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HESTEFORSK Optimize canagliflozin doses - decrease hyperinsulinemia and prevent laminitis H-21-47-641

Alternative title: Optimisering av canagliflozin-dosering hos hest - for å redusere forekomst av hyperinsulinemi og forebygge forfangenhet

Awarded: NOK 1.4 mill.

Equine metabolic syndrome (EMS) is a collective term used to describe risk factors for development of endocrine laminitis in horses. Laminitis is a frequently occurring, and very painful condition of the horses feet; of which only palliative treatment is available. The fatality of laminitis is high. Heavier horse breeds and ponies, as well as overweight individuals, are predisposed. Insulin dysregulation is central to the endocrine pathway for laminitis, and laminitis research has focused precisely in this area of late. This recent research have given some evidence for the use of sodium-glucose cotransporter (SGLT) inhibitors preventing endocrine laminitis through increased glucose urinary exertion, which directly affects insulin regulation. Pharmacological drugs in the SGLT-group, such as canagliflozin, are currently labelled for treatment of type-2 diabetes patients in human medicine. In these patients, SGLT2 is increased in the kidney, and treatment with SGLT-inhibitors results in both weight loss and increased glycemic control. However, a few, but serious side-effects of treatment have been reported, such as hypoglycemic incidents, and urinary tract infections. There is little knowledge regarding use of SGLT-inhibitors in horses. The objectives of this project are to gather pharmakokinetic and pharmakodynamic data regarding canagliflozin-use in horses, and to perform a safety-study of dosing canagliflozin to three different types of horses (Standardbreds, ponies, and Icelandic horses).

It is hypothesized that canagliflozin increase the amount glucose secreted in urine with an acceptable safety profile and thereby subsequently decrease insulin blood concentration and the risk for laminitis in horses with insulin dysregulation. Part I – Plasma exposure and effect in healthy horses The aim of this part of the study is to characterize the canagliflozin plasma concentration-time course and PD after oral administration of canagliflozin. Eight standardbred horses, eight ponies and eight Icelandic horses will be used in three separate experiments (two treatment cross-over studies) in order to investigate the pharmacology and potential breed differences for canagliflozin. Part II – Population study on clinically ill horses Blood samples from horses enrolled in another study (diagnosed with EMS and treated with canagliflozin) will be analyzed for canagliflozin and included in this project in order to provide information about safety, PK and PD in a greater population with a metabolic disorder. These factors are important to include in the pharmacological studies since they might be sources of variation (vide infra) that affects e.g. the PK and consequently the dosing regimen.

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