FLOW Trial: Semaglutide for Diabetic Kidney Disease

Trial design

FLOW (NCT03819153) was a randomized, double-blind, placebo-controlled trial conducted at 387 sites across 28 countries. Eligible participants were adults aged 18 or older with type 2 diabetes and chronic kidney disease defined as eGFR 50-75 mL/min/1.73m² with urine albumin-to-creatinine ratio (UACR) >300 mg/g, or eGFR 25-50 mL/min/1.73m² with UACR >100 mg/g. Participants were on stable doses of ACE inhibitors or angiotensin receptor blockers.

Randomization was 1:1 to semaglutide 1.0 mg weekly (the diabetes-indicated maximum dose, not the higher 2.4 mg obesity dose) or matching placebo. The trial was stopped early in October 2023 after interim analysis showed efficacy. Median follow-up was 3.4 years.

Primary outcome

The primary composite endpoint of major kidney disease events (≥50% reduction in eGFR, kidney failure requiring renal replacement therapy, or kidney-cause death), cardiovascular death, or all-cause death occurred in 18.7% of semaglutide-treated participants versus 23.2% with placebo. Hazard ratio 0.76 (95% CI 0.66-0.88; P=0.0003)¹.

Component endpoints favored semaglutide consistently: major kidney disease events HR 0.79, cardiovascular death HR 0.71, all-cause death HR 0.80. The number needed to treat over 3.4 years was approximately 22.

eGFR slope

Semaglutide preserved kidney function as measured by total eGFR slope. The annualized rate of eGFR decline was 2.2 mL/min/1.73m² with semaglutide versus 3.4 mL/min/1.73m² with placebo — a 1.2 mL/min/1.73m² annual difference. Over 5 years, this magnitude of slope preservation translates to an approximately 6 mL/min/1.73m² greater eGFR — clinically meaningful in patients close to dialysis thresholds.

The chronic eGFR slope (after the initial 16-week period during which semaglutide may produce a transient eGFR decrease similar to ACE inhibitors and SGLT2 inhibitors) showed an even more favorable separation.

Albuminuria

Mean change in urine albumin-to-creatinine ratio from baseline was -40% with semaglutide versus -3% with placebo — a substantial difference. Patients with macroalbuminuria (UACR >300 mg/g) at baseline showed the greatest absolute albuminuria reduction.

Albuminuria reduction is a validated surrogate for renal protection in CKD trials. The magnitude observed in FLOW is comparable to that achieved with high-dose ACE inhibitors and SGLT2 inhibitors, suggesting that semaglutide's renal benefit may be partly mediated through hemodynamic/glomerular pressure effects similar to those agents.

Mechanism of renal protection

Multiple mechanisms likely contribute to semaglutide's renal benefit. Weight loss (mean 5.4 kg in FLOW versus 0.4 kg placebo) reduces hyperfiltration. Improved glycemic control (HbA1c reduction 0.8% vs 0.2%) reduces glucotoxic kidney damage. Blood pressure reduction (3.7 mm Hg systolic) reduces glomerular pressure. Direct anti-inflammatory effects on renal tubular cells may contribute².

GLP-1 receptor expression in the kidney is present in glomerular endothelial cells, vascular smooth muscle, and proximal tubules. Activation appears to produce natriuretic, anti-inflammatory, and antifibrotic effects independent of weight or glycemic effects.

Implications and label update

Following FLOW results, the FDA approved a label expansion for Ozempic in January 2025 to include reduction in the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. This places semaglutide alongside SGLT2 inhibitors (empagliflozin per EMPA-KIDNEY, dapagliflozin per DAPA-CKD) as a renal-protective therapy.

Combined use of semaglutide and SGLT2 inhibitors in patients with both indications is supported by mechanism and by retrospective data; prospective trials of the combination are ongoing³.

Related editorial coverage

• SELECT trial: semaglutide CV outcomes in obesity
• Semaglutide peptide profile

Frequently asked questions

Does semaglutide protect the kidneys?

Yes, in patients with type 2 diabetes and chronic kidney disease. The FLOW trial showed a 24% reduction in major kidney disease events, cardiovascular death, or all-cause death with semaglutide 1.0 mg weekly versus placebo¹. The FDA approved a renal protection indication for Ozempic in January 2025.

Should I use semaglutide if I have CKD without diabetes?

FLOW enrolled only T2D patients. Whether semaglutide protects kidneys in non-diabetic CKD is not established. Patients with obesity and non-diabetic CKD may still benefit from the cardiovascular and weight effects shown in SELECT, but specific renal benefit data do not exist for this population.

Can I take semaglutide with an SGLT2 inhibitor?

Yes. Combined GLP-1 and SGLT2 inhibitor use is common in patients with T2D and CKD. Both classes have renal-protective effects through different mechanisms. Cost and tolerability are the practical limits; trial evidence for the combination's incremental benefit is growing.

Was the dose in FLOW the same as Wegovy?

No. FLOW used semaglutide 1.0 mg weekly (the maximum diabetes dose) rather than the 2.4 mg weekly Wegovy dose. The lower dose was chosen given the T2D-and-CKD population. Whether the higher 2.4 mg dose would produce greater renal benefit is unknown.