semaglutide: first GLP1 medication proven to protect kidney function

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We know that GLP1 receptor agonists have many health benefits in people with type 2 diabetes, including improvement in blood sugars, weight loss, and reduction in heart attack and stroke risk. We also know that GLP1 medications reduce protein in the urine in people with type 2 diabetes and kidney disease, but no study had ever been done to see whether GLP1 treatment could protect kidney function – until now.

The FLOW study, just published in The New England Journal of Medicine, is the first dedicated kidney outcome trial in people with type 2 diabetes and chronic kidney disease. The study enrolled 3,533 people with chronic kidney disease and type 2 diabetes from 28 countries around the world, and randomized them to receive semaglutide 1.0mg weekly (Ozempic) or placebo.

The average age of particiants was 67, about 70% were male, and most identified as being either white (65%) or Asian (24%). Baseline A1c (diabetes report card) was 7.8%, and baseline body mass index (BMI) was 32 kg/m2. Baseline GFR (kidney function) was 47 ml/min/1.73m2, median urine albumin:creatinine ratio was 568 mg/g (64 mg/mmol), and 23% had a prior heart attack or stroke.

The primary endpoint of the FLOW study was a composite endpoint of persistent ≥50% reduction in GFR, onset of kidney failure, persistent GFR <15, death from kidney failure, or cardiovascular death. At a median follow-up of 3.4 years, the risk of this primary outcome was reduced by 24% with semaglutide 1mg vs placebo. The composite kidney-specific outcome was reduced by 21%, and the mean annual GFR decline was reduced by 1.16 ml/min/1.73m2 with semaglutide. The cardiovascular event rate was reduced by 18%, cardiovascular death was reduced by 29%, and death from any cause was reduced by 20%.

Said another way: Over 3 years, 20 people would need to be treated to prevent one primary kidney outcome, 45 to prevent one cardiovascular event, and 39 to prevent one death.

Side effects were in keeping with what we already know of semaglutide and the GLP1 class, with serious adverse events being lower in the semaglutide group (49.6%) than in the placebo group (53.8%).

The mechanism by which semaglutide protects the kidneys is likely multifactorial, including decreasing inflammation, oxidative stress, and fibrosis (scarring). As SGLT2 inhibitors and nonsteroidal mineralocorticoid recepetor antagonists (MRAs) had not been approved for kidney protection at the time the trial began, only 16% were on SGLT2 inhibitors, and few were on nonsteroidal MRA therapy. There was no clear heterogeneity of effect by SGLT2i use.

BOTTOM LINE: In people with type 2 diabetes and chronic kidney disease, semaglutide provides powerful kidney protection, reduces the risk of cardiovascular events, and saves lives. This study places GLP1 receptor agonist therapy in the camp of foundational therapy for people with chronic kidney disease and type 2 diabetes alongside RAAS blockers, statins, SGLT2 inhibitors, and finerenone.

Disclaimer: I receive honoraria as a continuing medical education speaker and consultant from the maker of semaglutide (Novo Nordisk). I am an investigator in clinical trials of semaglutide.

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