What is the mechanism of SGLT2 inhibitors like velagliflozin and what veterinary conditions are they approved for?

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Sodium-glucose cotransporter-2 (SGLT2) inhibitors block SGLT2, the renal transporter responsible for reabsorbing glucose from the glomerular filtrate back into circulation, thereby lowering the renal threshold for glucose and increasing urinary glucose excretion in an insulin-independent manner. 2 This mechanism is distinct from insulin secretagogues and insulin sensitizers — glycemic control is achieved regardless of endogenous insulin status, though some residual β-cell function is still required to prevent ketosis when these drugs are used as monotherapy. 18 Two SGLT2 inhibitors are FDA-approved for veterinary use in cats: velagliflozin (Senvelgo, Boehringer Ingelheim) and bexagliflozin, both indicated for uncomplicated feline diabetes mellitus. 1 Velagliflozin is formulated as a 15 mg/mL oral solution administered once daily at 1 mg/kg PO. 2 Following oral dosing at 1 mg/kg in cats, peak plasma concentration is reached at a median of 0.25 hours, with a mean elimination half-life of 3.68 ± 0.34 hours. 2 Systemic exposure is 170% higher for peak concentration and 45% higher for overall exposure in the fasted versus fed state, which is relevant to consistent dosing timing. 2 In cats with uncomplicated diabetes mellitus, velagliflozin produces rapid clinical improvement — more than 50% of cats show improvement in polyuria and polydipsia by day 7, rising to more than 88% by day 180, with polyphagia improved in 75% of cats at 180 days. 4 Diabetic neuropathy (plantigrade stance) resolved in more than 75% of affected cats that completed the study. 4 The paradoxical improvement in polyuria and polydipsia despite glucosuria occurs because the large reduction in blood glucose reduces the total glucose load filtered at the glomerulus, decreasing the osmotic force retaining water in the tubules. 4 Velagliflozin is also used off-label in horses and ponies with insulin dysregulation (ID). Treatment decreases blood insulin concentrations in ID-affected horses and ponies, and po