A Medication for Laminitis
Now there is hope for thousands of horses and ponies suffering with laminitis.
By Margaret Evans
At Queensland University of Technology in Australia, Prof. Martin Sillence with the School of Earth, Environmental and Biological Sciences has been researching laminitis for over a decade. He says that Velagliflozin, a new veterinary drug related to one used to treat human metabolic syndrome, has been found to prevent laminitis in ponies with high levels of insulin and the equine version of metabolic syndrome.
What is laminitis and why is it so painful and crippling?
Laminitis is a complicated and ancient disease. Over 2,000 years ago Aristotle called it the “barley disease.” Today, we associate it with increasing sugar levels in spring grass. The symptoms include a shortened stride, a strong digital pulse, warm hooves with distinctive rings, stretching or bleeding of the laminae detected by the farrier, and the horse frequently lying down to relieve pressure on the hooves. The trigger is insulin.
In humans, metabolic syndrome is a condition in which too much glucose enters the blood and the pancreas produces more insulin to cope with it. When the pancreas fails, diabetes develops.
A typical x-ray or radiograph of a laminitic foot in a horse. The annotation P2 stands for the middle phalanx (pastern bone) and P3 denotes the distal phalanx (coffin bone). The white line marks the boundary of the outer hoof wall and the yellow lines show the distance between the top and bottom part of the coffin bone with the outer hoof wall. In this example the distal (bottom) part of the coffin bone is rotated away (greater distance) from the hoof wall, an indication of laminitis. Photo: Wikimedia Commons/Malcolm Morley
“Our team discovered that in ponies something quite different occurs, which led to the breakthrough finding that this common but mystifying disease was triggered by high concentrations of insulin,” says Sillence. “We discovered that when some ponies overeat energy-rich pasture or grains which release a lot of glucose, their pancreas pumps out even more insulin and this leads to insulin toxicity. In insulin-dysregulated ponies, the pancreas produces far more insulin than is healthy. We know this is partly due to the fact that they absorb more sugar than other horses, and that in some cases their tissues are resistant to taking this sugar out of the bloodstream, so more insulin is needed to activate the tissues.”
Insulin-dysregulation means abnormal insulin metabolism which underscores the process of equine metabolic syndrome. But what causes the pancreas to release such excessive amounts?
“Blood glucose is the main driver,” says Sillence. “But we are also investigating the action of so-called ‘incretin hormones’ which augment the secretion of insulin.” These hormones stimulate insulin secretion in response to meals. However, Sillence says that the jury is still out on how important these hormones are as they have seen a strong correlation between incretin and insulin levels in some studies. but not in others.
“It seems to depend on what is being fed, and on the individual horse,” he says.
When insulin reaches a toxic level, it breaks down the connective tissue in the feet of the horse or pony, causing lameness and excruciating pain. But why does insulin toxicity specifically target the hoof in the first place?
“We are currently doing experiments to discover how insulin causes the breakdown of lamellar tissue, but why this should happen is another matter,” he says. “What makes this research so interesting is the fact that the horse is so unlike many other species. One peculiar feature of the hoof is that the tissue can take up glucose without the need for insulin, which is also the case for skin, liver and brain, whereas every other tissue in the body needs insulin to activate glucose uptake. Our current theory is that the selectivity of insulin for binding only to its own insulin receptors is lost when the hormone reaches very high concentrations in the blood. In this case, insulin could be activating receptors for other hormones and growth factors that come into play in conditions such as cancer. In fact, one of the cancer researchers we work with has observed a striking similarity between the changes that occur in the hoof over a few days with the changes seen in cancerous tissue that normally take weeks or months to occur.”
The cancer tissue similarity has raised many fascinating questions and currently further research is being done. But the most important development is the confirmation that a drug used to treat human metabolic syndrome has shown success in treating horses and ponies with laminitis.
Clinical trials and testing are underway.
The drug, Velagliflozin, belongs to a family of drugs developed to treat human metabolic syndrome by the pharmaceutical company, Boehringer Ingelheim. The drugs are known as selective glucose transport inhibitors (SGLT inhibitors) and several new drugs in this category are undergoing clinical trials in humans.
“Velagliflozin has undergone several trials to determine a suitable dosage for horses and a study is currently underway to optimize the frequency of dosing,” says Sillence. “We have studied the drug for tolerability in a small group of horses at doses three times higher than the therapeutic dose and observed no adverse effects. The paper we have just published demonstrates the ability of Velagliflozin to prevent laminitis over a five to six-week period, and we are about to submit another report on its effects over four months, plus withdrawal effects. Clinical studies are underway in Europe at the moment under the supervision of the manufacturer, but we don’t have those results yet.”
Briefly, he explains, as blood passes through the first section of the kidneys’ filtration system, all the glucose is secreted into the urine. Further along the system, the kidney takes all the glucose out again and back into the blood, so that under normal conditions no glucose is seen in the urine when it leaves the body. This process requires specific proteins that transport glucose through the cell wall. However, these transport proteins act like a type of “thermostat,” so that when blood glucose levels get dangerously high (as in diabetes), the excess glucose is not reabsorbed, but passes out into the urine. Partially blocking these transport proteins using a drug such as Velagliflozin is similar to altering the temperature on a thermostat, so that the proteins recover less glucose and more of it leaves the body. During trials, the drug was administered as an oral paste from a large syringe and it was readily accepted.
Prof. Martin Sillence and friend. Photo courtesy Queensland University of Technology
“It works by causing the kidneys to excrete more glucose in the urine to take the pressure off the pancreas and lower insulin levels. We have tested the drug in controlled trials here in Brisbane and now clinical trials are running on farms in Europe. When we have enough cases to prove its efficacy and safety, the regulatory bodies can pass it for use.”
A critical question in understanding laminitis is knowing the level of insulin that will actually trigger its onset and start the cascading effect. Sillence says that there are three variations of a test that equine veterinarians in Australia, Europe, and the US have been conducting. All three tests involve the horse being fasted overnight, then given a fixed quantity of sugar. Blood insulin concentrations are then measured between 90 minutes and two hours after the sugar has been ingested.
“The oral sugar test (OST) is used in the US where the sugar is administered in the form of Kayro syrup,” says Sillence. “It’s a bit messy but very palatable for the horse. In Europe and Australia, where Kayro syrup is less readily available, we use an oral glucose test (OGT) at a dose of one gram/kilogram body weight mixed with water and some bran. A paper we published in Domestic Animal Endocrinology earlier [in 2018] charts the level of insulin reached in the blood following an OGT against the likelihood that the pony will develop laminitis. Put simply, the higher the insulin level, the higher the risk. Due to concerns about getting the animals to voluntarily consume all the sugar provided in the test meal in a similar time-frame, a German group has advocated delivering the sugar by stomach tube. Universal agreement on the best type of test has not been reached yet, but the bottom line is that the larger the insulin response to feeding (whatever the diet is), the higher the risk of laminitis.”
He added that the blood sugar could remain within safe limits if they lowered the insulin levels, but their approach was to lower sugar levels by increasing urinary glucose excretion, and that lets the insulin levels fall naturally.
The research continues.
There is little doubt that genetics must play a role in a horse’s predisposition to laminitis.
“Almost certainly there are one or more genes at play here,” says Sillence. “We know this because it is clear that some breeds are much more susceptible than others. This year we have been looking into a gene that was incriminated in a study of Arabian horses, but without much luck so far.”
He says that laminitis is more common in Shetland and Welsh Mountain ponies that evolved to survive harsh winters, feed on rough grasses, then graze on rich spring grasses. Seasonally they would store the glucose, fatten up, then lose it next winter. But now, domestic ponies do not experience seasonal food shortages. They can get fat and hold on to the weight. And exercise isn’t always the answer.
“Certainly, exercise is the key to maintaining tissue sensitivity to insulin so that less insulin is needed to encourage the tissue to clear excess glucose from the blood stream,” he says. “However, the exercise must be sufficiently frequent and intense to achieve this. Furthermore, as far as we know exercise does not alter the amount of glucose absorbed from the gut nor does it determine how the pancreas in a particular horse will react to that amount of glucose. That is why exercise is only part of the answer.”
Another curious dynamic is that while seasonality of laminitis is thought, logically, to be tied to seasonal pasture changes and sugar content in grass, Sillence says that there is also evidence of seasonal changes in the horse too, particularly in insulin dynamics. This is an area that is currently under investigation.
“In terms of seasonal changes within horses, there is clear evidence that adrenocorticotropic hormone (ACTH) concentrations show a marked seasonal change in horses with PPID (pituitary pars intermedia dysfunction, or Cushing’s disease),” says Sillence. “As many PPID horses are also insulin dysregulated, there is a possible link here. We are currently investigating this possibility. We have also noted recently that while some horses are very amenable to dietary manipulation, others remain stubbornly dysregulated under a variety of dietary management strategies and hence would be clear candidates for drug therapy. These results are currently being peer reviewed prior to publication.”
With the development of the equine drug Velagliflozin and its potential to deliver on a successful laminitis therapy, these are exciting times in the research theatre for this ancient and baffling disease. To that end, Sillence and his team are continuing to work on a variety of ambitious aims, including to:
- Determine the exact mechanism by which insulin damages the hoof tissue with the aim of blocking this effect;
- Understand the genetic make-up of horses with equine metabolic syndrome to identify the genes responsible;
- Characterize the microbiome of the horse as there is now strong evidence in humans that gut bacteria influence diabetes;
- Investigate a group of hormones and neurotransmitters that communicate between the gut, the pancreas, and the brain to control metabolism;
- Explore the potential of environmental contaminants that can influence metabolic hormones.
Horse owners should feel encouraged and heartened that, with the availability of the new veterinary drugs in the future, their horses and ponies won’t need to suffer the endless misery and frightening outcomes that laminitis can bring.
Main photo: The characteristic stance of a pony with laminitis.