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canagliflozin reduced the insulin response to an OST (Frank, 2018 ). However, direct comparisons are challenging as, in addition to other variables, the follow-up OST was performed 24 h following the last dose of canagliflozin. In contrast, in the current study of clinically affected horses, ertugliflozin was administered 90 min before the second OST as treatment was ongoing for clinical management. The duration of action of ertugliflozin in other species is short (Li et al., 2020 , 2021 ) and it seems unlikely that insulin will remain sup- pressed for 24 h. This might result in marked differences in results depending upon whether testing is performed before or after the repeat dose. Marked differences in duration of action and urinary glucose excretion (and other pharmacodynamic parameters) have been reported between SGLT2i in humans, with persistent glucos- uria noted for over 24 h in some, whilst with others the response di- minishes 12 h after each dose (Choi et al., 2020 ; Tahara et al., 2016 ). The differences may be due to variability in selectivity for the SGLT2 receptor (Suzuki et al., 2022 ) with ertugliflozin reported to be almost one hundred times more selective for SGLT2 com- pared to canagliflozin (Choi et al., 2020 ; Fediuk et al., 2020 ; Tahara et al., 2016 ). The duration of action of ertugliflozin in horses is un- known, highlighting the need for further studies to investigate the pharmacokinetics and pharmacodynamics of ertugliflozin in horses. Glucose concentrations were reduced after 4 days of treatment
in this study; however, the difference was not statistically signifi- cant. This was an unexpected finding, given the glucose-wasting mechanisms of SGLT2i (Kalra et al., 2016 ) and might be a result of the small sample size in the current study. However, a recent report investigating the effects of canagliflozin on pancreatic function in horses concluded that the reduction in insulin concentrations fol- lowing treatment is predominantly attributed to reduced β-cell sen- sitivity rather than an attenuated post-prandial glucose response (Bröjer et al., 2023 ). Given that much of our understanding of SGLT2i are extrapolated from other species, further studies to investigate the underlying mechanisms by which SGLT2i exert their effects in horses are warranted. The increase in triglycerides reported in this study is consistent
with previous reports on the use of SGLT2i in horses with EMS (Frank et al., 2023 ; Kellon & Gustafson, 2022 ; Sundra et al., 2023 ). However, this is the first study to report triglyceride changes so soon after the commencement of treatment. Emerging evidence from human medicine suggests that SGLT2i can modulate lipid me- tabolism in patients with diabetes mellitus (Szekeres et al., 2021 ; Yaribeygi et al., 2022 ) and the increase in triglycerides reported in horses is likely a result of increased glucagon secretion from the pancreatic alpha cells in response to lowered insulin concentra- tion (Janež & Fioretto, 2021 ; Sargent, 2015 ). Glucagon has been reported to stimulate fatty acid mobilisation and lipolysis follow- ing treatment with SGLT2i in other species (Ferrannini et al., 2014 , 2016 ) Unfortunately, a validated assay to measure glucagon in horses is not commercially available. Given the reduction in insulin concentration shortly after commencing treatment, the increase in triglyceride concentrations within a few days is not surprising. The single horse with a high GLDH concentration on day 4 also
SUNDRA ET AL.
reported the highest triglyceride concentration, which may ac- count for the increased hepatic enzyme activity. However, GLDH is a very reactive marker, and the increase was relatively small so it may have been unrelated to ertugliflozin administration and in- creased triglycerides. The increases in triglycerides in the current study were small and were not to levels that would be expected to result in hepatic lipidosis or clinical signs of hyperlipaemia. Hypertriglyceridemia and increases in hepatic enzymes have been reported previously in horses with endocrine dysfunction without any clinical abnormalities (Dunkel et al., 2013 ). Although clinical signs of hyperlipaemia were not observed in this or a previous study of ertugliflozin use in horses with EMS (Sundra et al., 2023 ), owners should be made aware of the potential complications which could develop shortly after commencing treatment and should be advised to be vigilant for signs of hyperlipaemia such as inappetence or a change in demeanour. This study was limited by its small sample size, retrospective data
collection, absence of a control group and short follow-up period. The dose of ertugliflozin used in this study is based on anecdotal experience, extrapolation from other species and preliminary data in horses (Sundra et al., 2023 ). Further studies to investigate the pharmacokinetics and pharmacodynamics of ertugliflozin are war- ranted to determine the optimal dose and dosing interval in horses. Extemporaneous ertugliflozin should be used in accordance with local regulations. In conclusion, the present study adds to the current under-
standing of SGLT2i use in horses with ID, HAL and EMS. The results demonstrate the potential for ertugliflozin to reduce insulin concen- tration and insulin responses to oral sugars within days of initiating treatment and provide a reference for clinicians seeking to use the OST to assess response to treatment.
AUTHOR CONTRIBUTIONS The study was conceived by T. Sundra, G. Rossi, G. Lester and D. Rendle and executed by T. Sundra. Data analysis was performed by T. Sundra and E. Kelty. The manuscript was prepared by T. Sundra and D. Rendle with assistance from all other authors. All authors ap- proved the final manuscript.
ACKNO WLE DGE MENTS The authors are grateful to the owners of the horses for agreeing to share the case data. Open access publishing facilitated by Murdoch University, as part of the Wiley - Murdoch University agreement via the Council of Australian University Librarians.
FUNDING INFORMATION No funding was received.
CONFLICT OF INTEREST STATEMENT David Rendle provides consultancy services to BOVA who produce an extemporaneous ertugliflozin paste specifically for horses. Tania Sundra has received subsidised travel expenses to CPD events from BOVA.
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