The FLOW Trial: Semaglutide's Kidney Results
GLP-1 and Kidney Disease
24% risk reduction
Semaglutide reduced major kidney events and cardiovascular death by 24% in patients with type 2 diabetes and chronic kidney disease, leading to early trial termination for efficacy.
Perkovic et al., NEJM, 2024
Perkovic et al., NEJM, 2024
View as imageThe FLOW trial is the first randomized controlled trial to demonstrate that a GLP-1 receptor agonist slows kidney disease progression as a primary endpoint. Published in the New England Journal of Medicine in 2024, this Novo Nordisk-funded study enrolled 3,533 patients with type 2 diabetes and chronic kidney disease and found that once-weekly subcutaneous semaglutide 1.0 mg reduced the composite of major kidney events and cardiovascular death by 24% compared to placebo.[1]
Earlier trials had hinted at kidney benefits. SUSTAIN-6 showed lower rates of new or worsening nephropathy with semaglutide in a high-risk cardiovascular population.[2] But those kidney findings were secondary endpoints in trials designed to answer cardiovascular questions. FLOW was designed from the start to answer the kidney question directly. For broader context on how GLP-1 drugs protect the kidneys, see GLP-1 Agonists and Kidney Disease: How Weight Loss Drugs Protect Kidneys.
Key Takeaways
- The FLOW trial randomized 3,533 patients with type 2 diabetes and CKD to semaglutide 1.0 mg or placebo weekly, with 3.4 years median follow-up[1]
- The primary composite endpoint (kidney failure, 50%+ eGFR decline, kidney death, or CV death) was 24% lower with semaglutide (HR 0.76, 95% CI 0.66-0.88, P=0.0003)
- Kidney-specific components alone showed a 21% risk reduction (HR 0.79, 95% CI 0.66-0.94)
- The annual eGFR decline was 1.16 ml/min/1.73m2 slower in the semaglutide group (P<0.001)
- Cardiovascular death was 29% lower (HR 0.71) and all-cause death 20% lower (HR 0.80) with semaglutide
- The trial was stopped early at a prespecified interim analysis because the benefit crossed the efficacy boundary
Who Was in the FLOW Trial
FLOW enrolled patients with type 2 diabetes and established chronic kidney disease, defined by two criteria windows:
- Window 1: eGFR 50-75 ml/min/1.73m2 with urinary albumin-to-creatinine ratio (UACR) above 300
- Window 2: eGFR 25-50 ml/min/1.73m2 with UACR above 100
This population represents moderate-to-severe diabetic kidney disease with active albuminuria. These patients face elevated risks of both kidney failure and cardiovascular events, making them among the highest-risk groups in diabetes care.
Of the 3,533 randomized participants, 1,767 received semaglutide and 1,766 received placebo. Both groups continued their existing standard of care, including renin-angiotensin system inhibitors, SGLT2 inhibitors, and other guideline-directed therapies. The median follow-up was 3.4 years before the trial was stopped early.
Primary Endpoint: 24% Reduction in Major Kidney Events
The primary composite outcome included onset of kidney failure (need for dialysis or transplant), a sustained 50% or greater reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes. In the semaglutide group, 331 first events occurred compared to 410 in the placebo group.[1]
The hazard ratio was 0.76 (95% CI: 0.66 to 0.88, P=0.0003). This means semaglutide reduced the relative risk of a major kidney or cardiovascular death event by 24%. The result was consistent across prespecified subgroups including age, sex, baseline eGFR, and baseline UACR.
When restricted to kidney-specific components only (removing CV death from the composite), the hazard ratio remained protective at 0.79 (95% CI: 0.66 to 0.94). This is an important distinction because it demonstrates that the benefit was not driven solely by cardiovascular protection. Semaglutide was protecting the kidneys independently.
eGFR Slope: Slowing the Decline
Beyond the composite endpoint, FLOW measured the annual rate of eGFR decline, which captures the trajectory of kidney function over time. The mean annual eGFR slope was 1.16 ml/min/1.73m2 less steep in the semaglutide group compared to placebo (P<0.001).[1]
To put that number in context: a typical patient with diabetic kidney disease loses approximately 3-5 ml/min/1.73m2 of eGFR per year. Slowing that decline by 1.16 ml/min/1.73m2 annually represents a meaningful preservation of kidney function over time, potentially delaying dialysis by years.
This eGFR slope finding is particularly relevant because it captures a continuous measure of kidney function rather than a binary event threshold. Even patients who did not cross the 50% eGFR decline threshold experienced slower progression. For related evidence on how GLP-1 drugs affect earlier markers of kidney damage, see GLP-1 Drugs and Albuminuria: Reducing the Early Sign of Kidney Damage.
Cardiovascular Outcomes: A Secondary Win
The FLOW trial was designed with the kidney as the primary question, but the cardiovascular results were themselves practice-changing:
- Death from cardiovascular causes: 29% lower (HR 0.71, 95% CI 0.56-0.89)
- Major adverse cardiovascular events (MACE): 18% lower (HR 0.82, 95% CI 0.68-0.98, P=0.029)
- Death from any cause: 20% lower (HR 0.80, 95% CI 0.67-0.95, P=0.01)
These cardiovascular benefits are consistent with earlier semaglutide trials. SUSTAIN-6, published in 2016, demonstrated a 26% reduction in MACE (HR 0.74, 95% CI 0.58-0.95) in 3,297 patients with type 2 diabetes at high cardiovascular risk.[2] FLOW extends this cardiovascular protection to a population defined by kidney disease, confirming that the benefits hold in patients with eGFRs as low as 25 ml/min/1.73m2.
The 20% reduction in all-cause mortality is the most striking secondary finding. Few diabetes interventions show mortality benefits in randomized trials. That semaglutide demonstrated this in a CKD population, where competing risks from both kidney and cardiovascular disease are high, reinforces the magnitude of the effect.
The SGLT2 Inhibitor Question: Additive Benefits?
A key sub-analysis by Mann and colleagues examined whether semaglutide's benefits were consistent in patients already taking SGLT2 inhibitors, since SGLT2 inhibitors are also kidney-protective in diabetic CKD.[3]
Of the 3,533 FLOW participants, 550 were taking an SGLT2 inhibitor at baseline. In this subgroup, the primary outcome hazard ratio was 1.07 (95% CI: 0.69-1.67), compared to 0.73 (95% CI: 0.63-0.85) in participants not taking SGLT2 inhibitors. The interaction P-value was 0.11, meaning the difference between subgroups did not reach statistical threshold.
However, the SGLT2 inhibitor subgroup was small (550 participants), and the confidence intervals were wide. The eGFR slope benefit was directionally consistent: 0.75 ml/min/1.73m2 per year slower decline in the SGLT2i subgroup versus 1.25 ml/min/1.73m2 in the non-SGLT2i subgroup, with an interaction P-value of 0.237. Cardiovascular benefits were similar regardless of SGLT2i use.
The practical takeaway: the data does not show that semaglutide fails in patients already on SGLT2 inhibitors, but neither does it prove additive benefit with adequate statistical power. Larger studies combining both drug classes are needed to answer this question definitively.
SUSTAIN-6 Kidney Sub-Analysis: Earlier Signals
Tuttle and colleagues published a post-hoc analysis of SUSTAIN-6 examining kidney outcomes by KDIGO (Kidney Disease: Improving Global Outcomes) risk category.[4] Among the 3,238 stratifiable SUSTAIN-6 participants:
- The kidney disease composite endpoint showed consistent benefit across all KDIGO risk categories (low, moderate, high, very high), with hazard ratios ranging from 0.35 to 0.87
- Patients on semaglutide were 69% more likely to move to a lower KDIGO risk category (OR 1.69, 95% CI 1.32-2.16)
- Patients on semaglutide were 29% less likely to worsen to a higher KDIGO risk category (OR 0.71, 95% CI 0.59-0.86)
This SUSTAIN-6 analysis provided the rationale for the FLOW trial and showed that kidney benefits were not restricted to patients with the most advanced disease. Even patients at moderate kidney risk showed directional benefit. For a comparison of how tirzepatide's kidney data compares to these semaglutide findings, see our pillar article on GLP-1s and renal function.
Why the Trial Was Stopped Early
The FLOW trial included a prespecified interim analysis at which the data safety monitoring board evaluated whether the efficacy boundary had been crossed. It had. The recommendation to stop the trial early was based on overwhelming evidence of benefit, meaning that continuing to randomize patients to placebo would be ethically difficult given the demonstrated kidney and mortality reductions.
Early stopping for efficacy is a double-edged feature in clinical trials. It confirms the treatment works but can also inflate effect sizes because the trial is terminated at a statistical peak. The true long-term effect size may be somewhat smaller than the 24% reduction observed. Longer follow-up data will be needed to refine the estimate, but the direction and statistical robustness of the finding are clear.
Safety Profile in FLOW
Serious adverse events occurred in 49.6% of semaglutide patients versus 53.8% of placebo patients.[1] This is an unusual finding for an active treatment: semaglutide had fewer serious adverse events than placebo. This likely reflects the treatment's ability to prevent cardiovascular and kidney events that would otherwise be classified as serious adverse events.
Gastrointestinal side effects (nausea, vomiting, diarrhea) were more common with semaglutide, consistent with the known GLP-1 receptor agonist profile. The FDA label for semaglutide includes a note about postmarketing reports of acute kidney injury, primarily in patients experiencing dehydration from gastrointestinal side effects.[5] In the FLOW trial specifically, kidney injury events were not elevated in the semaglutide group, but dehydration from GI side effects remains a practical concern in patients with already reduced kidney function.
FDA Approval for CKD Indication
In January 2025, the FDA approved injectable semaglutide (Ozempic) to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and death from kidney disease in adults with type 2 diabetes and chronic kidney disease. This was a new indication based primarily on the FLOW trial results, making semaglutide the first GLP-1 receptor agonist approved specifically for kidney disease.
The approval applies to the 1.0 mg once-weekly injectable formulation. The oral formulation (Rybelsus) and the higher-dose weight loss formulation (Wegovy) were not included in the CKD indication. For the difference between these formulations, see Ozempic vs Wegovy: Same Drug, Different Purpose.
Mechanisms: How Does Semaglutide Protect Kidneys?
The FLOW trial established that semaglutide protects kidneys but did not isolate the mechanism. Several pathways are plausible and likely additive:
Hemodynamic effects: GLP-1 receptor agonists reduce blood pressure and may reduce intraglomerular pressure, decreasing the mechanical stress on kidney filtration units.
Anti-inflammatory effects: A review of semaglutide's mechanisms in diabetic kidney disease identified altered expression of fibrosis-associated and inflammation-associated genes, including downregulation of the receptor for advanced glycation end products (RAGE).[6]
Weight loss and metabolic improvement: Semaglutide produces substantial weight loss (typically 10-15% in diabetes populations), which independently improves kidney hemodynamics, reduces proteinuria, and lowers the metabolic burden on the kidneys.
Glycemic control: HbA1c reduction reduces glucotoxicity to kidney tubular cells, though glycemic improvement alone does not account for the magnitude of kidney protection observed.
The relative contribution of each mechanism is unknown. The eGFR slope benefit (1.16 ml/min/1.73m2 per year) appears too large to be explained by glycemic control alone, suggesting direct or indirect renal protective effects beyond glucose lowering.
What FLOW Does Not Tell Us
The trial has clear limitations worth acknowledging:
Type 2 diabetes only: FLOW enrolled exclusively patients with type 2 diabetes and CKD. Whether semaglutide protects kidneys in non-diabetic CKD is unknown. The SELECT trial showed kidney benefits of semaglutide in obese patients without diabetes, but that was a secondary analysis, not a primary kidney endpoint trial.
Concurrent therapies: 15.6% of participants were on SGLT2 inhibitors. The sub-analysis in this group was underpowered, leaving the question of additive benefit unresolved.
Duration: Median follow-up was 3.4 years. Whether kidney protection persists, increases, or plateaus over longer timeframes is unknown.
Race and ethnicity: The trial was global but specific racial/ethnic subgroup analyses were limited. CKD progression rates vary by population, and whether semaglutide's benefits are uniform across demographics requires further data.
Cost and access: The practical impact of these results depends on whether payers cover semaglutide for the CKD indication, an issue that extends beyond the trial's scope.
The Bottom Line
The FLOW trial is the definitive evidence that semaglutide protects kidneys in type 2 diabetes with CKD. A 24% reduction in major kidney events, a 29% reduction in cardiovascular death, a 20% reduction in all-cause mortality, and a slower eGFR decline of 1.16 ml/min/1.73m2 per year are findings that led to early trial termination, FDA approval for a CKD indication, and a fundamental shift in how nephrologists think about GLP-1 receptor agonists. The key limitations are the restriction to type 2 diabetes, the underpowered SGLT2 inhibitor subgroup, and the 3.4-year follow-up duration.