There might be hope for horses that suffer from endocrinopathic laminitis with the trial of a new drug called velagliflozin from Boehringer Ingelheim Vetmedica GmbH.
Endocrinopathic laminitis is associated with insulin dysregulation and hyperinsulinemia, or pituitary pars intermedia dysfunction (PPID), also known as Cushing’s disease. Velagliflozin can help control levels of glucose in the blood, and therefore change the probability of laminitic events, according to researchers.
Hyperinsulinemia has many causes, but a diet high in non-structural carbohydrates, or starches and sugars, consumed by animals with a proclivity for enhanced glucose absorption is a likely factor. According to Horse Talk, “Velagliflozin is a sodium-glucose co-transport 2 inhibitor that reduces renal glucose reabsorption, promotes glucosuria (the excretion of glucose into the urine) and consequently, decreases blood glucose and insulin concentrations.”
Researchers Alexandra Meier, Dania Reiche, Melody de Laat, Christopher Pollitt, Donald Walsh and Martin Sillence noticed that registered drugs for treating insulin dysregulation and preventing insulin-related laminitis don’t exist. Together, they decided to analyze the effectiveness of velagliflozin and determine whether the drug reduces hyperinsulinemia and prevents laminitis in insulin-dysregulated ponies. The ponies that were used in the study were fed a challenge diet high in sugars and starches. Of 75 ponies screened with an oral glucose test for insulin deregulation, 49 were selected for having the highest insulin concentrations of the group.
The 49 ponies were divided into two groups at random, either a treated group of 12 or a control group of 37. For 3 weeks, all ponies were fed a maintenance diet of alfalfa hay. They were then transferred to the challenge diet, consisting of 12 grams of non-structural carbohydrates per kilogram of body weight per day for as many as 18 days. On day two of the diet, researchers measured blood glucose and serum insulin concentrations over 4 hours after feeding. Even this early in the study, maximum glucose concentration was already 22% lower in the ponies treated with velagliflozin than those that weren’t. The average became 45% lower than the control group over the course of the study.
Of the 37 control horses not treated with velagliflozin, 14 experienced low-grade laminitis. These afflicted ponies were immediately transferred from the diet high in sugars and starches to grass hay to resolve the problem.
Of the group treated with velagliflozin, none of the ponies experienced laminitis.
“Velagliflozin was well-tolerated, with no hypoglycemia or any clinical signs of adverse effects,” the researchers say. “Velagliflozin shows promise as a safe and effective compound for treating insulin dysregulation and preventing laminitis by reducing the hyperinsulinemic response to dietary non-structural carbohydrates.”
In taking the oral glucose levels of all the ponies before, during and after a laminitic event, the researchers could pinpoint what levels were normal. By taking regular glucose levels when the ponies were at optimal health, they could later retest the oral glucose levels to predict whether the pony would experience laminitis soon. Use of velagliflozin would eliminate the need for constant glucose testing.
This study was the first of its kind to use a pharmaceutical agent to prevent insulin-associated laminitis, according to researchers. And because of these positive results, further testing of the drug is justified. All 12 ponies tolerated the drug well over the 39-day treatment period.
“Interestingly, laminitis was not only prevented in insulin-dysregulated ponies, but also in ponies diagnosed with clinical PPID, four of which were included in the treatment group,” researchers say. “In comparison, the five ponies in the control group with clinical PPID all developed laminitis.”
These findings not only strongly correlate the positive effects of this drug with laminitis prevention but also connect the likelihood of laminitis occurring in PPID animals in relation to the degree of insulin dysregulation.
Other potential benefits of this drug could include better maintenance of lipid profiles or body weight, as triglyceride concentrations have been shown to decrease with long-term treatment, according to researchers. As weight increases on a horse, there is a positive correlation of increased triglyceride concentration.
When ponies binge on energy-rich pasture or grain, their pancreas sends out even more insulin in response to the high levels of sugar, which leads to insulin toxicity, according to Queensland University of Technology (QUT), where the research was carried out. The first exposure to new grass in the spring and some of the last grass in the fall is most dangerous, as both have high levels of glucose in the grass. Equines with metabolic syndrome shouldn’t be left to graze on cattle pasture that has been fertilized to fatten cattle. The richness is too much for the at-risk horse’s body to handle. Likewise, even on unfertilized grass, ponies and horses should be monitored for the quantity of grass they consume. Even unfertilized grass, in large amounts, can have potential health risks for a laminitic event.
Laminitis could be prevented with the use of velagliflozin to keep blood glucose levels in the normal range. This is especially beneficial in horse and pony breeds prone to obesity. For example, Shetland and Welsh Mountain ponies are meant to survive harsh winters by growing round bellies and thick coats. Now that they’ve been domesticized, ponies don’t need to eat ravenously in the spring because food is always available and they won’t use up their stored fat. The advent of velagliflozin could help ponies stay healthy while still getting the nutrition they need.
Although this study seems very beneficial, there are potential risks in using velagliflozin. Since this drug is a glucose-lowering treatment, there is the risk of bringing down the blood glucose levels too much, resulting in hypoglycemia. However, the treated pony with the lowest blood glucose level in the study was still within the normal range for horses.
Another concern regards horses’ kidney function. Since this drug allows the body to expel extra glucose in the urine, the kidneys would have to work harder. It could create a potential risk in using this drug in subjects with pre-existing kidney disease. Despite this risk, in the 39 days, no treated pony demonstrated elevated levels of creatinine or urea, which would indicate an issue with kidney function.
“The study team acknowledged that the main limitations of their study were the sample size, the infrequency of monitoring for pathology biomarkers, the lack of measurement of urinary glucose output, and the fact that despite randomization, the treated group was younger than the control group,” Horse Talkreports.
The scientists concluded that both primary aims of the study were accomplished. The hope was (1) that velagliflozin would improve insulin dysregulation by reducing the response of insulin to a high sugar and starch diet, and (2) that it would reduce the risk of insulin-associated laminitis.
With such positive outcomes, more testing could be made available. Furthermore, the research team is exploring the possibility of commercial use in horses and has sought patents for this use.
For more information, watch this video put together by the Queensland University of Technology research team here.
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