SGLT2i Use for EMS

Canagliflozin and Ertugliflozin for Horses with Equine Metabolic Syndrome (EMS)

Eleanor M. Kellon, VMD

Canagliflozin (Invokana^®) and ertugtliflozin (Steglatro^®) are the latest weapons in the war against difficult to control Equine Metabolic Syndrome (EMS). They can be dramatically successful but there are special precautions which are often not followed.

What is Equine Metabolic Syndrome?

Equine metabolic syndrome (EMS) is a constellation of laboratory findings and clinical signs with high blood insulin (hyperinsulinemia) at its core. The high insulin levels are related to insulin resistance, where insulin-sensitive cells do not respond to insulin by taking up glucose normally. As a result, insulin has to be higher than normal to control glucose.

The most serious consequence of high insulin is laminitis. It is now known that approximately 90% of laminitis cases are caused by high insulin. The mechanism is not completely understood but we do know that high insulin causes high levels of endothelin-1, which reduces blood flow to the hoof.

Other consequences include easy weight gain – although not all horses with EMS are overweight or obese. They do all have some degree of a fatty crest sitting on top of the nuchal ligament of the neck and may have unusual fat pads at the tail base, around the withers, in the hollows above the eyes, and virtually anywhere. There have been changes in circulating fats demonstrated, but these are usually minor. Blood pressure elevations have also been found.

Horses with EMS also become leptin resistant. Leptin is a hormone secreted by fat cells which normally tells the horse to stop eating but that "off switch" is lost when they are resistant to the effects. Another fat-derived hormone, adiponectin, is low. Adiponectin helps regulate fat burning and glucose production by the liver.

What Are Canagliflozin and Ertugliflozin?

Canagliflozin and ertugliflozin are prescription medications in the drug class SGLT2 inhibitors – SGLT2i's. SGLT2 is the sodium glucose transporter 2, one of a family of cellular transporters that absorb sodium and glucose.

SGLT2 is primarily located in the kidney and is responsible for reabsorbing glucose that is filtered out of the blood in the process of making urine. Normal urine does not contain any glucose. By blocking glucose uptake back into the blood, the burden on the pancreas to produce more insulin is reduced.

In humans, these drugs are documented to also have anti-inflammatory and antioxidant effects. They improve the risk for complications of type II diabetes including fatty liver, coronary disease, renal disease, and ocular involvement.

Elevated insulin is at the core of metabolic syndrome and is the cause of the laminitis many horses with equine metabolic syndrome suffer. These drugs can cause rapid reduction in insulin and relief of laminitis pain. There are even horses who have had relief from laminitis pain without dramatic drops in their insulin.

So What's The Problem?

The most common side effect in other species, particularly humans, is urinary tract infections. These occur because the high glucose in the urine is what feeds the bacteria. This has not been a common problem to date with horses but it's a good idea to observe your horse carefully for signs of urinary tract infection. These include passing only small amounts of urine, dribbling urine, and frequently positioning themselves to urinate, then stopping after passing only a small amount. There may be fever. Call your veterinarian if you suspect urinary tract infection.

Some people on SGLT2i's have developed increased BUN and creatinine indicating reduced kidney function. This is likely due to dehydration. Dehydration develops easily because the volume of urine is increased when glucose is in the urine. Research has shown that concurrent use of NSAID drugs – non steroidal anti- inflammatories (NSAIDs) like phenylbutazone, flunixin, aspirin, firocoxib, and others – increases the risk of impaired kidney function. Horses taking SGLT2i drugs should have plentiful water and a guaranteed intake of at least 30 grams of salt per 500 kg body weight in cool weather and 60+ grams in hot weather. NSAIDs should be used very judiciously, if at all.

A completely unexpected complication in horses is the development of hypertriglyceridemia, sometimes with elevated cholesterol as well, sometimes with liver enzyme elevations. This was unexpected because in humans these drugs actually improve triglycerides and fatty liver.

Release of triglycerides is a normal physiological response to exercise, fasting, or inadequate calorie intake. The high triglycerides seen in horses on SGLT2i's is different from the hyperlipemia syndrome seen in miniatures, donkeys, and ponies in that these horses do not lose their appetite and remain alert, but accelerated weight loss may be noticed. We also have not observed any increased problems with high triglycerides or hyperlipemia syndrome in ponies, minis, or donkeys. The main difference between humans and horses is that even diabetic humans have a much higher intake of carbohydrates than EMS horses, at least three times higher.

In our experience, you can't just start feeding grain or glucose to correct the situation or insulin will shoot up. Manage it by giving the horse free-choice hay with ESC + starch ideally at 10 to 12%, protein 10+%. Also supplement with ½ to 1 kg of beet pulp per day. If this doesn't correct liver enzyme elevations, add 50 to 100 grams of glycine to support synthesis of glucose in the liver (gluconeogenesis). Many other amino acids also support gluconeogenesis but this is the most palatable. Glycine also supports the production of oxaloacetate, needed for the first step of getting the triglycerides burned for energy. Also important is supplementation of L-carnitine, 1gram per 100 lbs of body weight. This compound is needed to carry the fats across the mitochondrial membrane so they can be burned. Triglycerides may still remain elevated but if liver enzymes normalize and the horse is asymptomatic, that is acceptable.

Summary

• Check kidney function and triglycerides before starting these drugs to have a baseline. Mild triglyceride elevations are not a contraindication
• Observe for signs of urinary tract infections
• Observe for rapid weight loss and immediately check triglycerides and liver enzymes if this is seen
• Guarantee adequate salt intake and keep water available free-choice
• Liberalize the diet to include free-choice hay, beet pulp, and glucogenic amino acids if needed
• Recheck kidney function and triglycerides 4 weeks after starting the drugs – or sooner if rapid weight loss is seen