Beneficial effect of sodium-glucose cotransporter 2 inhibitors on kidney function can be just a mirage

Table 1 Randomized placebo-controlled clinical trials revealing that sodium-glucose cotransporter-2 inhibitors increase serum creatinine-based estimated glomerular filtration rate

	Ref.	Study design	Sodium-glucose cotransporter-2 inhibitor	Formula used to estimate GFR	Study population	Number of participants	Primary outcome	Median surveillance period	Estimated GFR change	Main results on kidney disease
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy	Perkovic et al[1], 2019	Randomized, double-blind, placebo-controlled trial	Canagliflozin (100 mg/day) vs placebo	CKD-EPI equation	Patients with T2D treated with renin-angiotensin system blockade, estimated GFR 30-90 mL/min/1.73 m2, and albuminuria	4401	Composite of ESKD (sustained estimated GFR of < 15 mL/minute/1.73 m2, transplantation or dialysis), a doubling of the serum creatinine level, or death from renal or cardiovascular causes	2.62 years	After 3 weeks, the decline in the estimated GFR was slower in the canagliflozin group than in the placebo group (-1.85 ± 0.13 vs -4.59 ± 0.14 mL/minute/1.73 m2 per year)	The relative risks of the primary outcome, the renal-specific composite (ESKD, a doubling of the creatinine level, or death from renal causes), and ESKD were all lower in the canagliflozin group than in the placebo group, by 30%, 34% or 32%, respectively
Dapagliflozin in patients with chronic kidney disease	Heerspink et al[2], 2020	Randomized, double-blind, placebo-controlled trial	Dapagliflozin (10 mg/day) vs placebo	CKD-EPI equation	Patients with CKD with or without diabetes, estimated GFR 25-75 mL/min/1.73 m2 and albuminuria	4304	Composite of a sustained decline in the estimated GFR of at least 50%, ESKD, or death from renal or cardiovascular causes	2.4 years	After 2 weeks, the annual change in the estimated GFR was smaller with dapagliflozin than with placebo (-1.67 ± 0.11 and -3.59 ± 0.11 mL/minute/1.73 m2, respectively)	The risk of a composite of a sustained decline in the estimated GFR of at least 50%, ESKD, or death from cardiovascular or renal causes was significantly lower with dapagliflozin than with placebo. The effects were similar in participants with and without T2D
Empagliflozin in patients with chronic kidney disease	Herrington et al[3], 2023	Randomized, double-blind, placebo-controlled trial	Empagliflozin (10 mg/day) vs placebo	CKD-EPI equation	Patients with CKD and either estimated GFR 20-45 mL/minute/1.73 m2 or estimated GFR 45-90 mL/minute/1.73 m2 and albuminuria	6609	Composite of progression of kidney disease (ESKD, sustained decrease in estimated GFR to < 10 mL/minute/1.73 m2, sustained decrease in estimated GFR of ≥ 40% from baseline, or death from renal causes) and death from cardiovascular causes	2 years	After 2 months, there was a between-group (empagliflozin vs placebo) difference of 1.37 mL/minute/1.73 m2 (95%CI: 1.16-1.59) per year	Empagliflozin therapy led to a lower risk of the composite of progression of CKD and death from cardiovascular causes compared to placebo. The effects were similar in participants with and without T2D

GFR: Glomerular filtration rate; T2D: Type 2 diabetes; ESKD: End-stage kidney disease; CKD-EPI: Chronic kidney disease-epidemiology collaboration.