Efficacy and safety of canagliflozin in insulin dysregulated horses: a 4-week multi-arm, double-blind, randomized, clinical trial.

Overview

• This study evaluated the effectiveness and safety of canagliflozin, an SGLT2 inhibitor drug, in reducing high insulin levels in horses with insulin dysregulation over a four-week period.
• The researchers compared the drug at two different doses to a placebo, measuring glucose and insulin responses and monitoring adverse effects.

Background and Purpose

• Insulin dysregulation (ID) in horses is a condition characterized by abnormally high circulating insulin, which can lead to serious health issues like laminitis.
• SGLT2 inhibitors, such as canagliflozin, are medications designed to lower blood glucose by promoting its excretion via urine, and are being explored for managing hyperinsulinemia in horses.
• The objective was to assess whether canagliflozin effectively reduces insulin spikes after sugar intake and to evaluate any adverse side effects, providing evidence for its clinical use in horses with ID.

Study Design

• A multi-center, randomized, double-blind, placebo-controlled trial was conducted using 42 privately owned horses with severe insulin dysregulation.
• Horses were randomly assigned equally to three groups: receive canagliflozin 0.6 mg/kg, canagliflozin 1.2 mg/kg, or a placebo, administered orally once every 24 hours for four weeks.
• The trial consisted of three phases:
  • A 5-day baseline evaluation to establish initial glucose and insulin responses.
  • A 4-week double-blind treatment period where horses received their allocated intervention at home.
  • A 5-day follow-up to assess post-treatment effects.
• Two challenge tests were given at each clinical visit:
  • Oral Sugar Test (OST) on day 3 measured insulin and glucose response to a controlled sugar load.
  • Forage-based Feed Challenge Test (FCT) on day 4 assessed responses to natural feed intake.
• Adverse effects, especially changes in blood parameters like triglycerides, were monitored throughout.

Key Measurements and Outcomes

• Primary outcome: Peak insulin concentrations after glucose and feed challenges, serving as a marker of hyperinsulinemia severity.
• Secondary outcomes: Levels of triglycerides and reporting of any adverse clinical effects.

Results

• Canagliflozin significantly reduced peak insulin levels compared to placebo for both doses:
  • During OST, peak insulin levels dropped from approximately 289 μIU/mL in placebo to 122 and 109 μIU/mL in 0.6 mg/kg and 1.2 mg/kg groups respectively.
  • During FCT, peak insulin levels decreased from about 140 μIU/mL for placebo to 78 and 54 μIU/mL for the 0.6 mg/kg and 1.2 mg/kg groups.
  • These reductions were statistically significant (P ≤ 0.01).
• A dose-dependent increase in triglyceride concentrations was observed:
  • Placebo group maintained low triglyceride levels (~0.5 mmol/L).
  • Canagliflozin treated groups showed substantial increases, up to 2.9 mmol/L in the highest dose.
  • This indicates that while canagliflozin lowers insulin, it may affect lipid metabolism adversely.
• No other significant adverse clinical effects were reported in the abstract, suggesting the drug was generally well tolerated.

Conclusions and Implications

• Canagliflozin effectively reduces hyperinsulinemia in horses with insulin dysregulation, potentially offering a new treatment option to manage this condition and reduce risks associated with high insulin.
• The dose-dependent rise in triglycerides highlights the need for careful monitoring of lipid levels when using this drug, as elevated triglycerides can carry their own health risks.
• The four-week duration showed short-term efficacy and safety, but longer studies are likely necessary to understand long-term effects and clinical outcomes such as laminitis prevention.
• Overall, this study supports the potential for repurposing human diabetes medications like canagliflozin for veterinary use in managing equine metabolic conditions.