MANAGEMENT OF HYPERINSULINAEMIA
management of hyperinsulinaemia and HAL, long- term safety stud- ies and robust clinical trials are currently lacking. The most widely recognised adverse effects of SGLT2i use in peo-
ple are urinary tract infections (UTI) and diabetic ketoacidosis (DKA) (Singh & Kumar, 2018 ). The risk of urinary tract infections caused by glucosuria during SGLT2i use is still a matter of controversy with some studies reporting a significantly higher risk (Figueiredo et al., 2018 ), while other meta- analyses demonstrated no significant difference in patients treated with SGLT2i compared to placebo. While DKA is rarely associated with SGLT2i therapy (Donnan et al., 2019 ; Puckrin et al., 2018 ), it is a serious complication and the underlying mech- anism of DKA following the use of SGLT2i is not completely under- stood (Singh & Kumar, 2018 ). Given the potential for life- threatening illness, “sick- day” protocols have been developed, whereby patients are advised to stop their SGLT2i medication during periods of illness or reduce food intake to reduce the incidence of DKA (Goldenberg et al., 2016 ). Adverse effects associated with SGLT2i use in humans are influenced by patient frailty, comorbidities and concurrent medica- tions (Pollack & Cahn, 2022 ). Given the lack of safety data on SGLT2i use in horses, studies from human medicine highlight the potential for adverse effects when using these drugs. The use of SGLT2i
In horses has been associated with poly-
uria and polydipsia, but urinary tract infections have not been ob- served in horses to date (Kellon & Gustafson, 2022 ; Sundra, Kelty, & Rendle, 2023 ; Sundra, Lester, et al., 2023 ). Volume depletion, second- ary to the osmotic effects of glucosuria is a potential consequence (List & Whaley, 2011 ) and horses treated with SGLT2i should there- fore have access to clean, fresh drinking water at all times and the medication should be stopped if signs of dehydration are observed. Hypertriglyceridaemia has been reported during treatment with
velagliflozin, canagliflozin and ertugliflozin (Frank et al., 2023 ; Kellon & Gustafson, 2022 ; Sundra, Kelty, & Rendle, 2023 ; Sundra, Lester, et al., 2023 ). The authors ' clinical experience would suggest that follow- ing an initial surge in triglycerides during the first few weeks of treat- ment, concentrations return to near- normal in the majority of horses by 60 days (Sundra, Kelty, & Rendle, 2023 ; Sundra, Lester, et al., 2023 ). Classic clinical signs of hyperlipaemia such as dullness and anorexia, and biochemical changes directly associated with hepatic dysfunction have not been reported during treatment with velagliflozin or ertugli- flozin, however, a single horse with other comorbidities demonstrated signs of anorexia, colic and lethargy when treated with canagliflozin (Kellon & Gustafson, 2023 ) and the authors are aware of similar cases being treated with ertugliflozin and dapagliflozin that have developed critical illness and subsequently hyperlipaemia. It is important that he- patic and renal function and triglyceride concentrations are assessed prior to commencing treatment with SGLT2i as the use of these drugs in horses with compromised renal or hepatic function has not been investigated. Given that many breeds that are at increased risk for EMS are also susceptible to clinical hyperlipaemia, it is prudent to withdraw therapy if signs of reduced feed intake, colic or dullness are observed or if the feed is being withheld. Furthermore, abrupt feed restriction should not coincide with the start of SGLT2i treatment and dietary strategies to manage hyperinsulinaemia should have been
| 331
implemented prior to considering pharmaceuticals. Veterinarians are advised to monitor triglyceride concentration in horses treated with SGLT2i, and adjustments in dose might be warranted if severe hyper- triglyceridaemia is observed (EEG, 2022 ). In addition to insulin, the author routinely measures triglycerides, gamma- glutamyl transferase (GGT), glutamate dehydrogenase (GLDH) and creatinine prior to com- mencing treatment, at days 4–7 and then monthly in the initial stages to monitor the response to treatment. Based on the authors ' clinical experience, the duration of SGLT2i
use varies markedly between patients and is largely dependent on the clinical response. In horses that have demonstrated improved insulin sensitivity and have undergone changes in management, long- term use of SGLT2i may not be required once the horse has recovered from HAL. In these cases, the author reduces the dose by half for 2 weeks, then half again for a further 2 weeks before dis- continuing the medication to allow for the adjustment of metabolic pathways. Insulin should be monitored during the tapering period following each change of dose. Some horses, despite excellent man- agement by owners, demonstrate persistent ID and might require long- term treatment. Anecdotally, many of these cases can often be managed at lower doses (0.025 mg/kg of ertugliflozin), resulting in a potential cost- saving for the owner. A subset of horses treated with ertugliflozin reported an increase in insulin concentration after the first month of treatment (Sundra, Kelty, & Rendle, 2023 ; Sundra, Lester, et al., 2023 ). Studies in other species have demonstrated a compensatory up- regulation of SGLT1 in response to SGLT2 inhi- bition which might account for this increased insulin concentration (Rieg et al., 2014 ). Clinicians should be aware that this is a potential consequence in a subset of animals and highlight why long- term di- etary management is imperative to reduce the risk of HAL. Recent human studies demonstrated the use of SGLT2i in com-
bination with metformin was associated with improved glycaemic control, low incidences of adverse effects and risk of hypoglycaemia, reductions in body weight and improved patience adherence (Bailey et al., 2010 ; Frias, 2019 ; Hu et al., 2016 ). The metformin/SGLT2i combination has not been investigated in horses but may warrant further consideration if SGLT2i monotherapy fails to reduce plasma insulin concentration in horses with hyperinsulinaemia. It is import- ant to note that the long- term effects of SGLT2i therapy have not been investigated in horses. The author recommends monitoring in- sulin, triglycerides and hepatic and renal markers (mentioned above) at least every 3 months to monitor efficacy and detect any potential adverse effects of long- term term treatment.
Corticosteroids
The association between corticosteroids and laminitis is still a mat- ter of conjecture. However, it is recommended that corticosteroid use should be carefully evaluated in equids with or at risk for hy- perinsulinaemia (Knowles, 2018 ). Corticosteroids might increase insulin concentrations by preventing the uptake of glucose into adi- pose tissue and muscle and by stimulating gluconeogenesis (Bailey
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88
