PMID-38785209 — FLOW: Semaglutide and Kidney Outcomes in Type 2 Diabetes with CKD

[DRAFT — authored 2026-04-18. Requires Medical Director review.]

Citation

Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, Baeres FMM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R; FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024;391(2):109-121. doi: 10.1056/NEJMoa2403347. PMID: 38785209.

Study Design

Phase: 3
Design: Multicenter, randomized, double-blind, placebo-controlled, event-driven
Randomization: 1:1 to semaglutide 1.0 mg weekly SC or matching placebo
Blinding: Double-blind
Duration: Median follow-up ~3.4 years (trial stopped early for efficacy based on interim analysis)
N: 3,533 participants with type 2 diabetes and chronic kidney disease

Population

Inclusion criteria:
- Type 2 diabetes, HbA1c ≤10%
- Chronic kidney disease defined as:
  - eGFR 50–75 mL/min/1.73 m² with UACR 300–5,000 mg/g, OR
  - eGFR 25–<50 mL/min/1.73 m² with UACR 100–5,000 mg/g
- Adequate background therapy including RAAS inhibition (ACE-i or ARB) unless contraindicated
Exclusion criteria:
- Type 1 diabetes
- ESRD / dialysis
- Recent cardiovascular event
- MTC/MEN 2 history
Demographics:
- Mean age: 67 years
- Mean HbA1c: 7.8%
- Mean eGFR: ~47 mL/min/1.73 m²
- Mean UACR: ~568 mg/g
- Female: ~30%
- Background SGLT2 inhibitor use: ~16% at baseline

Intervention

Semaglutide: 0.25 mg → 0.5 mg → 1.0 mg weekly SC, titrated over 8 weeks
Control: Matching placebo weekly SC
Concomitant therapy: Standard CKD care including RAAS inhibition and (where appropriate) SGLT2 inhibitors

Outcomes

Primary

Composite first occurrence of: onset of kidney failure (dialysis, kidney transplant, or sustained eGFR <15 mL/min/1.73 m²), sustained ≥50% reduction in eGFR from baseline, death from kidney disease, or death from cardiovascular disease

Results:

Semaglutide: 18.7% (331/1,767) primary events
Placebo: 23.2% (410/1,766) primary events
Hazard ratio: 0.76 (95% CI, 0.66 to 0.88)
P = 0.0003
Number needed to treat: ~20 over 3.4 years to prevent one primary outcome event

Secondary

Total eGFR slope (annual rate of decline): −2.19 mL/min/1.73 m²/year with semaglutide vs. −3.36 with placebo (difference: 1.16 mL/min/1.73 m²/year slower decline) — P < 0.001
Major adverse cardiovascular events (MACE): HR 0.82 (95% CI, 0.68 to 0.98)
All-cause mortality: HR 0.80 (95% CI, 0.67 to 0.95)
HbA1c, weight, BP: improvements favoring semaglutide

Key Findings

FLOW is the first large-scale demonstration that a GLP-1 receptor agonist produces kidney-specific protection in patients with T2DM and CKD, independent of glucose lowering. The 24% relative reduction in the composite kidney endpoint positions semaglutide as a kidney-protective agent joining SGLT2 inhibitors (CREDENCE, DAPA-CKD) and non-steroidal mineralocorticoid receptor antagonists (FIDELIO-DKD/FIGARO-DKD) in the modern CKD-in-T2DM treatment paradigm.

The magnitude and consistency of the effect — across kidney failure, eGFR decline, and cardiovascular mortality — led the Data Monitoring Committee to stop the trial early for efficacy. The composite nature of the endpoint and the prespecified hierarchical testing permit straightforward clinical interpretation: semaglutide reduces kidney failure events, slows eGFR decline, and reduces cardiovascular mortality in this high-risk population.

Important context: Most participants were already on RAAS inhibition and a subset on SGLT2 inhibitors. The benefit of semaglutide was on top of standard CKD care, suggesting additive kidney protection from a novel mechanism (likely anti-inflammatory, anti-fibrotic, and hemodynamic effects beyond glucose and weight).

Clinical implications:

For patients with T2DM + CKD at stages 2–4, semaglutide should be considered for kidney protection, alongside standard care.
Combination of semaglutide + SGLT2 inhibitor is pharmacologically rational and was well-represented in the baseline population.
The dose (1.0 mg weekly) used in FLOW is the T2DM dose — not the weight-loss dose (2.4 mg). Kidney protection at the higher weight-loss dose is a reasonable but unproven extrapolation.

Limitations (Author-acknowledged)

Single-dose comparison (1.0 mg) — dose-response for kidney protection not characterized.
Stopped early for efficacy — shorter observation may magnify early-benefit signals.
Baseline SGLT2 inhibitor use was modest (~16%); current best-practice background therapy includes higher SGLT2 adoption.
Non-T2DM CKD populations not studied.
UACR-based inclusion; patients without proteinuria (normoalbuminuric CKD) not included.
Funded by Novo Nordisk.

Evidence Level

Level Ib (Oxford CEBM) — large, adequately-powered Phase 3 RCT with double-blinding, pre-specified primary endpoint, low risk of bias (early-stopping for efficacy is a minor caveat).

Linked Peptides

Semaglutide

Orchestrator Notes

Funded by Novo Nordisk.
Results expand semaglutide's FDA label trajectory; kidney-specific labeling updates are expected.
Builds on SUSTAIN-6 and SELECT cardiovascular data to position semaglutide as a multiorgan-protective agent in T2DM.
Parallel question for tirzepatide: SURPASS-CVOT (ongoing) is the tirzepatide CV outcomes trial; kidney outcomes in T2DM + CKD are a future research question.
Clinical implication: in patients with T2DM and CKD, semaglutide is now an evidence-based component of care, alongside RAAS inhibition and SGLT2 inhibition.

PMID-38785209 – FLOW Semaglutide Kidney Outcomes CKD T2DM