Ertugliflozin & Co. (SGLT2 inhibitors) in horses: Effects, risks, new insights

This article was translated using AI.

SGLT2 inhibitors such as Ertugliflozin, Canagliflozin, Dapagliflozin or Velagliflozin are increasingly being used to treat horses with pronounced insulin dysregulation. Particularly in the UK, they are now prescribed not only for treatment-resistant cases but sometimes even for overweight horses with elevated insulin levels.

These medications can significantly lower blood insulin concentrations and can be quite helpful in carefully selected patients. However, current studies show that they interfere deeply with energy and fat metabolism. A successful reduction in insulin levels does not, therefore, automatically mean that the horse's overall metabolism is improving.

Insulin dysregulation is not the same as diabetes mellitus

The previously commonly used term "insulin resistance" describes only part of the possible disorders. Today, in horses, the term insulin dysregulation is mostly used. This includes excessive insulin secretion after feeding, elevated fasting insulin levels, decreased insulin sensitivity of tissues, or a combination of these changes.

Unlike humans with advanced type 2 diabetes mellitus, most affected horses are not permanently hyperglycemic. They are often still able to keep their blood sugar levels within the normal range – but at the price of excessively high insulin secretion. Whether permanent insulin dysregulation in horses also leads to type 2 diabetes in the long term has not yet been scientifically investigated, so it can neither be confirmed nor denied.

Therefore, a single measurement of glucose and insulin is only of limited diagnostic value. While a significantly elevated fasting insulin level is relevant, a normal value does not reliably rule out insulin dysregulation. Dynamic tests such as a standardized oral sugar test are more informative in many cases, but always carry the risk of triggering a laminitis flare-up in an insulin-resistant horse.

How do SGLT2 inhibitors work?

The kidneys continuously filter glucose from the blood. Normally, most of this glucose is reabsorbed in the proximal renal tubule and returned to the bloodstream. A significant portion of this reabsorption is carried out by the so-called sodium-glucose cotransporter 2, or SGLT2 for short.

SGLT2 inhibitors block this transporter. As a result, less glucose is returned to the bloodstream and is instead excreted via the urine. The consequences are:

• increased glucose excretion via the urine,

• a lower glucose stimulus on the pancreas,

• reduced insulin secretion,

• often falling fasting and postprandial insulin levels,

• but at the same time, a continuous loss of energy - a factor that is often given too little attention.

The drugs do not restore original insulin sensitivity. They bypass part of the problem by removing glucose from the organism before it triggers further insulin secretion.

This is a special feature in horses: most treated horses are hyperinsulinemic but not permanently hyperglycemic. Under treatment, the organism therefore loses glucose, even though it was previously able to regulate blood sugar levels largely on its own.

Do SGLT2 inhibitors have to be activated via the first-pass effect?

This is always an important question, as biotransformation in the liver is apparently restricted in many horses, which is commonly referred to as KPU. For SGLT2 inhibitors, the clear answer is: No. The active ingredients used are already pharmacologically active. They do not first have to be converted into an effective form by the liver.

As with other orally ingested medications, however, the intestine and liver can influence what proportion of the administered dose actually reaches the systemic circulation. However, this is not the actual mechanism of action. The amount of active ingredient absorbed, the distribution in the body, individual clearance, half-life, and dosing interval are primarily decisive for possible overdoses and side effects.

A supposed disruption of the first-pass effect is therefore not a necessary explanation for unusually strong reactions. A much more plausible explanation is an exposure to the active ingredient that is too high or that builds up with repeated administration.

What do previous studies show regarding efficacy?

Several studies have now confirmed that SGLT2 inhibitors can effectively lower high insulin concentrations in horses.

In an experimental trial, velagliflozin prevented the development of laminitis provoked by high-carbohydrate feeding in insulin-dysregulated ponies. Another 16-week study also showed significantly lower postprandial insulin levels.

Case series and controlled studies on ertugliflozin and canagliflozin also reported sometimes substantial reductions in fasting and postprandial insulin concentrations. Clinical improvements were observed especially in horses with recurrent laminitis and extreme insulin levels that did not respond sufficiently to feeding and management measures alone.

SGLT2 inhibitors can therefore be a therapeutic option in selected, severe cases. However, they are no substitute for adjusted feeding, weight management, exercise, and addressing the causes of insulin dysregulation, and their use must be closely monitored diagnostically - which is unfortunately often forgotten in practice.

Long half-lives and the risk of accumulation

A crucial difference between humans and horses lies in the pharmacokinetics.

In a study of eight healthy Icelandic horses, canagliflozin had a mean terminal half-life of approximately 29.8 hours. After 24 hours, a significant portion of the previous dose is therefore still present in the organism when the next daily dose is already being administered.

A case report published in 2026 showed that this can indeed lead to relevant accumulation. In one mare, the daily administration of 0.6 mg canagliflozin per kilogram of body weight led to an accumulation rate of 2.73. Total drug exposure was approximately three times higher with daily administration than with the same dose at 48-hour intervals. Insulin control was maintained in this individual horse even with the longer dosing interval.

This is only a single case. No generally valid dosage recommendation can be derived from it. However, the study proves that daily administration derived from human medicine cannot automatically be regarded as unproblematic in horses.

For ertugliflozin, a mean half-life of around 17.7 hours was determined in healthy horses in 2026. With daily administration, a stable drug level is likely only reached after several days. Here too, the effect must therefore be assessed at steady state and not exclusively after the first dose.

The problem of dosing in practice

In controlled studies, horses are weighed, the dose is calculated in milligrams per kilogram of body weight, and the animals are kept, fed, and examined under defined conditions. In addition to insulin and glucose, triglycerides, liver values, electrolytes, weight, and other laboratory parameters are often monitored.

In veterinary practice, however, weight is often only estimated. Deviations of 50 to 100 kilograms are easily possible with a purely visual estimation. Added to this is rounding up or down to available tablet sizes and possibly a further dose increase if the desired reduction in insulin is not achieved immediately. Furthermore, many affected horses are multimorbid, so one cannot automatically assume that the metabolism of drugs proceeds at the same rate as in healthy test horses.

In the case of a drug with a long half-life, a seemingly moderate deviation can result in significantly higher drug exposure after several days. If only the reduction in insulin levels is monitored, changes in fat, protein, liver, or electrolyte metabolism may go undetected.

Hypertriglyceridemia is a proven side effect

The currently best-documented metabolic side effect is an increase in triglycerides. This has now been described for canagliflozin, ertugliflozin, dapagliflozin, and velagliflozin.

In a retrospective study of horses receiving ertugliflozin or dapagliflozin, 21 percent of the horses examined had triglyceride values above 2 mmol/l after 30 days. The highest measured value was 10.8 mmol/l. At the same time, β-hydroxybutyrate, total cholesterol, and GGT increased, among others.

A field study published in 2026 examined 70 horses that received canagliflozin for three weeks. In most, the postprandial insulin concentration fell significantly. However, 13 percent showed no improvement in insulin values. In nine percent, triglycerides rose to values above 5.6 mmol/l, and thus into the range of hyperlipemia. GLDH activity also increased on average.

The dose-response relationship was particularly clear in a randomized study from 2026. Increasing the canagliflozin dose from 0.6 to 1.2 mg/kg resulted in only a comparatively small additional reduction in the insulin response. At the same time, the mean triglyceride concentration more than doubled. Five out of 14 horses in the higher dose group developed values above 5 mmol/l. GLDH activity also increased in this group.

These data clearly show: more active ingredient does not automatically lead to a proportionally greater therapeutic benefit, but can disproportionately increase metabolic side effects.

Why do triglycerides rise?

Glucose excreted via the urine is no longer available to the body as an energy source. At the same time, the insulin concentration falls. Since insulin normally inhibits the mobilization of fat from adipose tissue, more fat is released at lower insulin levels.

Studies in humans show that SGLT2 inhibitors reduce the use of carbohydrates as an energy source and shift metabolism towards fat burning. At the same time, the body's own glucose production (gluconeogenesis) increases, as glucose is continuously lost via the urine.

In horses, too, the rising triglyceride values suggest that fat is increasingly being mobilized. The canagliflozin study published in 2026 also discusses the possibility that not only glycerol from fat metabolism and propionate from digestion, but possibly also glucogenic amino acids are used for increased gluconeogenesis. This could mean that in addition to fat mass, fat-free mass, such as muscle, could also be lost.

The possible metabolic cycle is:

Glucose loss via urine
→ negative energy balance
→ increased endogenous glucose production
→ mobilization of fat and possibly amino acids
→ renewed loss of the glucose produced via the urine.

The stronger and longer the SGLT2 inhibition acts, the more pronounced this catabolic metabolic state can theoretically become.

Massive edema: What is known and what is so far only a theory?

Massive generalized edema or rapid weight gains of 50 to 100 kilograms have not yet been described as typical side effects in controlled studies. On the contrary, the horses examined lost weight on average.

However, there are reports from therapeutic practice of individual horses that bloated massively within a short time after starting or increasing SGLT2 inhibitor therapy, were reluctant to move, and gained a significant amount of weight. In several observed cases, the condition improved rapidly after a veterinarian-monitored dose reduction or after discontinuing the drug.

This repeated improvement after dose reduction or discontinuation is known in pharmacology as a positive dechallenge. It does not prove the exact mechanism, but it is a serious signal for a possible connection with the drug.

A physiologically plausible working hypothesis would be as follows:

An exposure to the active ingredient that is too high or accumulating could cause particularly pronounced glucose and energy loss. This increases fat mobilization, gluconeogenesis, and possibly also the breakdown of muscle protein. At the same time, very high triglyceride values can put a strain on the liver.

If there is also reduced albumin synthesis, protein loss via the kidney or intestine, increased vascular permeability, or another disorder of the protein and fluid balance, the albumin concentration in the blood could fall. Albumin contributes significantly to keeping fluid in the vascular system. In the event of significant hypoalbuminemia, the colloid osmotic pressure drops and fluid can leak into the surrounding tissue.

The swellings colloquially referred to as "lymphatic fluid retention" would medically first be classified as edema, as long as no primary disease of the lymphatic system has been proven.

The clear restriction is important: SGLT2 inhibitor-induced hypoalbuminemia has not yet been scientifically proven in horses. In the controlled canagliflozin study of 2026, total protein, hematocrit, and plasma osmolality remained unchanged under the conditions studied. Albumin was not identified as the cause of massive edema there. But here, too, one must of course again point out that the dosage of the medications in practice is mostly based on estimates, which can lead to significant shifts in blood values that would not be captured in a study design with its strictly controlled conditions.

The hypothesis could therefore be relevant for horses with significantly higher drug exposure, longer duration of treatment, individual sensitivity, or additional liver, kidney, intestinal, or cardiovascular problems. To verify it, albumin, total protein, triglycerides, liver and kidney values, and urine parameters would have to be determined precisely during clinical deterioration.

The greatly reduced movement can also further increase edema. Horses rely on movement, muscle contractions, and the hoof mechanism for venous and lymphatic return from the limbs. If a horse barely moves due to weakness, malaise, or hoof pain, this return transport decreases and can significantly intensify the visible problem.

Can laminitis occur despite falling insulin levels?

SGLT2 inhibitors are used specifically because high insulin levels can trigger laminitis and lowering insulin is intended to reduce this risk. However, this does not mean that any laminitis occurring during therapy must automatically be independent of the drug.

In a horse that accumulates large amounts of fluid within a short time, the mechanical load on the hooves increases considerably. At the same time, it moves less and shifts its weight less frequently. If hoof structures are already damaged, additional mechanical, vascular, and metabolic stresses can become problematic.

Severe hypertriglyceridemia, liver strain, electrolyte changes, disturbed fluid distribution, or an underlying systemic disease can also contribute to this.

A direct causal chain from SGLT2 inhibitors via edema to laminitis has not yet been investigated and is therefore neither proven nor can it be ruled out. Physiologically, however, it is plausible that a massive metabolic derailment and rapid fluid gain in a horse already prone to laminitis represent an additional burden and can help promote a laminitis flare-up.

Long-term protein deficiency could also impair muscle mass, tissue regeneration, and horn quality. However, it does not alone explain acute laminitis developing within a few days.

What monitoring is necessary during therapy?

Monitoring glucose and insulin alone is not enough. Before starting treatment, the actual body weight should be determined as accurately as possible and the dose in milligrams per kilogram documented.

In addition to suitable insulin diagnostics, the following should be monitored depending on the individual case:

• triglycerides and, if necessary, other lipid parameters,

• albumin, total protein, and globulins,

• GLDH, GGT, AST, bilirubin and, if necessary, bile acids,

• creatinine and urea,

• sodium, potassium, chloride, calcium, phosphate, and magnesium,

• hematocrit and complete blood count,

• CK to assess possible muscle involvement,

• inflammatory parameters such as SAA and fibrinogen,

• urinalysis including glucose, protein, and specific gravity.

Regular weight checks and observation of water intake, urine volume, appetite, behavior, zest for movement, swelling, hoof heat, and digital pulse are also important.

One should be particularly alert if a horse, after starting or increasing the dose:

• bloats rapidly or gains weight significantly,

• becomes unusually lethargic or reluctant to move,

• drinks and urinates noticeably more,

• loses muscle mass,

• eats less,

• shows warm hooves or an increased digital pulse.

Such changes require a timely veterinary examination and a review of the dose and dosing interval. A medication should not be changed or discontinued independently. At the same time, a clinical deterioration must not be ignored just because glucose and insulin have decreased in the laboratory.

Which horses are candidates for SGLT2 inhibitors?

Previous studies primarily examined horses with significant or therapy-resistant insulin dysregulation and sometimes recurrent, therapy-resistant laminitis. It cannot be deduced from this that every overweight horse or every single elevated insulin value justifies pharmacological therapy.

SGLT2 inhibitors should not serve to compensate for sugar-rich roughage, lack of exercise, unsuitable management, or a lack of weight management.

The basis of treatment remains: control sugar and starch intake, analyze roughage, slowly reduce excess weight, enable regular exercise, reduce stress factors, and consider possible comorbid diseases.

In severe cases that cannot otherwise be sufficiently controlled, SGLT2 inhibitors can be a valuable supplement, especially to get a horse out of an acute laminitis flare-up caused by insulin dysregulation and an insulin peak. However, they are not harmless "insulin lowers". They change the entire energy metabolism and must therefore be individually dosed and comprehensively monitored.

The decisive question is not only:

"Has the insulin level dropped?"

Just as important is:

"What metabolic price does the horse pay for this reduction?"


More on the topic: You can find more information on insulin dysregulation in horses on our EMS & Insulin Resistance topic page and in our Podcast #22 Insulin Resistance in Horses – The Overlooked Metabolic Crisis with Dr. Christina Fritz. Scientific findings about horses can be found on the Science topic page.

If insulin dysregulation is suspected, we recommend consulting a qualified therapist from our Sanoanimal therapist network and adjusting the animal's diet accordingly.

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