ATC Vet Code: QA10BK90 (sodium-glucose co-transporter 2 (SGLT 2) inhibitors)

Velagliflozin is a selective inhibitor of the sodium-glucose co-transporter 2 (SGLT 2) which is predominantly expressed in the kidney. Velagliflozin also has a minor inhibitory effect on the SGLT-1 which is predominantly expressed in the small intestine, but also expressed at a lower level in the kidney. SGLT 2 is the primary transporter for the reabsorption of glucose from the urine. The inhibition of the SGLT 2 leads to glucose elimination in the urine and results in a decrease in elevated blood glucose levels in diabetic patients. This decrease is usually observed within 7 days after start of treatment. A low level of glucose will continue to be resorbed via incomplete inhibition of the SGLT-1 which prevents clinical hypoglycaemia. This minor inhibitory action on SGLT-1 can also contribute to a dose-dependent softening of stool and loose stool/diarrhoea due to the expression of SGLT-1 in the small intestine.

In a European clinical field trial, the safety and efficacy of 1 mg/kg once daily oral velagliflozin in diabetic cats was evaluated and compared to twice daily veterinary licensed porcine insulin therapy (individual dose adjustment) over 91 days. The efficacy assessment was performed after 45 treatment days and assessed if an animal showed a combined improvement in at least one clinical sign related to diabetes (e.g. water uptake, urination volume and frequency, diabetic polyneuropathy and appetite) and an improvement in at least one glycaemic laboratory parameter (mean blood glucose of the blood glucose curve ≤250 mg/dl [approximately 14 mmol/l], min blood glucose ≤160 mg/dl [approximately 9 mmol/l] and serum fructosamine ≤450 µmol/l). The study confirmed that once daily oral administration of velagliflozin is non-inferior to twice daily insulin injections.

In a US clinical field trial, the safety and efficacy of 1 mg/kg/day velagliflozin was evaluated in newly diagnosed diabetic cats as well as cats previously treated with insulin or other anti-diabetic medications. The study design utilised baseline control with all enrolled cats receiving velagliflozin. In this trial, 88.4% of the cats treated with velagliflozin and included in the efficacy analysis met the requirement for treatment success on day 30.

This efficacy assessment was performed after 30 days of treatment and cats determined eligible to continue into the extended use phase could be treated for up to 180 days. The efficacy assessment at Day 30 was judged by a combination of clinical and laboratory parameters related to diabetes mellitus.

The composite variable “treatment success” was comprised of an improvement in at least one clinical sign related to diabetes mellitus (polyuria, polydipsia, unintended weight loss, polyphagia, or diabetic neuropathy) and improvement in at least one glycaemic variable in comparison to the screening visit. The glycaemic variable could be either the mean of the blood glucose curve, which had to be ≤300 mg/dl (approximately 17 mmol/l) and below the fasted screening visit blood glucose, or serum fructosamine, which had to be ≤450 μmol/l and below the screening visit fructosamine value.

Most owners (67%) reported very good or excellent quality of life (QoL) in their cats by the Day 30 visit. In addition, by the Day 30 visit, 87% of cats were reported as having good, very good or excellent overall diabetic control by the Study Veterinarians.

After oral administration of velagliflozin to fasted healthy cats, plasma-concentration-time curves are characterised by rapid absorption with maximum plasma concentrations (Cmax) achieved after 0.6–1 hour (tmax). The mean Cmax ranged from 1293 to 2161 ng/ml and the mean areas under the curve within 24 hours (AUC0-24h) ranged from 6944 to 11035 h*ng/ml.

After oral administration of velagliflozin to fed healthy cats plasma-concentration-time curves are characterised by slightly delayed absorption with Cmax achieved after 1 3.67 hours (tmax). The mean Cmax ranged from 316 to 846 ng/ml and the mean areas under the curve within 24 hours (AUC0-24h) ranged from 2786 to 7142 h*ng/ml.

In summary, although fasted cats showed a higher Cmax and shorter tmax, resulting in a higher exposure (AUC0-24h) compared to cats in fed state, this is not considered to be of clinical relevance.

After repeat daily oral administration of 1, 3 and 5 mg/kg velagliflozin to healthy cats over six months, a slight increase of exposure (range: 1.3- to 1.9-fold) was observed. In addition, a tendency for a less than dose-proportional increase of exposure (AUC) and Cmax was observed for all dose levels.

An in vitro study using cat plasma showed high (91.3% to 93.7%) plasma protein binding.

An in vitro study using cat whole blood investigating partitioning of velagliflozin into red blood cells showed a blood-to-plasma ratio of 0.84.

Pharmacokinetics after intravenous administration in cats showed a volume of distribution similar to that of total body water, indicating distribution of velagliflozin into tissue.

The primary metabolic pathways observed in cats after oral administration of velagliflozin were oxidation, a combination of oxidation and dehydrogenation, and sulphate conjugation. Velagliflozin showed an absolute bioavailability of 96% in healthy fasted cats after oral administration.

After oral administration (fed/fasted) mean half-life (t1/2) ranged from 4.49 to 6.44 hours.

After oral administration to cats, velagliflozin was primarily excreted unchanged in faeces. Only minor renal excretion occurred (approximately 4%).