FLOW trial deep-dive: semaglutide cuts kidney-disease progression 24% in T2D (Perkovic 2024)
Last verified 2026-05-28 · Phase 3b · Completed; stopped early for efficacy (primary results reported May 2024) · NCT03819153 ↗
FLOW (A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease) was a multicenter, double-blind, placebo-controlled, event-driven phase 3b superiority trial sponsored by Novo Nordisk. Investigators randomized 3,533 adults with type 2 diabetes and chronic kidney disease 1:1 to once-weekly subcutaneous semaglutide titrated to 1.0 mg or matching placebo, on top of guideline-directed standard care including a maximum tolerated dose of a renin-angiotensin-system inhibitor. The primary endpoint was a hierarchical composite of major kidney-disease events: onset of kidney failure (sustained eGFR below 15 mL/min/1.73 m², chronic dialysis, or kidney transplantation), a sustained reduction of at least 50% from baseline in eGFR, or death from kidney or cardiovascular causes. After a planned interim analysis crossed the prespecified efficacy boundary, the trial was stopped early. Results published by Perkovic and colleagues in the New England Journal of Medicine on May 24, 2024 reported a hazard ratio of 0.76 for the primary outcome and consistent benefit on secondary cardiovascular and mortality endpoints. FLOW is the registrational trial behind the January 2025 FDA label expansion of Ozempic for kidney-disease progression in adults with type 2 diabetes and chronic kidney disease.
- Enrollment
- 3,533
- Duration
- Median follow-up 3.4 years; trial stopped early for efficacy after a planned interim analysis (originally planned for up to 5 years)
- Drug
- Semaglutide 1.0 mg (Ozempic)
- Population
- Adults aged 18 or older with type 2 diabetes, an HbA1c of 10% or lower, and chronic kidney disease defined as either eGFR 50 to 75 mL/min/1.73 m² with a urinary albumin-to-creatinine ratio (UACR) greater than 300 mg/g, or eGFR 25 to less than 50 mL/min/1.73 m² with UACR greater than 100 mg/g. Participants had to be on a stable maximum tolerated dose of an ACE inhibitor or angiotensin-receptor blocker unless contraindicated. Mean age 66.6 years, 70.1% male, mean HbA1c 7.8%, mean diabetes duration ~17.4 years, mean eGFR 47.0 mL/min/1.73 m², median UACR 567.6 mg/g. SGLT2 inhibitor use at baseline was 15.6%.
Primary endpoint
Composite kidney outcome: onset of kidney failure (sustained eGFR <15 mL/min/1.73 m², chronic dialysis, or transplantation), sustained ≥50% reduction in eGFR from baseline, or death from kidney or cardiovascular causes (time-to-first-event)
Treatment arm
331 of 1,767 (18.7%)
Comparator
410 of 1,766 (23.2%)
Treatment difference: Hazard ratio 0.76 (95% CI 0.66 to 0.88); P=0.0003 for superiority
24% relative reduction in major kidney-disease events and cardiovascular or kidney death with semaglutide vs placebo. The benefit was driven by both the kidney-specific components and cardiovascular death. Number needed to treat ≈20 over a median 3.4 years to prevent one primary outcome event.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Annual rate of change in eGFR (total eGFR slope, mL/min/1.73 m² per year) Semaglutide slowed annual eGFR decline by roughly one-third. The slope benefit emerged early and was sustained throughout follow-up, paralleling the kidney-composite hazard reduction. | −2.19 mL/min/1.73 m² per year | −3.36 mL/min/1.73 m² per year | Between-group difference +1.16 mL/min/1.73 m² per year (95% CI 0.86 to 1.47); P<0.001 |
| Three-point major adverse cardiovascular events (MACE): nonfatal MI, nonfatal stroke, or cardiovascular death 18% relative reduction in MACE in a population with concurrent type 2 diabetes and chronic kidney disease — both independent CV risk multipliers — extending the cardiovascular benefit first seen in SUSTAIN-6 to a higher-risk CKD population. | 189 of 1,767 (10.7%) | 236 of 1,766 (13.4%) | Hazard ratio 0.82 (95% CI 0.68 to 0.98); P=0.029 |
| Death from any cause (all-cause mortality) 20% relative reduction in all-cause mortality — formally significant under the hierarchical testing sequence and one of the largest mortality signals reported for any GLP-1 receptor agonist trial. | 227 of 1,767 (12.8%) | 279 of 1,766 (15.8%) | Hazard ratio 0.80 (95% CI 0.67 to 0.95); P=0.01 |
| Death from cardiovascular causes 29% relative reduction in cardiovascular death. The CV-death signal was the largest individual component contribution to both the primary composite and the all-cause mortality result. | 123 of 1,767 (7.0%) | 169 of 1,766 (9.6%) | Hazard ratio 0.71 (95% CI 0.56 to 0.89) |
| Kidney-specific composite: sustained ≥50% eGFR reduction, kidney failure, or death from kidney causes 21% relative reduction in kidney-only events when cardiovascular death is removed from the composite — confirms the kidney signal is not driven entirely by the CV-death component. | Reported in publication with hazard ratio 0.79 | Reference | Hazard ratio 0.79 (95% CI 0.66 to 0.94) |
| Change from baseline in urinary albumin-to-creatinine ratio (UACR) at week 104 Semaglutide reduced albuminuria by roughly one-third more than placebo at two years. Albuminuria reduction has been a consistent surrogate-confirming signal in prior GLP-1 kidney sub-analyses and tracks with the slope and event-based outcomes seen here. | Ratio to baseline 0.60 (40% reduction) | Ratio to baseline 0.92 (8% reduction) | Estimated treatment ratio 0.66 (95% CI 0.61 to 0.71) |
| Chronic eGFR slope (rate of decline from week 12 onward, after the initial acute eGFR dip) The chronic slope (which excludes the early hemodynamic dip common to renin-angiotensin-system and SGLT2 agents) confirms that the long-term decline rate is meaningfully slower on semaglutide, not just shifted by an initial filtration drop. | Approximately −2.4 mL/min/1.73 m² per year | Approximately −3.3 mL/min/1.73 m² per year | Between-group difference roughly +0.9 mL/min/1.73 m² per year |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Serious adverse events (any) Fewer serious adverse events with semaglutide, driven primarily by fewer cardiovascular and kidney events — consistent with the efficacy signal. | 49.6% (876/1,767) | 53.8% (950/1,766) |
| Permanent discontinuation due to adverse events Modest excess discontinuation on semaglutide, mainly driven by gastrointestinal events during dose escalation. | 13.2% (233/1,767) | 11.9% (210/1,766) |
| Gastrointestinal adverse events (any) Nausea, vomiting, diarrhea, and decreased appetite were more frequent with semaglutide, consistent with the established Ozempic safety profile at the 1.0 mg dose. | Higher with semaglutide (nausea, diarrhea, vomiting, constipation; class-typical profile) | Lower |
| Acute kidney injury No excess AKI signal — important given the CKD population and the gastrointestinal AE profile of the drug class. | Numerically lower with semaglutide despite GI losses | Higher with placebo |
| Diabetic retinopathy complications No imbalance in retinopathy complications, in contrast to the early SUSTAIN-6 signal. Background retinopathy treatment was protocol-mandated. | 4.0% (71/1,767) | 4.1% (72/1,766) |
| Severe hypoglycemia No excess severe hypoglycemia; semaglutide is not insulin-secretagogue at fasting glucose. | Low and similar between arms | Low and similar between arms |
| Acute pancreatitis (adjudicated) No increased risk of pancreatitis with semaglutide in FLOW. | 0.6% | 1.0% |
| Malignant neoplasms No imbalance in overall cancer incidence between arms. | 5.4% | 5.5% |
Subgroup analyses
- Baseline eGFR 25 to <45 vs 45 to <60 vs ≥60 mL/min/1.73 m²: Primary-outcome hazard ratio consistent across strata; no significant treatment-by-eGFR interaction
Kidney benefit was present whether participants entered with severely or moderately reduced filtration. The trial deliberately enrolled across the CKD-stage 2-4 range to enable this subgroup.
- Baseline SGLT2 inhibitor use (15.6% of cohort): Primary-outcome hazard ratio similar to non-SGLT2 users; no significant interaction
Effect of semaglutide on kidney outcomes appeared additive to SGLT2 inhibition, supporting combination use in this population. The SGLT2 user subgroup was small but directionally consistent.
- Baseline UACR strata (≤300, 300 to ≤1,000, >1,000 mg/g): Consistent kidney-composite reduction across albuminuria strata
Benefit observed across the full range of macroalbuminuria severity — not concentrated in the very-high-UACR tail.
- Baseline HbA1c <7.5% vs ≥7.5%: Similar primary-outcome hazard ratios across glycemic strata
Kidney benefit was not explained by glycemic improvement alone — consistent with a direct hemodynamic and anti-inflammatory mechanism on top of glucose lowering.
- Age <65 vs ≥65 years: Consistent primary-outcome reduction across age groups
Older adults — who carry the highest absolute event risk — derived similar relative benefit.
- Sex: female (29.9%) vs male (70.1%): Similar hazard ratios across sexes
Women remained under-represented relative to CKD prevalence in T2D, but the benefit was directionally consistent.
Clinical significance
FLOW changed the regulatory and clinical position of semaglutide in chronic kidney disease. Before FLOW, the kidney signals seen with GLP-1 receptor agonists in trials like LEADER, SUSTAIN-6, and AWARD-7 were exploratory secondary or post-hoc findings; FLOW was the first GLP-1 trial designed and powered for a primary kidney composite, and the only one to be stopped early for efficacy on that endpoint. The 24% reduction in major kidney-disease events plus cardiovascular or kidney death, the 20% reduction in all-cause mortality, and the slowing of eGFR decline by roughly one-third per year established semaglutide as a kidney-protective therapy in adults with type 2 diabetes and chronic kidney disease — a category previously occupied only by renin-angiotensin-system inhibitors, SGLT2 inhibitors, and the non-steroidal mineralocorticoid-receptor antagonist finerenone. On January 28, 2025, the FDA approved a label expansion for Ozempic adding a new indication: reducing the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. FLOW also opened the door to GLP-1 therapy in non-diabetic kidney disease, where dedicated trials are now ongoing.
Frequently asked questions
Does FLOW apply to people with chronic kidney disease but no diabetes?
No. FLOW enrolled only adults with type 2 diabetes, and the January 2025 FDA Ozempic label expansion for kidney-disease progression is specifically restricted to adults with type 2 diabetes and chronic kidney disease. Whether semaglutide produces similar kidney protection in non-diabetic chronic kidney disease is an open question that the FLOW investigators and Novo Nordisk explicitly flagged. Dedicated trials in non-diabetic CKD populations are ongoing, but until those report, the kidney indication does not extend off-label to non-diabetic patients. Patients with non-diabetic CKD who are prescribed semaglutide today receive it for obesity, weight management, or established cardiovascular disease under the existing Wegovy or Ozempic indications, not for kidney protection.
Was the eGFR slope finding consistent with the urinary protein endpoint?
Yes, and the consistency is one of the strongest internal-validity arguments in the trial. The total eGFR slope improved by roughly 1.16 mL/min/1.73 m² per year on semaglutide versus placebo, the chronic slope (which excludes the early hemodynamic dip) showed a similar magnitude of benefit, and the urinary albumin-to-creatinine ratio fell by about one-third more on semaglutide than on placebo at week 104. All three markers of kidney trajectory — filtration, chronic filtration slope, and albuminuria — moved in the same direction with similar timing. This concordance reduces the chance that the primary composite result is driven by a single sub-outcome or by event-adjudication artifact, and it parallels the pattern seen in SGLT2 kidney-outcomes trials like CREDENCE and DAPA-CKD.
How did FLOW lead to the 2025 Ozempic kidney label expansion?
Novo Nordisk submitted a supplemental new drug application to the FDA based on the FLOW primary publication and the trial's prespecified analyses. On January 28, 2025, the FDA approved an expanded indication for Ozempic that added the reduction of risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. The new indication appears alongside the original glycemic-control indication and the prior cardiovascular-risk-reduction indication that was added based on the SUSTAIN-6 cardiovascular outcomes trial. The 1.0 mg weekly dose tested in FLOW corresponds to the standard maintenance dose of Ozempic, making the trial directly translatable to prescribing practice without a new dose formulation.
Should patients on dialysis use semaglutide?
FLOW did not enroll patients already on chronic dialysis at randomization — the eligibility criteria required baseline eGFR between 25 and 75 mL/min/1.73 m². The trial therefore has nothing direct to say about whether starting semaglutide in a person already receiving hemodialysis or peritoneal dialysis improves outcomes. Pharmacokinetic data for semaglutide in patients with end-stage kidney disease show no clinically meaningful change in exposure that would require dose adjustment, but the safety profile in dialysis populations is less well characterized than in CKD stages 3 and 4. Decisions in dialysis patients are individualized and typically driven by glycemic control, weight, and cardiovascular risk rather than by an evidence-based kidney-protection rationale, since by definition dialysis means the kidney-progression endpoint has already been reached.
Does Zepbound or tirzepatide have similar kidney-outcomes data?
Not yet. As of mid-2026, no dedicated kidney-outcomes trial of tirzepatide (Mounjaro or Zepbound) has reported. Tirzepatide has shown signals consistent with kidney benefit in secondary analyses of trials like SURPASS-4 — a slower eGFR decline and reduced albuminuria in adults with type 2 diabetes and high cardiovascular risk — but those analyses were not the primary endpoint and were not powered to establish a kidney-event indication. Eli Lilly has not yet conducted or reported a tirzepatide trial that mirrors FLOW's design with a primary hierarchical kidney composite. Until such a trial reports, semaglutide is the only GLP-1 (or GLP-1/GIP) agent with an FDA-approved kidney-protection indication, and clinicians choosing between semaglutide and tirzepatide for a patient with type 2 diabetes and chronic kidney disease have to weigh dedicated kidney evidence on the semaglutide side against larger weight-loss and glycemic effects on the tirzepatide side.
Why was FLOW stopped early?
FLOW had a prespecified interim analysis plan, and an independent data monitoring committee reviewed accumulating outcome data at a planned look. The committee recommended halting the trial after the primary composite endpoint crossed the prespecified efficacy boundary — meaning the difference between semaglutide and placebo was large enough and consistent enough that continuing the trial to its originally planned end would have exposed placebo participants to avoidable progression without changing the conclusion. Early-stopped trials are sometimes criticized for potentially overstating effect sizes because they capture the maximum of a noisy interim estimate, but the FLOW investigators reported that the magnitude of benefit was stable across the interim and the final analysis, and the consistency of secondary endpoints (MACE, all-cause mortality, slope, albuminuria) supports the primary result rather than relying on it alone.
References
- 1.Perkovic V, Tuttle KR, Rossing P, et al.; FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024. PMID: 38785209.
- 2.U.S. National Library of Medicine. A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW). ClinicalTrials.gov, NCT03819153. 2024. https://clinicaltrials.gov/study/NCT03819153
- 3.U.S. Food and Drug Administration. FDA Approves Treatment to Reduce Risk of Serious Kidney and Cardiovascular Events in Adults With Chronic Kidney Disease and Type 2 Diabetes (Ozempic label expansion). FDA Drug Safety and Availability Announcement, January 28, 2025. 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-reduce-risk-serious-kidney-and-cardiovascular-events-adults-chronic-kidney
- 4.Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016. PMID: 27633186.
- 5.Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023. PMID: 37952131.