Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dual SGLT1/2 inhibitors have established themselves as central therapies for metabolic and cardiorenal disorders. Since their introduction, it has become evident that, despite all belonging to the class of gliflozins, these drugs show differences in their renal and possibly extrarenal effects. To better understand these drug-related differences, we performed the first direct comparative analysis of various gliflozins on their renal effects. We studied whether commonly used SGLT2 inhibitors (dapagliflozin dapa, empagliflozin empa, canagliflozin cana), a dual SGLT1/2 inhibitor (sotagliflozin sota), and the SGLT1 inhibitor (mizagliflozin miza) differ in their acute renal effects. Male and female mice were randomized to vehicle or to various doses of dapa, empa, cana, and sota (0.3-30 mg·kg - ¹ p.o.), or miza (0.3-10 mg·kg - ¹ i.v.), and subsequently placed in metabolic cages for 3 hours. Urine was collected and analyzed for glucose, electrolytes, organic acids (lactate/citrate/uric acid), and creatinine. Dose-response curves were fitted using four- or five-parameter logistic models, and Emax was reported. For non-dose-dependent parameters, the cumulative effect across all dosages is shown. Dapa produced the strongest glucosuric response, with urinary glucose excretion reaching 67±3 nmol/min/g BW, which was significantly greater compared to empa (38±3 nmol/min/g BW), sota (40±1 nmol/min/g BW), cana (55±1 nmol/min/g BW), and miza (6 nmol/min/g BW). Dapa also produced the greatest increase in Na+ excretion (6±1 nmol/min/g BW), indicating a more robust natriuretic effect compared to the other tested gliflozins. Distinct solute-handling profiles were observed across the tested gliflozins. Cana and miza showed the greatest effect on urinary lactate (5±1 nmol/min/g BW and 6±1 nmol/min/g BW, respectively) and Cl- excretion (72±14 nmol/min/g BW and 53±11 nmol/min/g BW, respectively) across doses. Cana was unique in producing dose-dependent increases in urinary citrate (55 nmol/min/g BW) and uric acid excretion (21±1 pmol/min/g BW), whereas dapa was the only gliflozin that dose-dependently increased urinary Mg2+ excretion (0.7 nmol/min/g BW). Additionally, cana and empa both increased urinary phosphate excretion in a dose-dependent manner (1.5 nmol/min/g BW and 1.2 nmol/min/g BW, respectively). We also demonstrate that SGLT1 inhibition by sota is only partial, as simultaneous administration of miza significantly increased urinary glucose excretion compared to sota alone (P< 0.05). Despite these differences in tubular solute handling, no significant differences were observed among inhibitors in urinary flow rate or creatinine excretion. In summary, our findings demonstrate that gliflozins differ markedly in efficacy and potency as well as other tubular effects on solute handling. Mechanistically, our results highlight different pleiotropic effects across inhibitors, since SGLT2 inhibition alone cannot fully explain differences between these gliflozins. These drug-specific renal signatures highlight the need to interpret presumed “class effects” with caution and support the hypothesis that individual gliflozins may confer distinct renal and metabolic benefits, an important consideration for precision medicine approaches. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Coelho et al. (Fri,) studied this question.