renin–angiotensin–aldosterone by restoring tubulo-glomerular feedback. The combined result of these effects would not only reduce blood pressure but also reduce hyperfiltration.
I have previously noted that the blood-pressure lowering effects of GLP-1 analogues are currently largely underappreciated.
There is also some evidence suggesting that GLP-1RA may inhibit mesangial expansion, reduce the endothelial expression of profibrotic molecules, increases the availability of intraglomerular nitric oxide, and reduce the release of free oxygen species, all of which would be expected to slow the progression of chronic kidney disease.
While we wait for further details from the FLOW trial, it may be in order to speculate whether or not the renal benefits of semaglutide will extend to non-diabetic CKD, as has been demonstrated for SGLT-2 inhibitors.