FLOW Trial: Semaglutide Reduced Major Kidney Disease Events by 24%

The first dedicated kidney outcomes trial for any GLP-1 drug was stopped early because the drug worked too well. Here's every number that matters from the 3,533-patient trial — and what it means for the 37 million Americans with chronic kidney disease.

On May 24, 2024, the New England Journal of Medicine published results from FLOW — the first randomized controlled trial ever designed to test whether a GLP-1 receptor agonist could protect the kidneys. The answer was unambiguous. Semaglutide reduced the composite primary endpoint of major kidney events and cardiovascular death by 24%, and the trial's independent data monitoring committee recommended stopping the study early because continued randomization to placebo was no longer ethical.

This was not a secondary analysis bolted onto an obesity trial. FLOW was built from the ground up as a kidney trial, enrolling patients specifically because they had type 2 diabetes and chronic kidney disease. The result lands semaglutide alongside SGLT2 inhibitors and finerenone as a foundational therapy for diabetic kidney disease — and raises the question of whether GLP-1 drugs may eventually be tested in kidney disease patients without diabetes.

Trial Design: What FLOW Actually Tested

FLOW (NCT03819153) was a double-blind, randomized, placebo-controlled trial sponsored by Novo Nordisk. It enrolled 3,533 adults with type 2 diabetes and chronic kidney disease across 387 sites in 28 countries. Participants were randomized 1:1 to receive either injectable semaglutide 1.0 mg once weekly or placebo, on top of standard-of-care therapy (which could include SGLT2 inhibitors, ACE inhibitors, or ARBs).

Median follow-up was 3.4 years before the trial was stopped early based on the interim analysis. The primary endpoint was a composite of kidney failure (dialysis, transplantation, or eGFR below 15), at least a 50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes.

Primary and Secondary Results

The kidney function preservation was measurable directly in eGFR slopes. The mean annual decline in eGFR was 1.16 ml/min/1.73m² slower in the semaglutide group. The drug also reduced urine albumin-to-creatinine ratio (UACR) by 38%, reduced HbA1c by 0.81%, lowered body weight by 4.1 kg, and dropped systolic blood pressure by 2.23 mmHg. Importantly, there was a characteristic initial dip in eGFR (a hemodynamic effect seen with other kidney-protective drugs) followed by a clear U-shaped rebound and sustained preservation.

Safety Profile

Serious adverse events were actually less common in the semaglutide group (49.6%) than in the placebo group (53.8%). The most common adverse events were gastrointestinal — nausea, vomiting, diarrhea — consistent with the known GLP-1 side effect profile. No new safety signals emerged in this CKD population, which is notable given that kidney impairment can alter drug clearance and amplify side effects for many medications.

Why FLOW Matters Beyond the Numbers

Before FLOW, the evidence for GLP-1 kidney protection came from secondary analyses of cardiovascular and obesity trials. The SELECT trial showed a prespecified composite kidney outcome was lower with semaglutide 2.4 mg (HR 0.78, 95% CI 0.63–0.96), but that trial enrolled patients based on cardiovascular risk, not kidney disease. FLOW is the first trial where kidney outcomes were the primary reason the study existed.

The trial also demonstrated that semaglutide's kidney benefit is additive to existing therapies. Patients were already receiving standard care including renin-angiotensin system blockade and, in many cases, SGLT2 inhibitors. Semaglutide reduced kidney events on top of those treatments.

The Clinical Implications

FLOW positions semaglutide as a potential third pillar of kidney protection alongside SGLT2 inhibitors and finerenone for patients with diabetic kidney disease. Approximately 40% of people with type 2 diabetes develop chronic kidney disease, and CKD affects an estimated 37 million Americans overall. For nephrologists, the result opens a new therapeutic class in a field that has historically had limited options to slow disease progression.

The trial registration is NCT03819153 on ClinicalTrials.gov. The primary publication appeared in NEJM on May 24, 2024. Additional analyses were presented at the ADA 84th Scientific Sessions in June 2024 and published in Nature Medicine.