FLOW Trial Kidney Outcomes for Semaglutide
Semaglutide reduces the risk of major kidney disease events by 24% in patients with type 2 diabetes and chronic kidney disease, and should be used in these patients to prevent kidney failure, cardiovascular death, and all-cause mortality. 1
Key FLOW Trial Results
The FLOW trial (Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes) was stopped early due to overwhelming efficacy at a prespecified interim analysis after median follow-up of 3.4 years. 1
Primary Kidney Outcomes
Major kidney disease events reduced by 24% (hazard ratio 0.76; 95% CI 0.66-0.88; P=0.0003) 1
- This composite included kidney failure (dialysis, transplantation, or eGFR <15 mL/min/1.73 m²), ≥50% reduction in eGFR, or death from kidney-related or cardiovascular causes 1
Kidney-specific outcomes reduced by 21% (hazard ratio 0.79; 95% CI 0.66-0.94) when excluding cardiovascular death 1
eGFR decline slowed by 1.16 mL/min/1.73 m² per year compared to placebo (P<0.001) 1
Additional Critical Outcomes
Cardiovascular death reduced by 29% (hazard ratio 0.71; 95% CI 0.56-0.89) 1
Major cardiovascular events reduced by 18% (hazard ratio 0.82; 95% CI 0.68-0.98; P=0.029) 1
All-cause mortality reduced by 20% (hazard ratio 0.80; 95% CI 0.67-0.95; P=0.01) 1
Patient Population in FLOW
The trial enrolled 3,533 patients with type 2 diabetes and chronic kidney disease defined as: 1
- eGFR 50-75 mL/min/1.73 m² with urinary albumin-to-creatinine ratio (UACR) >300 and <5,000 mg/g, OR
- **eGFR 25 to <50 mL/min/1.73 m²** with UACR >100 and <5,000 mg/g
Guideline-Based Recommendations
When to Use Semaglutide for Kidney Protection
GLP-1 receptor agonists with proven cardiovascular benefit (including semaglutide) are recommended for patients with type 2 diabetes and CKD who do not meet glycemic targets with metformin and/or SGLT2 inhibitors, or who cannot use these drugs. 2
The 2022 ADA/KDIGO consensus specifically states that long-acting GLP-1 RAs with proven cardiovascular benefits can be used in patients with eGFR below 60 mL/min/1.73 m² or those with albuminuria who are intolerant of SGLT2 inhibitors. 2
Positioning in Treatment Algorithm
First-line consideration: For patients with type 2 diabetes and established cardiovascular disease or diabetic kidney disease, semaglutide should be initiated alongside or instead of SGLT2 inhibitors 2
No eGFR adjustment required: Unlike SGLT2 inhibitors, semaglutide requires no dosage adjustments for kidney function and can be used down to very low eGFR levels 2
Preferred over SGLT2i when eGFR <30 mL/min/1.73 m²: GLP-1 RAs become the preferred glucose-lowering agent with cardiovascular and kidney benefits at this threshold 2
Monitoring Recommendations
Baseline Assessment
- Measure eGFR and UACR before initiating therapy 2
- Perform dilated eye examination within 12 months if not done recently, particularly given the proliferative retinopathy signal seen with semaglutide in SUSTAIN-6 2
- Assess for gastroparesis history as this is a relative contraindication 2
Ongoing Monitoring
Monitor kidney function regularly: Check eGFR and UACR at least annually, or more frequently if CKD is progressing 2
Expect initial eGFR decline: Semaglutide causes an early decrease in eGFR (approximately 1-3 mL/min/1.73 m² by week 12-16) that plateaus and then stabilizes or improves over time 3, 1
Monitor for hypoglycemia: If A1C is well-controlled at baseline, reduce sulfonylurea dose by 50% or basal insulin by 20% when starting semaglutide 2
Home glucose monitoring: Instruct patients to monitor glucose more closely for the first 4 weeks 2
Albuminuria Reduction
Semaglutide produces substantial reductions in albuminuria across all baseline categories: 3, 4, 5
In SUSTAIN trials: UACR decreased by 26-34% compared to placebo (estimated treatment ratios 0.66-0.75) 3
In macroalbuminuria: Real-world data shows 51% reduction in UACR in patients with baseline UACR >300 mg/g 4
In non-diabetic CKD: Even in patients without diabetes but with obesity and CKD, semaglutide reduced UACR by 52% over 24 weeks 5
Safety Considerations
Common Adverse Effects
Gastrointestinal symptoms (nausea, vomiting, abdominal pain) are the most common side effects, occurring more frequently than placebo but manageable with dose titration 3, 6, 1
Discontinuation rate: Only 5.7% of patients discontinued due to digestive intolerance in real-world CKD populations 4
Serious adverse events: Actually occurred in a lower percentage with semaglutide (49.6%) than placebo (53.8%) in the FLOW trial 1
Specific Precautions
Proliferative retinopathy: Use caution in patients with proliferative diabetic retinopathy based on SUSTAIN-6 findings 2
History of pancreatitis: Consider alternative agents 2
MEN2 or medullary thyroid cancer: Contraindicated 2
Pregnancy planning: Should not be used if patient is considering pregnancy 2
Dosing in CKD
No dose adjustment is required for any level of kidney function. 2, 6
Standard initiation: 0.25 mg subcutaneously once weekly, titrated to 0.5 mg after 4 weeks, then to 1.0 mg after another 4 weeks as tolerated 2
Oral formulation: Can start at 3 mg daily and titrate up to 14 mg daily, though injectable form was used in FLOW 2, 6
Advanced CKD (stage 4-5): Semaglutide has been safely used in patients with eGFR 15-29 mL/min/1.73 m² and even in dialysis patients without dose adjustment 6
Clinical Pitfalls to Avoid
Do not discontinue semaglutide due to early eGFR decline - this is an expected hemodynamic effect that reverses over time while kidney protection continues. 3, 1
Do not withhold semaglutide in advanced CKD - unlike SGLT2 inhibitors, semaglutide maintains efficacy and safety even at very low eGFR levels. 6, 5
Do not forget to reduce insulin/sulfonylurea doses - failure to do so increases hypoglycemia risk unnecessarily. 2
Do not skip eye examination - the proliferative retinopathy signal from SUSTAIN-6 requires baseline and ongoing ophthalmologic monitoring. 2