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| INTRODUCTION
Equine metabolic syndrome (EMS) is characterised by obesity, in- sulin dysregulation (ID) and an increased risk for the development of laminitis in horses and ponies (hereafter collectively referred to as horses; Durham et al., 2019 ). Hyperinsulinaemia, defined as the presence of excess insulin in the blood (de Laat et al., 2016 ; Suagee et al., 2011 ), is central to the development of laminitis in horses with EMS (de Laat & Sillence, 2020 ; Frank & Tadros, 2013 ). The term ‘hy- perinsulinaemia-associated laminitis’ or HAL is used to differentiate these cases from horses that develop laminitis because of sepsis or excessive weight-bearing on a single limb (Frank et al., 2022 ). The oral sugar test (OST) has been advocated as a simple, reliable
means of identifying ID in horses and can be used in an ambulatory setting (Schuver et al., 2014 ). The test assesses the insulin response to a measured dose of corn syrup (de Laat et al., 2016 ). A recent study found no statistical difference between the insulin responses to two different doses of corn syrup (Macon et al., 2021 ); however, another study demonstrated improved sensitivity and repeatability of the OST using a high dose (0.45 mL/kg) of corn syrup (Jocelyn et al., 2018 ) and this is the dose that is recommended currently (Frank et al., 2022 ). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively
new class of human antidiabetic drugs that lower insulin concentra- tion by inhibiting glucose resorption in the kidney thus increasing urinary glucose excretion, reducing plasma glucose concentration and reducing insulin secretion from the pancreas (Kalra et al., 2016 ; Nauck, 2014 ). Under normal physiological conditions, the SGLT2 is re- sponsible for approximately 90% of glucose reabsorption in the prox- imal convoluted tubule of the kidney (Bays, 2013 ; Kalra, 2014 ; Sha et al., 2011 ). Experimental studies have demonstrated that velagli- flozin lowers insulin concentration and prevents the development of laminitis in ponies fed a high nonstructural carbohydrate diet (Meier et al., 2018 , 2019 ). Ertugliflozin and canagliflozin have both been re- ported to lower post-prandial insulin concentrations and hasten the recovery from clinical cases of laminitis associated with hyperinsu- linaemia (Kellon & Gustafson, 2022 ; Sundra et al., 2023 ). In a series of 51 horses with HAL, ertugliflozin treatment was associated with a marked reduction in insulin concentration and lameness by 30 days; however, the more immediate insulin response and insulin responses to the OST were not assessed (Sundra et al., 2023 ). Canagliflozin has been shown to lower the insulin response to an OST in horses with ID (Frank, 2018 ) after 3 weeks of treatment; however, marked differences in pharmacodynamic and clinical effects of different SGLT2i have been identified in other species (Choi et al., 2020 ; Suzuki et al., 2022 ; Tahara et al., 2016 ). Horses with HAL exhibit a rapid clinical improve- ment within days of treatment with ertugliflozin (Sundra et al., 2023 ) and anecdotal reports indicate that insulin drops rapidly in response to treatment. It is, therefore, assumed that the clinical improvement in laminitis is associated with reducing insulin concentrations. Although the initial drop in insulin concentration is being used to assess the re- sponse to treatment in equine practice, insulin responses in the first few days of treatment have not been documented. This report documents the response to the OST in clinical cases of ID treated with ertugliflozin after 4 days of treatment.
MATERIALS AND METHODS Horses
A review of medical records pertaining to horses presenting to Avon Ridge Veterinary Services for investigation of ID between October 2022 (mid-spring) and January 2023 (mid-summer) was conducted to identify horses with HAL that had been treated with ertugliflozin and had had the initial response assessed using an OST. Consistent with current expert recommendations and a previous study (Frank, 2018 ), the practice had a pre-determined protocol for assessing hyperinsu- linaemia and selected clinical chemistry analytes prior to, and 4 days after, the onset of treatment. The assessment at 4 days enabled early adverse effects such as hypertriglyceridaemia to be identified (Frank et al., 2023 ; Kellon & Gustafson, 2022 ; Sundra et al., 2023 ) and the response to treatment to be assessed and adjusted if necessary. This follow-up also coincided with repeat clinical assessment of laminitis in those that were lame. Horse weight was estimated using a vali- dated weight tape (Virbac) and body condition scored out of 9 using a validated scale (Henneke et al., 1983 ). Lameness was graded using the modified Obel scale and scored out of 12 as per a previously described protocol (Meier et al., 2021 ).
Oral sugar test
Horses were housed in their home premises and fasted in a dry lot or stable by their owners from 2100 h the night prior until after comple- tion of the OST (Durham et al., 2019 ). The OST commenced between 0600 and 0800 h. Karo-Light syrup (ACH Food Companies) was ad- ministered by one of the authors at 0.45 mL/kg bwt using 60 mL catheter-tipped syringes. A blood insulin concentration ≥ 20 uU/ mL at T0 (Bertin & de Laat, 2017 ) and/or ≥63 uU/mL at T60 or T90 (Frank et al., 2022 ) was considered indicative of EMS.
Medication
Ertugliflozin is currently produced as an extemporaneous formu- lation in regulated premises. No registered human or equine for- mulations are available where the work was performed and in the absence of a registered formulation or suitable registered alterna- tive, ertugliflozin was used for the treatment of hyperinsulinaemia in accordance with the local legal framework. The product is sup- plied as a 30 mL syringe containing 30 mL ertugliflozin paste (BOVA Aus) at 5 mg/mL, which is manufactured in batches and subject to quality and stability testing. Informed client consent was obtained prior to commencing treatment. Treatment commenced between 24 and 48 h after the first oral sugar test depending on the time taken by the laboratory to report results. Ertugliflozin paste was administered at 0.05 mg/kg bodyweight PO s.i.d. between 0500– 0800. On day 4, ertugliflozin was administered 80–100 min prior to the collection of the T0 sample and the administration of corn syrup.
SUNDRA ET AL.
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