Canagliflozin: pharmacokinetics, tolerability and effects in healthy horses

Canagliflozin (Invokana) may be in the future of your Insulin Resistant (Metabolic Syndrome) horse. Here are the results of a single dose test, checking for toxicity and effects. There was improvement in glucose and insulin numbers. Following is a brief Wiki report about pharmokinetics in humans. Of note is how canagliflozin is potentiated by the addition of metformin, a drug already being experimented with in IR horses.
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Canagliflozin: pharmacokinetics, tolerability and glucose/insulin effects of supratherapeutic doses in healthy horses
Vet J. 2025 Aug 2:106412. doi: 10.1016/j.tvjl.2025.106412. Online ahead of print.
Authors
Peter Michanek 1 , Johan Bröjer 2 , Inger Lilliehöök 2 , Cathrine Fjordbakk 3 , Malin Erkas 2 , Minerva Löwgren 4 , Mikael Hedeland 5 , Jonas Bergquist 6 , Carl Ekstrand 4
Affiliations

1 Department of Animal Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden. Electronic address: peter.michanek@slu.se.
2 Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
3 Department of Companion Animal Clinical Sciences, Norwegian University of Life Sciences, Oslo, Norway.
4 Department of Animal Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
5 Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
6 Department of Animal Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden; Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.

PMID: 40759271
DOI: 10.1016/j.tvjl.2025.106412

Abstract

Sodium-glucose co-transporter 2 inhibitors like canagliflozin (CFZ) have shown promise in preventing hyperinsulinemia-associated laminitis in horses, but data on pharmacokinetics, tolerability, and controlled studies are limited. This randomized, open-label, placebo-controlled, crossover study evaluated these aspects of CFZ treatment in eight healthy Standardbred mares. Each horse received single supratherapeutic oral doses of CFZ (1.8mg/kg or 3.6mg/kg) and placebo, with a two-week washout between treatments. A graded glucose infusion (GGI) was administered post-treatment to evaluate glucose and insulin responses. Plasma CFZ, glucose, insulin, urinary glucose, serum biochemistry, and urinalysis samples were collected over 72hours post-treatment. For CFZ 1.8mg/kg, median Cmax was 2623ng/mL, Tmax 2.2hours, and T1/2Z 21.8hours; for 3.6mg/kg, Cmax was 4975ng/mL, Tmax 2.8hours, and T1/2Z 23.0hours. The pharmacokinetics of CFZ displayed dose-proportionality across the two tested doses. Insulin and glucose responses to a GGI, measured by the area under the concentration-time curve (AUC), were similar between CFZ doses but significantly reduced compared to placebo (p < 0.001). Specifically, mean glucose AUC for CFZ treatments was approximately 14-15% lower, and mean insulin AUC 22-29% lower, than for placebo. For CFZ-treated horses, mean urinary glucose concentrations ranged from 277 to 347mmol/L at 24, 48, and 72hours post-administration, with no significant differences between dose levels. No clinical signs of adverse effects were observed, although a significant increase in GLDH levels compared to placebo (p< 0.05) was observed with the CFZ 3.6mg/kg dose.

Keywords: SGLT2 inhibitor; canagliflozin; equine, laminitis; graded glucose infusion; horse; pharmacokinetics.
Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.

From Wikipeddia:
Pharmacology
Mechanism of action
Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of renal glucose reabsorption (the remaining 10% is done by SGLT1 inhibition[33][34]). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,[35] corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.

This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other types of anti-diabetic drugs such as sulfonylurea derivatives and insulin.[36]

Pharmacokinetics
When taken by mouth, canagliflozin reaches highest blood plasma concentrations after one to two hours and has an absolute bioavailability of 65%, independently of food intake. When in the bloodstream, 99% of the substance are bound to plasma proteins, mainly albumin. It is metabolized mainly by O-glucuronidation via the enzymes UGT1A9 and UGT2B4, and by hydroxylation to a lesser extent. The terminal half life is 10.6 hours for a 100 mg dose and 13.1 hours for a 300 mg dose, with 43% being excreted in the faeces (mostly in unchanged form) and 33% in the urine (mostly as glucuronide).[37]