The effect of the sodium-glucose cotransporter type-2 inhibitor dapagliflozin on glomerular filtration rate in healthy cats

Abstract Sodium-glucose cotransporter type-2 inhibitors reduce glomerular hyperfiltration in diabetic people with early diabetic nephropathy. The objective of this report was to assess changes in glomerular filtration rate in healthy cats following treatment with a sodium-glucose cotransporter type-2 inhibitor. Eight healthy research adult castrated male cats were used in a randomized, controlled, cross-over study design. We induced isolated renal tubular glucosuria by dosing cats with the sodium-glucose cotransporter type-2 inhibitor, dapagliflozin. The cats received 10 mg dapagliflozin or control every 24 h by mouth in each of the four, 5 d trial periods that were separated by a 7 d washout period. We assessed glomerular filtration rate (iohexol clearance method), serum urea, creatinine, symmetric dimethylarginine, and 24 h sodium and chloride urinary excretion on the 5th d of each trial period. We analyzed the data with a mixed linear model that included the fixed effects of treatment (treated and control) and trial period, and the random effect of the cat. Compared to controls, cats treated with dapagliflozin had a significant increase in mean (±SE) glomerular filtration rate (3.1 ± 0.2 vs. 2.5 ± 0.2 mL/kg/min; P = 0.01); whereas, there were no significant differences in serum urea, creatinine and symmetric dimethylarginine, and 24 h urine sodium and chloride excretion. We propose that dapagliflozin-mediated delivery of sodium and glucose distal from the proximal convoluted tubule induced a compensatory increased sodium absorption at the thick ascending loop of Henle that resulted in decreased sodium delivery to the distal tubule leading to tubuloglomerular feedback-mediated glomerular hyperfiltration. Future studies should determine if sodium-glucose cotransporter type-2 inhibitors’ reno-protective effect in people can be enhanced with the addition of a Na+-K+-Cl- diuretic and whether dapagliflozin will be useful in mitigating proteinuria and hypertension that follow glomerular hyperfiltration in diabetic companion animals in a similar mechanism as in people.