Mechanism of Action
Sodium-glucose cotransporter-2 (SGLT2; ie, sodium-glucose linked transporter-2) proteins are expressed in the proximal tubules and reabsorb filtered glucose from the lumen of renal tubules back into systemic circulation.1 SGLT2 inhibitors (eg, bexagliflozin, velagliflozin) prevent reabsorption of a substantial proportion of filtered glucose. The resulting nonreabsorbed glucose is excreted in urine, lowering blood glucose concentrations in hyperglycemic patients. These drugs are administered orally once daily and can be mixed with food or given directly by mouth. SGLT2 inhibitors do not mimic the actions of insulin; some residual insulin production is needed to prevent ketosis.
Patient Evaluation & Selection
Cats may exhibit transient hyperglycemia due to stress; therefore, this finding alone is insufficient for diagnosis of diabetes mellitus (DM). Serum fructosamine concentrations should be measured if there is diagnostic uncertainty.2
Most cats with DM have viable pancreatic beta cells at the time of diagnosis and are therefore appropriate candidates for an SGLT2 inhibitor.2 Cats with significant weight loss, comorbid conditions, inappetence, or dehydration should not be started on an SGLT2 inhibitor; thorough physical examination, CBC, serum chemistry profile, urinalysis, and measurement of total thyroxine are recommended as part of the initial patient evaluation.1
Cats with ketosis (positive urine dipstick for acetoacetate or blood beta-hydroxybutyrate [BHB] >3.6 mmol/L) should be prescribed insulin rather than an SGLT2 inhibitor.3,4 A cutoff of 2.4 mmol/L should be used in cats with a history of metabolic acidosis or renal disease, and some sources suggest insulin is indicated in any patient with a BHB >2.4 mmol/L.1
Efficacy of SGLT2 Inhibitors in Cats
Polydipsia and polyuria have been reported to improve in >50% of cats after one week of treatment with an SGLT2 inhibitor.4 Serum fructosamine has been shown to return to the reference interval within 30 days of treatment in ≈70% of naive diabetic cats, and peripheral neuropathy resolved in 75% of affected cats after 6 months of treatment4; however, some cats exhibit persistent clinical signs of DM and hyperglycemia (indicators of a lack of response to an SLGT2 inhibitor) and should be transitioned to insulin.
In one study, velagliflozin was shown to be more effective than twice daily, titrated, porcine lente insulin injections. By day 45, serum fructosamine was <450 μmol/L in 76% of cats administered velagliflozin and 61% of cats administered insulin.5
Although various other oral hypoglycemic agents have been investigated for use in cats with DM, safety and efficacy have been problematic. SGLT2 inhibitors are more effective and/or safer than other oral hypoglycemic agents.1
Adverse Effects & Risks
Mild, self-limiting diarrhea has been reported in 30% to 50% of cats.2,3 Transitioning to a low-carbohydrate diet may be helpful.3,4 SGLT2 inhibitors do not appear to increase risk for UTI. The most significant adverse effect is diabetic ketoacidosis (reported in 5%-6% of cats), which usually occurs within the first 2 weeks of treatment. Affected cats are often euglycemic (ie, blood glucose <250 mg/dL).3-5 Most significant complications occur in the first 2 weeks of treatment. Careful patient selection and appropriate monitoring can minimize the risk for severe adverse effects.1 Inadvertent duplicate administration or missing a dose are not concerns; the next usual dose can be administered at the normal time.
Dietary Considerations
Cats should be maintained on their usual diet for the first 2 weeks of therapy. Subsequently, anecdotal evidence supports transitioning to a low-carbohydrate diet (ie, <14% of metabolizable energy derived from carbohydrates).2 Canned foods improve feelings of satiety and are thus preferable. A careful weight loss program should be created for overweight cats, with a target loss of <2% of body weight weekly.
Management & Monitoring
In the author’s experience, many pet owners prefer to administer drugs orally rather than give an injectable insulin. In contrast to insulin therapy, there is essentially no risk for clinical hypoglycemia in cats administered an SGLT2 inhibitor.3-5
Treatment goals (ie, stable body weight, mitigation of clinical signs, improved glycemia, good quality of life) are similar to those in cats receiving insulin. Monitoring should include regular assessments for ketosis and, ideally, measurement of BHB concentration, which can be performed with inexpensive handheld devices. Cats should be re-evaluated several times during the first 2 weeks of therapy (days 2-3, 7, and 14).1 Insulin therapy is indicated if BHB is >2.4 mmol/L during treatment, as this value indicates significant ketosis and profound insulin deficiency. Response to therapy should be assessed after 1 month. Patients with ongoing signs of DM or with serum fructosamine levels that have not decreased by >50 μmol/L should be transitioned to insulin.1
Additional Considerations
Velagliflozin oral solution and bexagliflozin tablets are the only SGLT2 inhibitors FDA approved for use in cats and are only approved for naive diabetic cats; administration to a cat that has previously received insulin is considered extra-label. Extra-label coadministration of an SGLT2 inhibitor with insulin has been reported in dogs and cats with poorly regulated DM, including feline patients with acromegaly, and appears to be an effective strategy for some patients6-8; however, careful monitoring for hypoglycemia is necessary.
SGLT2 inhibitors are not approved for use in dogs and should never be administered alone to a dog with DM, as this species best fits the model for human type 1 DM. Canine diabetes is therefore assumed to be insulin dependent.