The Modern Equine Vet
September 2023
Vol 13 Issue 9 2023
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Cover Story | Endocrinology

The Promise of SGLT-2s

By Marie Rosenthal MS

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors may be an effective way to control hyperinsulinemia and insulin dysregulation in horses, according to a recent study.

SGLT-2s are a class of medication used to lower high-blood glucose levels in humans and felines (Bexacat, Increvet), and is being researched for use in equids and canines. However, SGLT-2 inhibitors have not been approved for use in animals outside of cats, explained Nicholas Frank, DVM, PhD, DACVIM, who recently was appointed dean of the College of Veterinary Medicine at Mississippi State University. He is an expert in equine endocrinology.

“These drugs work by inhibiting the re-uptake of glucose from the proximal tubule of the kidney, and by inhibiting the re-uptake of glucose, the animal wastes glucose in the urine,” Dr. Frank explained, when he discussed a recent study he and his colleagues did on the SGLT-2 inhibitor, velagliflozin, being studied in horses.

Persistent Insulin Dysregulation
“In contrast to dogs, cats and people, horses remain in this persistent state of hyperinsulinemia and insulin dysregulation,” he explained at the recent ACVIM Forum, held in Philadelphia.

Although a few horses might go on to develop diabetes, most horses “remain in this state of hyperinsulinemia where they’re secreting large amounts of insulin and quite successfully keeping glucose concentrations at least somewhat in normal range or in a high-normal range. But the only way they’re able to do that is to secrete large amounts of insulin.”

Wasting glucose in the urine provides a way to lower the need for secreting more insulin. They hoped that insulin concentrations decrease when the blood glucose concentrations are lowered because the animal is wasting glucose in the urine. This is what they found with velagliflozin, which is being developed by Boehringer Ingelheim Animal Health.

Velagliflozin was tested successfully in ponies, where the SGLT-2 inhibitor decreased insulin concentrations in the ponies. This drug has been developed specifically for horses, but it is only available for research at this time.

In the randomized, double-blind, placebo-controlled study, Dr. Frank and his colleague from Tufts University, Kristen Thane, DVM, strove to look for horses with moderate to severe hyperinsulinemia, because they tend to be animals that are more difficult to manage, he explained.

“So, the aim of this study was to investigate the efficacy of velagliflozin, a novel SGLT 2 inhibitor designed for use in horses, to see if it would decrease insulin concentrations in horses with moderate-to-severe hyperinsulinemia,” which was defined as ≥75 µIU/mL of insulin during an oral sugar test where blood was sampled at 60 and 90 minutes. Basal hyperinsulinemia was also measured.

Thirty-seven client-owned horses, with moderate-to-severe hyperinsulinemia, were enrolled and randomly chosen for the 0.3 mg/kg of velagliflozin or placebo groups (given as an oral suspension). Most had a history of clinical laminitis, and because of the degree of hyperinsulinemia allowed for entry, some horses had concurrent pituitary pars intermedia dysfunction (PPID).

“The physical characteristics of equine metabolic syndrome, including the cresty neck and other forms of regional adiposity were present in these horses,” Dr. Frank said.

There were 2 treatment periods, which both lasted 20 weeks, he explained. “In the first period, we had horses randomly assigned to the velagliflozin or placebo groups, and they received 0.3 mg/kg of velagliflozin or placebo. After 20 weeks, they switched the placebo group to the velagliflozin. So, both groups received velagliflozin.”

They monitored the animals at study entry and then again at 2, 4, 8, 12 and 20 weeks, with chemistries, physical examinations, lameness scores, body weight and condition, and cresty neck scores. The main variables of interest were plasma insulin and serum glucose, but they also looked at liver and kidney function, complete blood counts and adrenocorticotropic hormone (ACTH) testing results.

“We did ask the clients and the primary care veterinarians to hold the horses on the same dose of pergolide if they were on pergoglide—and not to vary treatment unless they talked with us,” Dr. Frank explained. They did not make any changes during the study period.

There were 18 horses, 10 ponies and 9 miniature horses with a median age of 21, a median body condition score of 6 and a median cresty neck score of 3. Thirty-three (89%) had a history of laminitis, and 22 (61%) had concurrent PPID.

After random selection, 19 equids (11 horses, 8 ponies/miniature horses) were in the velagliflozin group and 18 equids (8 horses, 8 ponies/miniature horses) were in the placebo group, and they had similar characteristics.

“So as always happens in a clinical trial, we had some attrition from the study,” he said. “I’m going to go through some of the reasons for this because it’s important. The first part of this that I will discuss in more detail is horses receiving velagliflozin developed a degree of hypertriglyceridemia when treatment was initiated, and there was a lot of individual horse variability in the amount of hypertriglyceridemia.”

This was anticipated, so if they developed a triglyceride concentration of 1,000 mg/dL during the first period, they would be given a period without velagliflozin to allow the triglyceride concentration to lower and then be restarted at a lower dose. This occurred in 6 horses in the velagliflozin group. However, all these horses remained clinically normal, and they did not develop clinical signs of equine hyperlipemia such as inappetence.

Treatment Effect
Two other horses left the placebo group because of medical problems (laminitis in 1 horse and suspensory ligament disease in another), and some horses were withdrawn due to scheduling conflicts, so they evaluated 17 horses in the placebo group and 12 in the velagliflozin group. Data collected from these horses were included up until the time of their withdrawal from the study.

They saw a significant decrease in serum glucose and plasma insulin in the velagliflozin patients, and they remained at that lower concentration for the duration of the first 20 weeks versus placebo, according to Dr. Frank. However, if approved, horses will need to be monitored for hypertriglyceridemia when treatment is started, he added.

“There was a clear treatment effect that we were hoping to see,” he said.

They looked separately at the placebo group that switched to velagliflozin and saw the same positive effects, although they were not statistically significant because of the lower number of horses remaining in the study at this point, he explained.

“We can conclude that the velagliflozin was effective in this study at reducing plasma insulin concentration and, therefore, is a potential treatment for moderate to severe hyperinsulinemia in horses,” Dr. Frank said. MeV

The study was performed while Dr. Frank was at Tufts Cummings School of Veterinary Medicine. Kristen Thane, DVM, DACVIM, of Tufts was the investigator responsible for running the project. This study was funded by Boehringer Ingelheim Animal Health.

 

The cresty neck of a horse with metabolic syndrome.
Courtesy of Dr. Frank