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

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors suppress glucose reabsorption in the kidney proximal tubule through the SGLT2 protein, leading to glucosuria and osmotic diuresis. Randomized placebo-controlled clinical trials show that SGLT2 inhibitors increase long-term estimated glomerular filtration rate (GFR), calculated with serum creatinine-based equations. However, this effect of SGLT2 inhibitors may not reflect an improvement of kidney function. Investigations conducted in healthy volunteers and patients with chronic kidney disease and population-based studies reveal a positive association between urinary osmolality and GFR, either measured or estimated, indicating that glucosuria and osmotic diuresis are associated with glomerular hyperfiltration. Further, glomerular hyperfiltration is magnified by animal meat consumption. Therefore, the elevation of estimated GFR observed in patients receiving SGLT2 inhibitors may represent an adaptive response to glucosuria and osmotic diuresis driven by these drugs rather than an improvement of kidney function. Additionally, SGLT2 inhibitors have been consistently associated with loss of skeletal muscle mass. Reduction of muscle mass lowers serum creatinine. Serum creatinine-based equations to evaluate GFR overestimate kidney function in patients with reduced muscle mass. In patients receiving SGLT2 inhibitors, estimation of GFR using serum creatinine formulas may yield misleading high values of GFR that do not reflect a beneficial effect on kidney function.

Keywords: Sodium-glucose cotransporter-2 inhibitors; Estimated glomerular filtration rate; Glomerular hyperfiltration; osmotic diuresis; Glucosuria; Skeletal muscle mass; Serum creatinine-based estimation of glomerular filtration rate; Kidney function overestimation

Core Tip: Sodium-glucose cotransporter-2 (SGLT2) inhibitors increase long-term serum creatinine-based estimated glomerular filtration rate (GFR), but this effect may not represent a kidney protective effect. Subjects undergoing osmotic diuresis exhibit glomerular hyperfiltration. In patients receiving SGLT2 inhibitors, the elevated estimated GFR may reflect an adaptive response to osmotic diuresis rather than an improvement of kidney function. In addition, loss of skeletal muscle mass has been consistently associated with use of SGLT2 inhibitors. In patients with reduced muscle mass, serum creatinine-based estimation of GFR produces a deceptive increase of estimated GFR. In patients receiving SGLT2 inhibitors, increased estimated GFR may represent an overestimation of the factual kidney function rather than an actual improvement.