FLOW Trial: Semaglutide for Chronic Kidney Disease
The FLOW trial showed semaglutide reduces kidney disease progression by 24% in diabetic CKD. Here's the trial design, results, and clinical implications.
The FLOW trial (Evaluate Renal Function with Semaglutide Once Weekly) was the first major cardiovascular outcomes trial to demonstrate that a GLP-1 receptor agonist slows the progression of chronic kidney disease in patients with type 2 diabetes. Published in NEJM in mid-2024, FLOW showed a 24% reduction in the primary composite kidney outcome with semaglutide versus placebo, establishing semaglutide as a meaningful addition to the kidney-protective medication armamentarium.
Trial Design
FLOW enrolled approximately 3,533 adults with type 2 diabetes and chronic kidney disease (eGFR 25-75 mL/min/1.73m² plus urine albumin-creatinine ratio 100-5,000 mg/g). Participants were randomized 1:1 to weekly subcutaneous semaglutide 1 mg or placebo, on top of standard-of-care kidney-protective therapy including ACE inhibitors or ARBs and, where indicated, SGLT2 inhibitors.
The primary endpoint was a composite of kidney failure (initiation of chronic dialysis or kidney transplantation), sustained 50% decline in eGFR, kidney-related death, or cardiovascular death. The composite was chosen to capture the clinically relevant spectrum of adverse kidney and cardiovascular outcomes in this population.
Primary Results
| Endpoint | Semaglutide | Placebo | Hazard Ratio |
|---|---|---|---|
| Primary composite | 18.7% | 23.2% | 0.76 (95% CI 0.66-0.88) |
| Sustained 50% eGFR decline | Reduced | Reference | Favorable |
| Cardiovascular death | 3.9% | 5.0% | 0.71 |
| All-cause death | 6.5% | 7.9% | 0.80 |
| MACE | Reduced | Reference | Favorable |
The 24% reduction in the primary composite was highly statistically significant and clinically meaningful. The benefit was consistent across pre-specified subgroups including baseline eGFR, albuminuria level, age, and concurrent SGLT2 inhibitor use.
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Mechanism of Renal Protection
The mechanisms by which semaglutide protects kidney function appear to involve both direct and indirect pathways. Direct effects include reduced glomerular hyperfiltration, improved endothelial function, and anti-inflammatory effects in renal tissue. Indirect effects include improved blood pressure, better glycemic control, and weight loss. Statistical mediation analyses from FLOW and related studies suggest the kidney benefit is only partially explained by changes in glycemia, weight, or blood pressure — consistent with direct pharmacologic effects on renal biology.
Relationship to SGLT2 Inhibitor Use
An important question is whether FLOW's benefit is additive to SGLT2 inhibitor therapy, which has independently shown strong kidney protection. FLOW's subgroup analysis suggested the semaglutide benefit was consistent regardless of SGLT2 inhibitor use at baseline, supporting a potentially additive effect. This is clinically important because SGLT2 inhibitors are now widely used in patients with diabetic kidney disease, and FLOW supports adding semaglutide rather than substituting.
The Broader Cardiovascular Benefit
FLOW also showed reductions in cardiovascular death and MACE, consistent with the SUSTAIN-6 and SELECT cardiovascular programs. In a population with established kidney disease — where cardiovascular risk is elevated — the combined kidney and cardiovascular benefits make semaglutide a particularly valuable therapeutic addition.
Regulatory and Practice Implications
FLOW established semaglutide as a kidney-protective therapy in diabetic kidney disease, complementing the SGLT2 inhibitor class. The 24% composite reduction is in the range expected for meaningful kidney-protective interventions and has reshaped nephrology treatment algorithms.
Based on FLOW, the FDA approved an expanded indication for Ozempic in early 2025 for reduction of the risk of kidney disease progression and cardiovascular death in patients with type 2 diabetes and chronic kidney disease. Nephrology society guidelines have integrated GLP-1 receptor agonists into kidney-protective treatment recommendations for appropriate patients.
Open Questions
FLOW was specific to patients with type 2 diabetes. Whether semaglutide provides kidney protection in non-diabetic chronic kidney disease populations is not established, though trials are ongoing. Whether tirzepatide provides comparable kidney protection is also under investigation. The FLOW-style evidence for tirzepatide is less mature than the semaglutide evidence, which currently gives semaglutide a differentiating advantage in patients with concurrent kidney disease priorities. For related reviews, see our SELECT review and SURPASS-CVOT review.
Sources
- NEJM. FLOW trial primary publication. Perkovic et al, 2024. www.nejm.org
- ClinicalTrials.gov. FLOW trial NCT03819153. clinicaltrials.gov
- FDA. Ozempic kidney disease indication approval, 2025. www.accessdata.fda.gov
- KDIGO. Clinical Practice Guideline integration of GLP-1 receptor agonists. kdigo.org
- American Society of Nephrology. FLOW trial clinical commentary. www.asn-online.org
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