A new class of medication called sodium-glucose co-transporter 2 inhibitors (SGLT2is) is the most recent addition to veterinarians’ toolbox of treatment options for horses with equine metabolic syndrome (EMS). This drug class has garnered a great deal of attention due to widespread success stories and several scientific publications supporting its use. But before you decide to pursue SGLT2i for your horse, there are some important facts you need to know.

Get Appropriate EMS Diagnostics First

Before initiating any treatment, your horse should receive a veterinary diagnosis of EMS. This involves identifying horses with insulin dysregulation (ID) that have elevated circulating insulin levels in their bloodstream.

“The best first-line test is the oral sugar test because it challenges the horse’s system and identifies animals with mild insulin dysregulation,” says Nicholas Frank, DVM, PhD, Dipl. ACVIM, professor of large animal internal medicine at Tufts University’s Cummings School of Veterinary Medicine, in North Grafton, Massachusetts.

Another testing option involves measuring basal (resting) insulin levels in a single blood sample.

“We should collect the blood one to two hours after the horse has been given its hay in the morning,” says Frank. “This way we are seeing how high the insulin concentrations are after eating, which helps us understand how the horse is responding to the sugars in the hay. It is easier to perform than the oral sugar test but not as sensitive, which means we may miss some mildly affected animals.”

Diet Changes

“Despite the success and gaining popularity of SGLT21s, controlling the nonstructural carbohydrates in an EMS horse’s diet is still the foundation for management,” says Frank.

The two most important diet changes are taking the horse off any grain or pellets that contain high levels of sugar levels and limiting pasture grass consumption if the horse is turned out, he says.

“Grain and pellets stimulate insulin release because of the sugars they can contain,” says Frank. If the horse is obese these should be eliminated from the diet or, if the horse is lean, replaced with a low-nonstructural-carbohydrate (NSC) pelleted feed, he adds.

Limit pasture access to a small grass paddock that has already been grazed down by other horses. You can also use a grazing muzzle to limit grass intake while the horse is in the paddock.

SGLT2is’ Mechanism of Action in EMS Horses

SGLT2is work by blocking resorption of glucose by the kidneys. In a normal, healthy horse, blood glucose levels stay within a normal range. After a meal, the stomach digests feeds and the sugars from those feeds get absorbed into the bloodstream. In response to the elevated blood glucose levels, the pancreas releases insulin, prompting tissues such as liver, fat, and muscle to remove the sugar from the bloodstream.

Horses with EMS are often called insulin resistant because the liver, muscle, and other tissues do not respond well to insulin, which means glucose remains in circulation. The pancreas therefore releases more insulin, attempting to lower blood glucose levels. As a result, the horse has high blood insulin levels (hyperinsulinemia). These horses are at high risk of developing hyperinsulinemia-associated laminitis (HAL), a life-threatening condition.

When the kidneys filter the blood to produce urine, glucose is normally resorbed back into the bloodstream. When SGLT2is block this resorption, glucose is excreted in the urine, lowering blood sugar levels.

“It was obvious that most of the decrease in insulin response after a glucose load in canagliflozin (an SGLT2i) treated horses was caused by decreased β-cell (the cells in the pancreas that produce insulin) sensitivity to glucose,” says Johan Bröjer, DVM, MSc, PhD, Dipl. ACVIM–LAIM, ECEIM, professor of equine internal medicine at the Swedish University of Agricultural Sciences, in Uppsala. “This means that treatment with canagliflozin in insulin-dysregulated horses made the β-cells less responsive to glucose, approaching but not fully reaching normal β-cell function.”

Essentially, treating with SGLT2i reduces the postprandial (after a meal) insulin response using two mechanisms: decreased glycemic response due to urinary loss of glucose and decreased β-cell sensitivity to glucose, which allows these drugs to be efficient in decreasing postprandial insulin concentrations and preventing laminitis, he adds.

The Facts Behind the SGLT2i Fervor

“So far, we have completed two randomized, double-blind, placebo-controlled clinical trials with approximately 60 participating horses,” says Bröjer. “In addition, we have horses included in ongoing long-term studies. Currently, we are preparing for larger studies involving field veterinarians located all over Sweden. In these studies, we transfer our knowledge from our extensive studies with canagliflozin to more practical guidelines that can be used in the field. We also have clinical patients that are on treatment but not involved in clinical trials.”

“We have performed a clinical trial with velagliflozin, the SGLT2i being developed for horses, and currently use two SGLT2is clinically, canagliflozin and ertugliflozin, which can be purchased from local pharmacies,” adds Frank. “We have now treated more than 60 horses with these drugs.”

In the United States canagliflozin and ertugliflozin are both expensive, limiting their use in horses and making it more realistic to treat Miniature Horses and small ponies, says Frank. However, in Sweden, the drug is accessible to more horse owners due to a lower cost, says Bröjer.

Selecting SGLT2i Candidates

Veterinarians usually reserve these drugs for horses that do not respond well to diet and management changes and have continually high insulin levels, says Frank: “These patients are at high risk for developing laminitis, and the expense of using an SGLT2 inhibitor is warranted in these cases to try to prevent laminitis from occurring again.”

Dude, a 14-year-old Miniature Horse, was a patient of Frank’s who fit the selection criteria for SGLTi2 treatment. Dude was only 4- years- old when he experienced his first bout of laminitis, but after another flare-up just a few months later his owner brought him to Frank and his colleagues for treatment.

Bloodwork and an oral sugar test revealed Dude was severely insulin resistant. Veterinarians prescribed metformin and a low-carbohydrate diet of soaked hay and low-carb grain. Dude also needed specialized orthopedic and orthotic care from his veterinary and farrier team.

“He once again bounced back, but over the next three years he had three more episodes of laminitis secondary to his EMS/ID, and his prognosis became more guarded as his hooves suffered more damage,” says Lynn Paulson, Dude’s owner. Even with treatment, specialized hoof care, multiple hospitalizations, and strict management at home, Dude’s insulin levels remained dangerously high, so in 2016 Frank prescribed an SGLT2i, which has greatly improved the horse’s quality of life.

A Grain of Salt

“Treatment with SGLT2is is a fantastic new pharmacological option for preventing laminitis in insulin-dysregulated horses,” says Bröjer, cautioning that the treatment is not without side effects and not for every insulin-dysregulated horse. “I would never prescribe an SGLT2i as a substitute for appropriate changes in diet and exercise,” he adds.

First, the drug can lead to elevated triglycerides (a type of fat circulating in the bloodstream) in patients. “High blood triglyceride concentrations (hypertriglyceridemia) are the main side effect,” says Frank. “If concentrations go too high, it is possible that the horse will go off feed and enter a vicious cycle that could lead to fat being deposited in organs. “We have not seen this happen so far, but we still monitor horses when they are on treatment, and if triglyceride concentrations go too high, we lower the dose or stop treatment, and they return to normal.”

Blood triglyceride concentrations will decrease over time as treatment continues, so the worst effects are seen at the beginning of treatment. By starting the horse on a lower dose and gradually increasing the dose over time, practitioners can avoid problems in most cases, Frank says.

Further, owners must commit to not only the cost of treatment but also follow-up veterinary care. “Preventing laminitis and minimizing side effects save money for the owner in the long run, and routine follow-up care is important for the welfare of the horse,” Bröjer says.

Take-Home Message

The key to developing a successful treatment plan for horses with EMS is an accurate diagnosis. While SGLT2is are a promising new  option for treating horses and ponies with EMS that have not responded well to other medications, limiting nonstructural carbohydrates is still the foundation for managing horses with EMS. Owners who choose to treat their horses with SGLT2is should be alert for any side effects and maintain regular follow-up appointments with their veterinarians.