A drug called velagliflozin has again shown its potential to help ponies with insulin problems, keeping levels in affected animals below the laminitis risk threshold.
Researchers have followed up on a previous six-week trial of the drug which indicated the potential of velagliflozin to help manage equine insulin dysregulation.
Queensland University of Technology Professor Martin Sillence and his colleagues have gone on to examine the safety and effectiveness of the drug over 16 weeks of treatment, followed by four weeks of withdrawal.
Twenty-four insulin dysregulated ponies were selected for the study.
Insulin dysregulation, including hyperinsulinemia and insulin resistance, is a core component of equine metabolic syndrome, linked to development of laminitis
Half the ponies were randomly selected to received either a daily dose of velagliflozin, at 0.3mg per kilogram of body weight, or a placebo.
The ponies were each fed 7.5 grams of non-structural carbohydrates per kilogram of body weight per day in order to maintain a fat body condition. It would not be a diet recommended for horses at risk of laminitis.
Safety was assessed through daily monitoring, veterinary examination, and the measurement of fasting blood glucose, biochemistry and blood parameters.
The effectiveness of the drug in reducing spikes in insulin levels after meals was assessed using a diet challenge every eight weeks during treatment and four weeks after withdrawal.
The researchers, writing in the journal BMC Veterinary Research, reported that velagliflozin was well accepted by all subjects. It caused no adverse effects or hypoglycaemia (low blood sugar).
As would be expected, spikes in insulin levels after meals continued to be seen in the animals on the placebo.
In contrast, maximum insulin concentrations fell over time in the velagliflozin-treated group.
It was found that post-meal insulin levels in the treated animals fell about 40 percent when compared to the results in the same animals before they began treatment. This put all 12 treated ponies below the previously determined risk threshold for laminitis, albeit without normalising the insulin levels.
After four weeks withdrawal from the medication, post-meal insulin levels in the treatment had largely returned to the same level as before they received velagliflozin.
“Velagliflozin appears to be a promising and safe treatment for equine insulin dysregulation,” the study team concluded.
The authors note that there are no registered drugs for reducing hyperinsulinemia in horses or ponies.
Current treatment options are limited to pasture restriction and/or the provision of a diet low in non-structural carbohydrates. Exercise, when physically possible, can improve insulin sensitivity, though it is not effective in all animals.
Metformin and levothyroxine are currently recommended as adjuncts to management practices in treating insulin dysregulation, although they are unregistered and studies show conflicting results.
Velagliflozin is a sodium-glucose co-transport 2 inhibitor. It reduces renal glucose reabsorption, promotes the excretion of glucose in the urine, and consequently decreases blood glucose and insulin concentrations.
The study team, discussing their findings, said the use of sodium-glucose linked transport inhibitors within the veterinary field was new.
“It is encouraging that no clinical signs of adverse effects were seen during daily monitoring by the researchers, or during regular physical examinations conducted by experienced veterinarians.
“The absence of any remarkable changes in blood biochemistry and haematology attests further to the safety of this compound.
“Importantly, no hypoglycaemia was evident during the present study, either clinically, or during the measurement of basal blood glucose after a 13-hour overnight fast.”
They said the reduction in hyper-responsiveness to oral carbohydrates among the treated ponies was convincing.
The success of the drug in dropping the insulin response to well below the laminitis risk threshold was “strongly encouraging,” they said.
“The present study has also established that the effects of velagliflozin are not long-lasting, as the insulin concentrations returned to within 3% of the pre-trial measurements after a four-week withdrawal.
“The absence of any rebound increase in the insulin response to the diet challenge is a promising finding, although we cannot rule out the possibility of a short-term rebound effect within the four-week period between diet challenge tests.”
They continued: “A factor important to the interpretation of the present results is that the ponies were maintained on a high non-structural carbohydrate diet throughout the study, in order keep the animals in a ‘fat’ body condition.
“This diet provided considerably more energy and non-structural carbohydrates than is currently recommended for feeding insulin-dysregulated horses, and indeed, laminitis was incited in one control.”
They said the ponies were stabled and fed their carefully controlled diets, which meant the relevance of the results to animals at pasture could be questioned.
“Future studies should examine velagliflozin under grazing conditions,” they said.
The authors said their findings built on earlier work in showing the effectiveness and safety of velagliflozin in insulin-dysregulated ponies.
“Velagliflozin warrants further investigation as a much-needed treatment for equine metabolic syndrome and a preventive for insulin-associated laminitis in horses and ponies.”
The study team comprised Sillence, Alexandra Meier, Melody de Laat and D. Fitzgerald, all with the Queensland University of Technology; and Dania Reiche, with the German pharmaceutical company Boehringer Ingelheim Vetmedica, which supplied the drug for the study.
The efficacy and safety of velagliflozin over 16 weeks as a treatment for insulin dysregulation in ponies
A. Meier, M. de Laat, D. Reiche, D. Fitzgerald and M. Sillence
BMC Veterinary Research 2019 15:65 https://doi.org/10.1186/s12917-019-1811-2