Weekly semaglutide cut major kidney disease events 24% in FLOW trial, NEJM reports

The New England Journal of Medicine published the results of the FLOW trial on May 24, 2024, showing that weekly semaglutide injections lowered the risk of major kidney disease events by 24% in adults who had both type 2 diabetes and chronic kidney disease ^[1].

FLOW enrolled 3,533 people, randomly assigning 1,767 to semaglutide 1.0 mg injected under the skin once a week and 1,766 to a placebo ^[1]. Median follow-up was 3.4 years, shortened after a prespecified interim analysis recommended stopping the trial early ^[1]. To qualify, participants had to meet one of two kidney-related criteria: an estimated glomerular filtration rate (eGFR) of 50 to 75 ml per minute per 1.73 m2 of body-surface area with a urine albumin-to-creatinine ratio above 300, or an eGFR of 25 to under 50 with an albumin-to-creatinine ratio above 100 ^[1].

The primary outcome was a composite of kidney failure (dialysis, transplantation, or an eGFR below 15), at least a 50% drop in eGFR from the starting level, or death from kidney-related or cardiovascular causes ^[1]. That composite occurred 331 times in the semaglutide group and 410 times in the placebo group, a hazard ratio of 0.76 (95% CI, 0.66 to 0.88; P = 0.0003) ^[1].

Confirmatory secondary outcomes also favored semaglutide ^[1]:

• Death from cardiovascular causes was 29% lower (hazard ratio, 0.71; 95% CI, 0.56 to 0.89) ^[1].
• The composite of the kidney-specific components of the primary outcome had a hazard ratio of 0.79 (95% CI, 0.66 to 0.94) ^[1].
• Kidney function declined more slowly. The mean annual eGFR slope was less steep by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001) ^[1].
• Major cardiovascular events were 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029) ^[1].
• Death from any cause was 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) ^[1].

Serious adverse events were reported in 49.6% of participants taking semaglutide and 53.8% of those taking placebo ^[1]. Novo Nordisk, which markets semaglutide as Ozempic, Wegovy and Rybelsus, funded the trial, registered as NCT03819153 ^[1][4].

Why it matters for patients

Chronic kidney disease is common alongside type 2 diabetes; in the general type 2 diabetes population, roughly 25% to 40% of people have it ^[3]. The FLOW results are the basis for a label change. On January 28, 2025, the FDA approved Ozempic injection to reduce the risk of sustained eGFR decline, end-stage kidney disease and cardiovascular death in adults with type 2 diabetes and chronic kidney disease ^[4]. Ozempic injection was already approved to improve blood sugar and to reduce the risk of major cardiovascular events in adults with type 2 diabetes and established cardiovascular disease ^[4].

The kidney finding has not been shown for oral semaglutide. In the SOUL trial, oral semaglutide (up to 14 mg daily, sold as Rybelsus) reduced major cardiovascular events by 14% in people with type 2 diabetes at high cardiovascular risk, but major kidney disease events did not differ between the oral semaglutide and placebo groups, and testing of secondary outcomes stopped there ^[3]. FLOW and SOUL enrolled different populations and used different primary outcomes, so the two sets of results should not be compared directly, and the SOUL authors offered possible explanations including higher eGFR in SOUL, lower bioavailability of the oral form, or chance ^[3].

FLOW enrolled only people who already had both type 2 diabetes and chronic kidney disease, so whether semaglutide protects the kidneys in people without diabetes has not been established by this trial ^[1].

What happens next

Additional analyses from FLOW continue to be published, including a report on heart failure outcomes in diabetes and chronic kidney disease that appeared in the Journal of the American College of Cardiology in October 2024 ^[1]. Whether the kidney benefit extends to other GLP-1 medications or to oral semaglutide at other doses has not been reported.