FLOW: How Semaglutide Became the First GLP-1 Approved for Diabetic Kidney Disease

On January 28, 2025, the FDA approved Ozempic (semaglutide 1.0 mg) to reduce the risk of kidney disease worsening, kidney failure, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease [3]. It was the first time any GLP-1 receptor agonist had received an FDA-approved kidney indication. The approval was based on the FLOW trial (Perkovic et al., NEJM 2024) [1], a 3,533-patient randomized outcomes trial that was stopped early in October 2023 because the prespecified interim analysis showed semaglutide had crossed the efficacy boundary on the primary kidney composite. This article walks through the FLOW design, the verified primary and secondary results, the FDA approval language, and how semaglutide's kidney protection compares with the established SGLT2 inhibitor evidence in the same population.

Why a kidney trial for a diabetes drug

Diabetic kidney disease is the leading cause of end-stage renal disease in the United States. Roughly 40% of patients with type 2 diabetes will develop chronic kidney disease in their lifetime, and a meaningful fraction will progress to dialysis or transplant. Until the SGLT2 inhibitor era began with the CREDENCE trial in 2019, the only proven kidney protection in diabetic CKD was tight glycemic and blood pressure control plus renin-angiotensin system blockade — useful but incomplete.

Cardiovascular outcomes trials of GLP-1 receptor agonists (LEADER for liraglutide [7], SUSTAIN-6 for semaglutide, REWIND for dulaglutide) had hinted at kidney benefit in prespecified secondary kidney composites, but no GLP-1 trial had ever been designed with a primary kidney outcome — until FLOW.

FLOW trial design

FLOW (NCT03819153) was a phase 3, double-blind, randomized, placebo-controlled outcomes trial conducted at 387 sites across 28 countries [1, 2]. The protocol and rationale were prespecified in 2023 [2]. Key design parameters:

• Randomization: 1,767 to semaglutide and 1,766 to placebo (1:1) for a total of 3,533 patients
• Population: Adults with type 2 diabetes and CKD, defined as either eGFR 50-75 mL/min/1.73m² with urinary albumin-to-creatinine ratio (UACR) 300-5,000 mg/g, OR eGFR 25 to less than 50 mL/min/1.73m² with UACR 100-5,000 mg/g
• Drug: Semaglutide 1.0 mg subcutaneously once weekly (the maintenance dose used in SUSTAIN-6 and the standard Ozempic diabetes dose), titrated over 8 weeks from 0.25 mg
• Background therapy: All patients on maximum-tolerated ACE inhibitor or ARB
• Median follow-up: 3.4 years (event-driven; stopped early at the prespecified interim analysis)
• Primary composite endpoint: Major kidney disease events, defined as kidney failure (persistent eGFR less than 15 mL/min/1.73m² or initiation of chronic kidney replacement therapy), sustained ≥50% reduction in eGFR from baseline, kidney death, or cardiovascular death

The early-stopping decision was made by the independent data monitoring committee in October 2023 after 741 of the 854 planned primary events had accrued, on the basis that the prespecified efficacy boundary had been crossed [1]. Mean baseline characteristics: age 66.6 years, 67% male, baseline eGFR 47.0 mL/min/1.73m², HbA1c 7.8%, BMI 32 kg/m².

The primary result

FLOW hit its primary composite endpoint with a clear and clinically meaningful reduction [1]:

The 24% relative risk reduction in major kidney events translates to an absolute risk reduction of about 4.9 percentage points over 3.4 years and a number needed to treat (NNT) of approximately 18 patients treated for 3.4 years to prevent one primary endpoint event. The accompanying 20% all-cause mortality reduction is striking — relatively few kidney trials have shown a clean all-cause mortality benefit, and the NNT for mortality of approximately 39 over the trial duration is clinically important.

The eGFR slope difference of 1.16 mL/min/1.73m² per year is the most mechanistically informative number in the table. That difference, sustained over a decade, is roughly the difference between progressing to dialysis and not — and the slope benefit appeared early in the trial and was maintained throughout follow-up.

Adverse events: what FLOW did and did not find

The headline safety finding from FLOW is that there was no signal of acute kidney injury from semaglutide despite the well-known GI side-effect profile of the drug class. Reported AKI rates were 9.7% in the semaglutide arm and 10.3% in the placebo arm [1]. This matters because the theoretical concern with starting a GLP-1 agonist in CKD patients is that nausea-induced volume depletion could precipitate prerenal AKI; FLOW saw no such signal at trial scale.

Permanent treatment discontinuation due to adverse events was 13% in the semaglutide arm versus 11.3% in placebo, with a 4.5% versus 1.1% gap attributable to GI symptoms — consistent with the broader semaglutide GI side-effect profile documented in the STEP and SUSTAIN trials [1]. For the broader GI tolerability picture, see our GLP-1 side effects investigation.

Diabetic retinopathy was a known concern from SUSTAIN-6, which had reported a transient retinopathy worsening signal with rapid HbA1c improvement on semaglutide. FLOW required baseline ophthalmologic screening and excluded patients with active proliferative retinopathy. The published primary manuscript focuses on the kidney composite; a more detailed retinopathy analysis specific to FLOW participants was not yet available at the time of this writing.

The FDA approval

Novo Nordisk submitted a supplemental new drug application for the kidney indication after the FLOW results were unblinded. The FDA approved the new indication on January 28, 2025 [3]. The approved indication language reads: to reduce the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes mellitus and chronic kidney disease.

Two practical points about the approval. First, it applies specifically to Ozempic (semaglutide 1.0 mg) — the diabetes-dose product, not the higher-dose Wegovy (semaglutide 2.4 mg) used for chronic weight management. Second, it applies only to patients who already have type 2 diabetes; FLOW did not enroll non-diabetic CKD patients, and the FDA approval reflects that.

How FLOW compares to the SGLT2 inhibitor kidney trials

Three large SGLT2 inhibitor trials established the modern baseline for kidney protection in CKD before FLOW:

Two interpretive points are worth being careful about. First, the SGLT2 trials and FLOW enrolled different populations (CREDENCE most similar to FLOW; DAPA-CKD and EMPA-KIDNEY broader) with different endpoint definitions and follow-up durations, so the hazard ratios are not strictly comparable. Second, the confidence intervals overlap meaningfully; the SGLT2 inhibitors as a class appear modestly more potent on the renal composite, but the SGLT2 and GLP-1 mechanisms are independent and the most likely future use is combination therapy in the patients who tolerate both. Several ongoing trials are directly testing GLP-1 + SGLT2 inhibitor combinations for additive kidney protection.

Open questions

1. Non-diabetic CKD. FLOW enrolled only patients with type 2 diabetes. Whether semaglutide's kidney protection extends to non-diabetic CKD is unknown. A 24-week proof-of-concept trial (Apperloo et al., Nature Medicine 2024 [8]) reported albuminuria reduction in non-diabetic CKD patients with obesity, but this is a surrogate endpoint study, not an outcomes trial. A dedicated outcomes trial in non-diabetic CKD has not yet been launched as of this writing.
2. Mechanism. The kidney benefit cannot be fully explained by glycemic improvement or weight loss alone — the eGFR slope separation appeared early and was larger than HbA1c-matched comparisons would predict. The mechanism is likely multifactorial, including reduced glomerular hyperfiltration, anti-inflammatory effects, and direct effects on tubular handling of sodium. Mechanistic substudies are ongoing.
3. Combination with SGLT2 inhibitors. Most FLOW participants were not on background SGLT2 inhibitor therapy when the trial began (SGLT2 use grew during the trial as guidelines evolved). The additive benefit of GLP-1 + SGLT2 + RAS blockade is the most clinically important open question for the next decade of diabetic CKD care.
4. Wegovy-dose data. FLOW used the 1.0 mg dose. Whether the higher Wegovy 2.4 mg dose provides additional kidney protection — or worsens tolerability enough to negate the benefit — has not been studied in a dedicated outcomes trial.

What this means for patients

For adults with type 2 diabetes and chronic kidney disease — particularly those with albuminuria and eGFR in the 25-75 range — semaglutide is now an evidence-based, FDA-approved option for slowing kidney disease progression and reducing cardiovascular and all-cause mortality. The most likely best-practice regimen, supported by the FLOW and SGLT2 trials together, is a combination of an ACE inhibitor or ARB, an SGLT2 inhibitor, and a GLP-1 receptor agonist (semaglutide), individualized to tolerability and kidney function.

For adults with chronic kidney disease who do not have diabetes, FLOW does not provide direct evidence. Until a dedicated non-diabetic CKD outcomes trial is run and published, off-label use of semaglutide for kidney protection in this population should be discussed carefully with a nephrologist.

Related research

For the broader cardiovascular outcomes data on semaglutide in non-diabetic adults, see our SELECT trial deep-dive. For the GI side-effect profile that drove the small FLOW discontinuation gap, see our side effects investigation. For the difference between semaglutide doses (Ozempic 1.0 mg vs Wegovy 2.4 mg), see our Wegovy vs compounded vial comparison. And for the head-to-head comparison with tirzepatide, see our tirzepatide vs semaglutide deep-dive.