Cardio-kidney-metabolic protective effects of semaglutide across the spectrum of chronic kidney disease

Table 1 Key characteristics and kidney endpoints from the Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes, Evaluate Renal Function with Semaglutide Once Weekly, and Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity trials of semaglutide

Trial	Population	Key inclusion criteria	Baseline characteristics	Semaglutide subcutaneous dose	Duration of follow-up	Kidney endpoints
SUSTAIN-6	3297 adults with T2D at high CV risk	T2D patients ≥ 50 years with established CV disease, CKD, or both	Mean age: 65.4 years- 64.5% male- HbA1c: 8.4%- Diabetes duration: 14.4 years- 83% with CV disease, CKD, or both	0.5 mg or 1.0 mg weekly	Median 2.1 years	New or worsening nephropathy: Macroalbuminuria, doubling of serum creatinine with eGFR ≤ 45, initiation of renal replacement, or renal death
FLOW	3534 adults with T2D and CKD	eGFR 25-75 + UACR 100-5000 mg/gOn stable RAAS blockade	Mean age: Approximately 65 years- 69.7% Male- Mean eGFR: Approximately 47 mL/min- Median UACR: Approximately 1000 mg/g	Up to 1.0 mg weekly	Median 3.4 years	Composite: Kidney failure (dialysis, transplant), sustained ≥ 50% decline in eGFR, or death from kidney/CV causes
SELECT	17604 adults with overweight/obesity & CV disease, no diabetes	Age ≥ 45, BMI ≥ 27, established CV disease, no diabetes	Mean age: Approximately 61 years- 72% male- Mean BMI: Approximately 33- 100% with CV disease	2.4 mg weekly	Median 3.5 years	Composite: ≥ 50% decline in eGFR, kidney failure, or kidney-related death

FLOW: Evaluate Renal Function with Semaglutide Once Weekly; SELECT: Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity; SUSTAIN-6: Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes; eGFR: Estimated glomerular filtration rate; ETD: Estimated treatment difference; CV: Cardiovascular; T2D: Type 2 diabetes; CKD: Chronic kidney disease; UACR: Urinary albumin-creatinine ratio.

Table 2 Effects of semaglutide on kidney outcomes in the semaglutide use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes, Evaluate Renal Function with Semaglutide Once Weekly, and Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity trials

Trial	Primary composite kidney endpoint	Effect of semaglutide on albuminuria	Composite kidney endpoint (Excl. albuminuria)	Effect of semaglutide on change in eGFR	Effect on ESKD
SUSTAIN-6	Reduced risk by 36% (HR: 0.64; 95%CI: 0.46-0.88; P = 0.005). Endpoint included macroalbuminuria, doubling of serum creatinine with eGFR ≤ 45, renal replacement, or renal death	New onset macroalbuminuria reduced by 46% (HR: 0.54, 95%CI: 0.37-0.77), P = 0.003 for semaglutide vs placebo	NR	Significant reduction in annual change in eGFR: Estimated treatment difference 06 mL/min/1.73 m2 (95%CI: 0.24-0.96, P = .001) Doubling of serum creatinine not reduced (HR: 1.28, 95%CI: 0.64-2.58)	No significant difference for semaglutide vs placebo, (HR: 0.91, 95%CI: 0.40-2.07)
FLOW	24% risk reduction (HR: 0.76; 95%CI: 0.66-0.88; P = 0.0003). Endpoint included kidney failure, ≥ 50% eGFR decline, or death from kidney/CV causes	Reduction of UACR ratio compared to placebo at week 104 to UACR at baseline (0.60 vs 0.88, HR: 0.68; 95%CI: 0.62-0.75) - significance not reached	24% risk reduction (same as primary endpoint; albuminuria not included)	Significant reduction in eGFR slope decline vs placebo (-2.19 vs -3.36 mL/min/1.73 m2 per year; between group difference, 1.16; 95%CI: 0.86-1.47; P < 0.001)	Semaglutide treated group reduced rate of persistent ≥ 50% reduction from baseline in eGFR (HR: 0.73; 95%CI: 0.59 to 0.89) and persistent eGFR < 15 mL/min/1.73 m2 (HR: 0.80; 95%CI: 0.61 to 1.06) - significance not reached
SELECT	22% reduction in composite endpoint (HR: 0.78; 95%CI: 0.64-0.95). Included eGFR < 15, ≥ 50% eGFR decline, renal death, dialysis, macroalbuminuria	Significant UACR reduction (P < 0.001)	18% risk reduction (HR 0.82; 95%CI 0.68-0.99) for endpoint excluding macroalbuminuria	Attenuated eGFR decline vs placebo at 104 weeks (-0.86 vs -1.61 mL/min/1.73 m2) with reduced eGFR slope decline in semaglutide treated group (-0.78 vs -1.17 mL/min/1.73 m2 per year (95%CI 0.3-0.48 P < 0.001)	Fewer ESKD events in semaglutide group however not significant due to low number of events

FLOW: Evaluate Renal Function with Semaglutide Once Weekly; SELECT: Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity; SUSTAIN-6: Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes; eGFR: Estimated glomerular filtration rate; UACR: Urinary albumin-creatinine ratio.

Table 3 Kidney Outcomes from the Semaglutide Cardiovascular Outcomes Trial (oral semaglutide in type 2 diabetes with cardiovascular or kidney disease)

Feature	Description	Oral semaglutide	Placebo	Hazard ratio (95%CI)
Major inclusion criteria	Adults ≥ 50 years with T2D and at least one of: CAD, cerebrovascular disease, symptomatic PAD, or- CKD (eGFR < 60 mL/min/1.73 m2)	-	-	-
5-point kidney composite outcome	Includes: CV death, kidney death, ≥ 50% eGFR decline, sustained eGFR < 15, or initiation of dialysis/transplant	10.4% (n = 502)	11.2% (n = 539)	0.91 (95%CI: 0.80-1.05)
4-point kidney outcome (excl. CV death)	Includes: Kidney death, ≥ 50% eGFR decline, sustained eGFR < 15, or dialysis/transplant	4.5% (n = 207)	5.2% (n = 251)	0.82 (95%CI: 0.68-0.98)
Kidney-related death	Death adjudicated as kidney-related	0.3% (n = 12)	0.3% (n = 13)	0.92 (95%CI: 0.42-2.00)
eGFR loss	Annual change in eGFR (mL/minute/1.73 m2)	-2.06	-1.67	ETD: 0.40 (95%CI: 0.27-0.53, P < 0.0001)

CV: Cardiovascular; eGFR: Estimated glomerular filtration rate; T2D: Type 2 diabetes; CKD: Chronic kidney disease; CAD: Coronary artery disease; ETD: Estimated treatment difference; PAD: Peripheral artery disease.