Using New Medication for EMS

There are two new drugs which are transforming the landscape of the treatment of equine metabolic syndrome in horses. These innovative drugs are looking like the best medication for EMS, especially in an emergency where insulin dysregulation makes insulin levels difficult to control and laminitis may strike.

In this article, Dr Eleanor Kellon, VMD, discusses EMS and the success and useof the best new medicines in controlling laminitis in horses, caused by EMS

What is the best medication for EMS in horses?

Canagliflozin (Invokana®) and ertugliflozin (Steglatro®) are new medications for EMS and the latest weapons in the war against difficult-to-control equine metabolic syndrome. They can be dramatically successful, but there are special precautions which are often not followed.

These medications should be used when other management practices are not resulting in a decrease in insulin concentrations to safe levels. You can read more about endocrinopthic laminitis and management control here.

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, leading to elevated blood glucose concentration. As a result, insulin has to be higher than normal to control glucose.

What happens when a horse has high insulin?

The most serious consequence of high insulin is laminitis. It is now known that approximately 90% of laminitis cases are associated with elevated insulin levels. The exact mechanism is not completely understood, but research indicates that high insulin concentrations increase levels of endothelin-1, a potent vasoconstrictor that reduces blood flow to the hoof tissues.

Other consequences include easy weight gain, although not all horses with EMS are overweight or obese. Horses with EMS often develop regional fat deposits, including a fatty crest along the nuchal ligament of the neck, fat pads around the tail head and withers, and sometimes in the hollows above the eyes. Abnormal fat deposits can occur in other areas as well. Some horses also show mild changes in circulating blood fats and may develop elevated blood pressure.

What is leptin resistance in horses?

Horses with EMS become leptin-resistant as well as insulin-resistant, making it challenging to decrease body weight. 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 leptin.

How is adiponectin connected to EMS?

When another fat-derived hormone, adiponectin, is low, this indicates insulin resistance and EMS. Adiponectin helps regulate fat-burning and glucose production by the liver. Adiponectin can be measured through a simple blood sample to indicate if a horse might be at risk of developing laminitis.

What is the new medication for EMS in horses?

Invokana® (canagliflozin) and Steglatro® (ertugliflozin) are prescription medications for EMS. They are in the drug class SGLT2 inhibitors – SGLT2i’s.  SGLT2 is the sodium-glucose transporter 2, one of a family of cellular transporters which 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.

Invokana® and Steglatro® look like effective medications for EMS in horses and ponies, as described in these research papers:

……… once daily administration of the SGLT2 inhibitor canagliflozin corrected hyperglycemia, reduced insulin to normal or near normal levels, and was 100% effective in reversing or reducing abnormal fat pads and eliminating laminitis pain in horses with refractory hyperinsulinemia and laminitis. There were no drug refusals. The expected polyuria was noted, which was mild. Despite its effectiveness, increases in insulin were observed when concomitant PPID was not controlled or diet was liberalized. It is recommended that the core aspects of therapy–diet control, exercise when possible and adequate treatment of PPID– must also be maintained if using canagliflozin. Furthermore, since these modalities are often successful themselves, canagliflozin should be reserved for refractory cases. Further controlled trials to investigate canagliflozin pharmacokinetics, pharmacodynamics, efficacy, safety, and long-term use in horses are needed.

Use of the SGLT2 inhibitor canagliflozin for control of refractory equine hyperinsulinemia and laminitis – Kellon & Gustafson 2022

After 30 days of treatment with ertugliflozin, there was a reduction in insulin concentrations from a median of >300 μu/ml (IQR: 149, >300) to 43 μu/ml (IQR: 20, 66) (p < 0.001). Modified Obel laminitis scores improved, reducing from a median of 10/12 to 1/12 (p < 0.001). Median serum triglyceride concentrations increased from 0.6 (IQR: 0.4, 0.9) before treatment to 1.4 (IQR: 0.8, 3.7) mmol/L after 30 days of treatment (p < 0.001) before declining, however, none of the horses developed any clinical signs of hyperlipaemia. Ten horses (19%) were reported to have polyuria and polydipsia during treatment, otherwise no adverse clinical effects were identified.

Preliminary observations on the use of ertugliflozin in the management of hyperinsulinaemia and laminitis in 51 horses: A case series – Sundra Kelty & Rendle 2022

What do the medications Invokana® and Steglatro® do for EMS horses?

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 that many horses with equine metabolic syndrome suffer from. This new medication for EMS can cause a rapid reduction in insulin, increase insulin sensitivity, and provide relief of laminitis pain.

There are even horses that have had relief from laminitis pain without dramatic drops in their insulin. This new medication for EMS may well be among the best choices for horses and ponies.

Are there side effects with Invokana® and Steglatro®?

The most common side effect in other species, particularly humans, is urinary tract infections. These occur because the high glucose in the urine feeds bacteria in the urinary tract.  This has not been a problem to date with horses, but it’s a good idea to observe your horse carefully for signs of urinary tract infection.

Signs of a urine infection 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 a high temperature. Call your veterinarian if you suspect a urinary tract infection.

Some people on SGLT2is 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.

Are there other drugs to be avoided when using a new medication for EMS?

Research has shown that concurrent use of NSAID drugs (non-steroidal anti-inflammatory medications) such as phenylbutazone, flunixin, aspirin, firocoxib and others may increase the risk of impaired kidney function when used alongside SGLT2 inhibitor medications.

Horses receiving SGLT2 inhibitor drugs should always have unrestricted access to fresh water and a guaranteed intake of salt to maintain hydration. As a guideline, horses should receive at least 30 grams of salt per 500 kg body weight in cool weather, and 60 grams or more in hot weather.

NSAIDs should therefore be used very judiciously, if at all, when horses are being treated with SGLT2 inhibitor medications, and veterinary guidance should always be followed.

Does the new medication for EMS have any complications?

A complication that has been observed in some horses receiving SGLT2 inhibitor medications is the development of elevated triglycerides in the blood (hypertriglyceridemia). In some cases, cholesterol and liver enzyme levels may also increase.

This finding was unexpected because in humans, these medications often improve triglyceride levels and fatty liver disease.

Because of this possibility, it is advisable to perform baseline blood testing to assess kidney function and triglyceride levels before starting treatment. Follow-up monitoring of kidney function, liver enzymes and triglycerides should be carried out around four weeks after starting the medication, or immediately if rapid weight loss occurs.

Triglycerides are a combination of:

• Three fatty acids (i.e. saturated fat, unsaturated fat or both – these are the building blocks of fats) 
• Glycerol – a form of glucose (a simple sugar).

Release of triglycerides is a normal physiological response to exercise, fasting or inadequate calorie intake. Triglycerides are a vital energy source for cells. 

The high triglycerides seen in horses on SGLT2i are 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.

Members of the Equine Cushings and Insulin Resistance Group have not observed any increased problems with high triglycerides or hyperlipemia syndrome in ponies, minis or donkeys. This problem has only been seen in horses on this new medication for EMS.

The main difference between humans and horses is that diabetic humans have a much higher intake of carbohydrates than EMS horses, at least three times higher.

What should I do if there is rapid weight loss on these medications?

Some horses treated with SGLT2 inhibitor medications may experience noticeable or rapid weight loss. This occurs because glucose is being excreted in the urine, resulting in a loss of calories. While weight reduction can be beneficial in overweight horses, excessive or rapid weight loss should be monitored carefully.

Owners may be tempted to increase calories using cereals or high-energy compound feeds, but this should be avoided. Introducing high starch or sugar feeds can cause insulin levels to rise sharply, which may increase the risk of laminitis.

If triglyceride levels rise or rapid weight loss occurs, the diet should be adjusted carefully. Horses should be provided with free-choice hay with combined ESC + starch ideally between 10–12% and protein levels of at least 10%. Testing the hay is recommended so the sugar, starch and protein levels are known. In the UK, it can be difficult to find hay with adequate protein, so a protein supplement is often required.

To increase calorie intake safely, 500 grams to 1 kg of unmolassed beet pulp per day can be added to the diet.

If liver enzymes remain elevated, 50–100 grams of glycine per day may be helpful. Glycine supports gluconeogenesis in the liver and also contributes to the production of oxaloacetate, which plays an important role in the metabolism and utilisation of fats.

Another helpful nutritional support is L-carnitine, which assists in the transport of fatty acids into mitochondria, where they can be used as an energy source. A typical guideline is approximately 1 gram of L-carnitine per 100 pounds (45 kg) of body weight per day.

Triglyceride levels may remain elevated in some horses, but if liver enzymes return to normal and the horse remains bright, eating normally and comfortable, this is generally considered acceptable.

Summary

Before starting SGLT2 inhibitor medications such as canagliflozin or ertugliflozin:

• Check kidney function and triglycerides to establish baseline values. Mild triglyceride elevations are not necessarily a contraindication.
• Ensure the horse has constant access to fresh water and receives adequate salt intake.
• Observe the horse closely for signs of urinary tract infection.

During treatment:

• Monitor for rapid weight loss and check triglycerides and liver enzymes immediately if this occurs.
• Avoid feeding cereals or high-starch concentrates to increase calories.
• Provide free-choice hay and consider adding unmolassed beet pulp if additional calories are required.
• Nutritional support, such as glycine or acetyl-L-carnitine, may help support normal fat metabolism if triglycerides rise.

Follow-up blood tests to reassess kidney function, liver enzymes and triglycerides should be performed around four weeks after starting the medication, or earlier if clinical changes occur