What is the FLOW trial, including its design, population (adults with type 2 diabetes and chronic kidney disease), intervention (once‑weekly subcutaneous semaglutide 1 mg), comparator (placebo), duration, and primary outcome?

What is the FLOW Trial?

The FLOW trial (A Research Study to See How Semaglutide Works Compared with Placebo in People With Type 2 Diabetes and Chronic Kidney Disease) is a landmark randomized, double-blind, placebo-controlled trial that demonstrated once-weekly subcutaneous semaglutide 1.0 mg significantly reduces kidney failure, cardiovascular events, and mortality in adults with type 2 diabetes and chronic kidney disease. 1

Trial Design and Population

Study Design:

• The FLOW trial randomized 3,533 participants in a 1:1 ratio to receive either once-weekly subcutaneous semaglutide 1.0 mg or matching placebo, with a median follow-up of 3.4 years. 2, 3
• This was a multicenter, international trial designed to assess both renal and cardiovascular outcomes as primary endpoints. 1

Patient Population:

• Adults with type 2 diabetes and established chronic kidney disease were enrolled, specifically those with:
  • Estimated glomerular filtration rate (eGFR) ranging from 25–75 mL/min/1.73 m² at baseline (mean eGFR approximately 47 mL/min/1.73 m²) 1
  • Median urine albumin-to-creatinine ratio (UACR) of 568 mg/g (range 300–5,000 mg/g) 1
  • More than 99% of participants were on background ACE inhibitor or ARB therapy 1
• The trial enrolled a high-risk population: 68.3% had very high KDIGO risk classification, 24.9% had high risk, and only 6.9% had low/moderate risk. 2
• Approximately 19% of participants had heart failure at baseline. 3

Primary and Key Secondary Outcomes

Primary Kidney Outcome:

• The primary endpoint was a composite of time to first occurrence of:
  • Persistent ≥50% decline in eGFR from baseline, or
  • Persistent eGFR <15 mL/min/1.73 m², or
  • Kidney replacement therapy (chronic dialysis or transplantation), or
  • Death from kidney or cardiovascular causes 4

Key Cardiovascular Outcomes:

• Major adverse cardiovascular events (MACE): composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke 2
• Heart failure events: new onset or worsening heart failure requiring hospitalization or urgent visit with diuretic/vasoactive therapy intensification 3
• All-cause mortality 2

Landmark Results

Kidney Protection:

• Semaglutide reduced the primary kidney outcome by 24% overall (hazard ratio 0.76; 95% CI not specified in provided excerpts but trial was stopped early for efficacy) 4
• In participants not taking mineralocorticoid receptor antagonists at baseline, semaglutide reduced the primary kidney outcome by 21% (HR 0.79; 95% CI 0.68–0.92) 4
• In the smaller subgroup taking MRAs at baseline, the reduction was 49% (HR 0.51; 95% CI 0.30–0.86), though the interaction was not statistically significant (P-interaction = 0.12) 4
• Albuminuria was reduced by 33% at 104 weeks in non-MRA users (95% CI 26–39%) compared to placebo. 4

Cardiovascular Protection:

• Semaglutide reduced MACE by 18% (HR 0.82; 95% CI 0.68–0.98; P = 0.03), with consistent benefit across all eGFR categories, UACR levels, and KDIGO risk classifications (all P-interaction >0.13). 2
• The composite of heart failure events or cardiovascular death was reduced by 27% (HR 0.73; 95% CI 0.62–0.87; P = 0.0005). 3
• Heart failure events alone were reduced by 27% (HR 0.73; 95% CI 0.58–0.92; P = 0.0068). 3
• Cardiovascular death alone was reduced by 29% (HR 0.71; 95% CI 0.56–0.89; P = 0.0036). 3

Mortality Benefit:

• All-cause mortality was reduced by 20% overall (HR 0.80; 95% CI 0.67–0.95; P = 0.01). 2
• The mortality benefit was particularly pronounced in participants with UACR ≥300 mg/g (HR 0.70; 95% CI 0.57–0.85), whereas those with UACR <300 mg/g showed no significant benefit (HR 1.17; 95% CI 0.83–1.65; P-interaction = 0.01). 2

Clinical Context and Significance

Addressing the Evidence Gap:

• Prior to FLOW, cardiovascular outcome trials of GLP-1 receptor agonists had demonstrated cardiovascular benefits in people with type 2 diabetes, but dedicated renal outcome data were limited to secondary endpoints. 1
• The 2021 and 2023 ADA Standards of Care explicitly stated that "proof of benefit on renal outcomes will come with the results of the ongoing FLOW trial with injectable semaglutide." 1
• FLOW provides the first Level A evidence that a GLP-1 receptor agonist reduces hard kidney outcomes (kidney failure, dialysis, transplantation) as a primary endpoint. 1

Comparison to SGLT2 Inhibitor Trials:

• The FLOW trial design parallels landmark SGLT2 inhibitor trials (CREDENCE with canagliflozin, DAPA-CKD with dapagliflozin) that established the renal protective effects of that drug class. 1
• CREDENCE showed a 30% reduction in the primary composite endpoint (ESRD, doubling of creatinine, or renal/cardiovascular death) with canagliflozin. 1
• DAPA-CKD demonstrated a 39% reduction in the primary outcome (≥50% eGFR decline, ESRD, or cardiovascular/renal death) with dapagliflozin. 1
• FLOW establishes that semaglutide provides complementary renal protection to SGLT2 inhibitors, with benefits observed regardless of baseline SGLT2 inhibitor use. 5

Subgroup Analyses:

• In participants taking SGLT2 inhibitors at baseline (N=550), the primary kidney outcome occurred in 41/277 semaglutide-treated versus 38/273 placebo-treated participants (HR 1.07; 95% CI 0.69–1.67; P = 0.755). 5
• In those not taking SGLT2 inhibitors (N=2,983), semaglutide reduced the primary outcome by 27% (290/1,490 vs 372/1,493; HR 0.73; 95% CI 0.63–0.85; P <0.001). 5
• The P-interaction was 0.109, suggesting no significant heterogeneity, though the trial was underpowered to detect smaller but clinically relevant additive effects in the SGLT2i subgroup. 5
• Benefits on MACE and all-cause mortality were consistent regardless of SGLT2 inhibitor use (P-interaction 0.741 and 0.901, respectively). 5

Heart Failure Findings:

• The heart failure benefit was consistent in participants with (HR 0.73; 95% CI 0.54–0.98) and without (HR 0.72; 95% CI 0.58–0.89) baseline heart failure. 3
• This represents primary prevention of heart failure in a CKD population, a particularly high-risk group for developing heart failure. 3

Safety Profile

• The safety profile of semaglutide in FLOW was comparable across subgroups, including those taking versus not taking SGLT2 inhibitors or mineralocorticoid receptor antagonists at baseline. 4, 5
• Gastrointestinal adverse events (nausea, vomiting, diarrhea) are the most common side effects of GLP-1 receptor agonists, typically mild-to-moderate and transient. 6
• Serious but rare risks include pancreatitis and gallbladder disease, though causality has not been definitively established. 6

Clinical Implications and Guideline Integration

Current Guideline Recommendations:

• The 2023 ADA Standards of Care now recommend SGLT2 inhibitors for patients with type 2 diabetes and diabetic kidney disease (eGFR >20 mL/min/1.73 m² and UACR >200 mg/g) to reduce CKD progression and cardiovascular events. 1
• With FLOW results now published, GLP-1 receptor agonists—specifically semaglutide—should be considered as complementary therapy to SGLT2 inhibitors for comprehensive cardiorenal protection in this population. 1, 5

Treatment Algorithm:

• For patients with type 2 diabetes and CKD (eGFR 25–75 mL/min/1.73 m² and albuminuria):
  1. First-line: SGLT2 inhibitor (if eGFR ≥20 mL/min/1.73 m²) 1
  2. Add: GLP-1 receptor agonist (semaglutide 1.0 mg weekly) for additional cardiorenal protection, particularly if:
     • UACR ≥300 mg/g (greatest mortality benefit) 2
     • Established cardiovascular disease or high cardiovascular risk 2
     • Heart failure or high heart failure risk 3
  3. Continue: ACE inhibitor or ARB as background therapy 1, 4
  4. Consider: Mineralocorticoid receptor antagonist (finerenone) for additional renal protection 4

Key Clinical Pearls:

• The benefits of semaglutide were consistent across the spectrum of CKD severity, including those with very high KDIGO risk. 2
• Semaglutide reduced cardiovascular death specifically, not just composite cardiovascular events—a mortality benefit that extends beyond glucose lowering. 2, 3
• The trial was stopped early for efficacy, underscoring the magnitude of benefit observed. 4
• FLOW establishes semaglutide as a disease-modifying therapy for diabetic kidney disease, not merely a glucose-lowering agent. 1, 2

Meta-Analytic Confirmation

• A 2025 meta-analysis of three RCTs (including FLOW) involving 10,013 patients confirmed:
  • 29% reduction in cardiovascular mortality (RR 0.71; 95% CI 0.52–0.97) 7
  • 20% reduction in MACE (RR 0.80; 95% CI 0.71–0.91) 7
  • 20% reduction in kidney-related adverse events (RR 0.80; 95% CI 0.71–0.89) 7
  • 14% reduction in need for cardiovascular medications (RR 0.86; 95% CI 0.81–0.91) 7

The FLOW trial fundamentally changes the treatment paradigm for type 2 diabetes and chronic kidney disease by establishing semaglutide as a cornerstone therapy for preventing kidney failure, cardiovascular events, and premature death in this high-risk population.