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

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.