24 Sept 2024
Nicola Menzies-Gow takes a look at the causes and latest on management of this endocrine condition in horses.
Nicola Menzies-Gow
Job Title
Image © callipso88 / Adobe Stock
Equine metabolic syndrome (EMS) is a collection of risk factors for hyperinsulinaemia-associated laminitis. Insulin dysregulation (ID) is the key central feature of EMS and additional features include obesity (generalised or regional), adipose dysregulation and cardiovascular changes.
Possible factors that contribute towards the development of ID in animals with EMS include genetics, epigenetics, obesity, diet, gut microbiome and endocrine-disrupting chemicals.
Management consists of dietary modification, exercise and short-term (three to six months) use of pharmacologic agents. The pharmacologic agents that have received most attention recently in the management of ID and hyperinsulinaemia-associated laminitis are the sodium glucose-like transporter-2 (SGLT2) inhibitors.
SGLT2 inhibitors that are reported to have been used to date include the gliflozins velagliflozin, canagliflozin, ertugliflozin, dapagliflozin and empagliflozin. These drugs have been shown to decrease circulating insulin and glucose concentrations, and improve laminitis lameness scores; however, hypertriglyceridaemia is a potential side effect that should be monitored for.
Equine metabolic syndrome (EMS) is a collection of risk factors for hyperinsulinaemia-associated laminitis. The key central and consistent feature of EMS is insulin dysregulation (ID), which can manifest as any combination of basal (resting) hyperinsulinaemia – an excessive insulin response to an oral or IV carbohydrate challenge and/or tissue insulin resistance.
Further inconsistent features of EMS comprise obesity, which may be generalised or regional; cardiovascular changes, including increased blood pressure, heart rate and cardiac dimensions; and adipose dysregulation manifesting as abnormal plasma adipokine concentrations, including hypoadiponectinaemia and hyperleptinaemia, and/or increased fasting serum triglyceride concentrations.
The exact mechanism(s) underlying ID in EMS remain(s) uncertain. Evidence suggests that several mechanisms might play a role.
Horses with EMS are often considered to be “good doers” or “easy keepers”, and genes contributing to this phenotype are likely to be advantageous for survival in the wild during periods of famine by enhancing feed efficiency.
Initial research found that the prevalence of EMS-associated laminitis was consistent with the action of a major gene or genes expressed dominantly, but with reduced penetrance attributable to sex-mediated factors, age of onset and further epigenetic factors1.
More recently, genome-wide association studies (GWAS) using Arabian horses, Welsh ponies and Morgan horses have identified several candidate genes that were associated with relevant traits, including height and insulin, triglyceride and adiponectin concentrations. In Arabian horses, single-nucleotide polymorphisms (SNPs) associated with EMS were detected, suggesting a single candidate locus located at Equus caballus chromosome 142.
However, the positional candidate gene identified – Family with Sequence Similarity 174 Member A (FAM174A) – has not consistently been associated with EMS in other breeds3. Other studies have suggested that SNPs detected using GWAS in Finnhorses were associated with arginine and glutamate-rich 1 and ephrin-B24, and a variant in the high mobility group AT-hook 2 gene appears to have a pleiotropic effect on height and basal insulin concentrations in Welsh ponies5.
Therefore, it appears that the genetic risk factors for EMS may differ between equine breeds, as it is likely that the disease is genetically multifactorial and multiple alleles underlie genetic susceptibility. Identifying these factors and elucidating the complexity of gene interactions with the environment will lead to a better understanding of pathogenesis; this is an area of ongoing research.
The environment in utero influences the metabolic health of the fetus later in life. Certain genes are switched on or off depending on the nutritional status of the mother, which then influence the offspring’s metabolic health over time.
Both maternal overnutrition and undernutrition appear to increase the risk of obesity – and of being metabolically unhealthy in people – and limited evidence exists to support the supposition that this also occurs in horses6.
The gastrointestinal microbiome influences metabolism, endocrine signalling and the immune system in humans. For example, perturbations of the faecal microbiome in humans and mice have been associated with alterations in insulin secretion and sensitivity, incretin action and obesity, such as a microbe-gut-endocrine axis.
Horses with EMS have been shown to have a decreased gastrointestinal microbial diversity and differences in community structure compared to control animals7.
Adipose tissue is the largest endocrine organ in the body, producing an array of hormones with normal physiological roles.
Obesity results in adipose dysregulation such that the production of some hormones is increased (for example, leptin) and others is decreased (for example, adiponectin). Some of the affected hormones affect insulin sensitivity, with the overall result being insulin dysregulation.
Diets high in non-structural carbohydrate will reduce insulin sensitivity and adiponectin sensitivity in horses compared to forage or fat-rich diets8,9.
Endocrine-disrupting chemicals (EDCs) are found in numerous commercially produced compounds, including organochlorine pesticides such as dichlorodiphenyltrichloroethane and as by-products during synthesis of various chlorophenols and herbicides. They tend to be polychlorinated, lipophilic and persist in the environment.
Exposure to EDCs is associated with metabolic syndrome, obesity and type 2 diabetes in humans. EDCs have been shown to be present in horse plasma and animals living within a short radius of Superfund sites (chemical dump sites in the US) appear to be at an increased risk of EMS10.
The management of EMS consists of dietary modification, exercise and the short-term use (three to six months) of pharmacologic agents in some cases.
The pharmacologic agents that have received most attention recently are the sodium glucose-like transporter-2 (SGLT2) inhibitors.
Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are features of human metabolic syndrome (HMS)11 as well as EMS. SGLT2 inhibitors are a novel class of oral hypoglycaemic agent used in combination with lifestyle changes in the management of HMS.
SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Therefore, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate, resulting in urinary glucose – and, therefore, calorie loss – with consequent weight loss and improvements in ID, hyperglycaemia, hypoadiponectinaemia and hyperleptinaemia12,13.
The overall result is significant cardiorenal protective effects14. While some of these beneficial effects can be explained by improved glycaemic control, other mechanisms are thought to be involved. Natriuresis (as sodium is loss alongside the glucose) with a reduction in plasma volume, a consequent rise in haematocrit, improved vascular function, a reduction in blood pressure and changes in tissue sodium handling are all likely to have a role15.
Additional mechanisms of SGLT2 inhibitors that might be beneficial include a reduction in adipose tissue-mediated inflammation and pro-inflammatory cytokine production, a shift towards ketone bodies as the metabolic substrate for the heart and kidneys, reduced oxidative stress, lowered serum uric acid level, reduced glomerular hyperfiltration and albuminuria, and suppression of advanced glycation end-product signalling15.
No licensed veterinary drugs are available for treating ID and preventing insulin-associated laminitis in horses. Therefore, the use of SGLT2 inhibitors for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated16-18.
The SGLT2 inhibitors that have been reportedly used in the horse to date include velagliflozin19,20 canagliflozin16,18,21,22 ertugliflozin17,23 dapagliflozin and empagliflozin (anecdotal reports). All of these are used in humans apart from velagliflozin, which was recently licensed for the treatment of diabetes mellitus in cats not previously treated with insulin24.
Use of canagliflozin was first reported in a study of six horses with ID treated for three days18. It reportedly lowered serum insulin concentration following an oral sugar test when given at “medium” and “high” doses, but dose rates were not reported. No adverse health effects were observed, but serum triglyceride concentrations were not reported.
In a second study, two standardbred mares received canagliflozin at the relatively high doses of 1.8mg/kg and 3.6mg/kg by mouth, and treatment reduced serum insulin and glucose concentrations in response to a graded glucose infusion21.
The first use of canagliflozin in equine clinical practice was reported in a case series. Ten horses with hyperinsulinaemia refractory to dietary control and pharmacologic management of ID and pituitary pars intermedia dysfunction (PPID) were treated with canagliflozin at 0.3mg/kg 0.6mg/kg once daily by mouth; nine of these animals were also hyperglycaemic16.
Treatment corrected hyperglycaemia, reduced insulin to normal (7/10) or near normal (3/10) concentrations, and was 100% effective in reversing or reducing abnormal fat pads and eliminating laminitis pain; however, increases in insulin were observed when the concomitant PPID was not controlled, or diet was liberalised16.
In a second retrospective case series, canagliflozin treatment of 17 horses with refractory hyperinsulinaemia was described; 25 animals were concurrently meant to be fed a low carbohydrate forage diet.
Treatment resulted in decreases in mean glucose and insulin concentrations, but significant increases in triglyceride concentrations. In cases where diet and PPID were not fully controlled, the result was an increase in insulin concentration.
Doses below 0.3mg/kg were ineffective for insulin control, but doses of 0.6mg/kg appeared to result in a greater increase in triglyceride concentration. Nineteen of twenty treated horses were reported sound, despite variable individual insulin responses to the drug and many animals having insulin concentrations above normal, but one horse developed laminitis despite good insulin control. The time to resolution of laminitis lameness ranged from 24 hours to several weeks.
Finally, in a double-blinded, randomised, placebo-controlled trial, the short-term effect of canagliflozin (0.6mg/kg once daily by mouth for three weeks) versus placebo on glucose and insulin responses to an oral sugar test (OST), as well as the effects on bodyweight and triglyceride concentrations, were compared in 16 horses with ID, but normoglycaemia22.
Canagliflozin significantly decreased the insulin response to an OST; however, only 50% of the treated horses had normal insulin concentrations after the OST. The canagliflozin-treated horses also experienced greater weight loss overall compared to those treated with placebo.
While anecdotal reports of using dapagliflozin and empagliflozin to aid management of ID in horses exist, no reports are published in the scientific literature.
Preliminary observations on the use of ertugliflozin in the management of hyperinsulinaemia and laminitis in 51 horses have been reported17 and 0.05mg/kg once daily by mouth was associated with a reduction in circulating insulin concentrations and lameness grade associated with laminitis after 30 days.
Insulin concentrations remained low through subsequent follow-up tests in most horses, but in 8/51 an increase in insulin was identified beyond 30 days of treatment – potentially due to a compensatory role of renal SLGT1 receptors or due to owners failing to adhere to the concurrent long-term diet and management recommendations.
Although most horses lost weight while they were on treatment, rates of weight reduction were variable, and a lack of an untreated control group means that it is possible that this weight loss was a consequence of the concurrent dietary restriction.
In a second study, clinical records were reviewed to identify horses with ID that had an OST performed before and after four days of treatment with ertugliflozin23.
Ten horses met the inclusion criteria and four once-daily oral doses of ertugliflozin (0.05 mg/kg) were associated with lowering of insulin concentrations at baseline and in response to an OST; however, insulin concentrations did not return to normal in all horses.
Velagliflozin is currently only commercially available in an oral formulation for cats; however, it has been used in equine experimental studies. Following a four-week, placebo-controlled trial treatment (n=4 control and n=4 treated horse [0.1mg/kg to 1mg/kg by mouth once daily]) glucose and insulin responses to an OST, plasma leptin concentrations and bodyweight were all reduced26.
In as second study, treatment with velagliflozin (0.3mg/kg once daily by mouth for three weeks) also lowered post-prandial insulin and glucose concentrations, and prevented laminitis development in 12 ponies with ID, but normoglycaemia fed a challenge diet high in non-structural carbohydrate for up to 18 days compared to 37 similar, but untreated, ponies, but bodyweight was unchanged19.
In a third study, 24 ponies with ID and normoglycaemia were treated with velagliflozin at the same dose for 16 weeks, and fed a maintenance diet20. Post-prandial serum insulin concentrations were significantly decreased at week 16, but not week 8, and had returned to pre-treatment values 4 weeks after withdrawal of treatment, with no rebound effect; bodyweight remained unchanged.
Hypertriglyceridaemia: Use of SGLT2 inhibitors in horses is associated with hypertriglyceridaemia16,17,22,23. This appears to be mild in most cases, not associated with triglyceride-induced renal or hepatic dysfunction, and not linked to any treatment-associated weight loss, but in isolated cases may be severe25.
Additionally, it appears to occur predominantly in the short term and mostly improves with continued therapy17. However, studies that monitor serum triglyceride concentrations and their impact on organ function over a longer period are lacking.
Other side effects: The other side effect reported to be associated with SGLT2 inhibitor use in horses is polyuria and polydipsia (PU/PD). In total, 10 out of 51 horses (16%) treated with ertugliflozin exhibited PU/PD17.
Although these horses did not develop signs of dehydration or hypovolaemia, the authors recommended that clinicians should be aware of the potential for volume depletion, and should ensure free access to ample quantities of water17. In contrast, PU/PD was not noted in association with velagliflozin therapy20.
A small, but steadily increasing, amount of scientific literature is reporting the use of SGLT2 inhibitors to aid the management of equine ID and consequently reduce the risk of hyperinsulinaemia-associated laminitis. It is paramount that treatment is recommended in conjunction with dietary management and treatment of any concurrent PPID.
The doses used are extrapolated from human studies with limited consideration of species-specific variations. In addition, no consideration of the fundamental differences between ID in horses and humans exists – particularly the fact that most horses with ID remain hyperinsulinaemic, but normoglycaemic, such that increased urinary loss of glucose may not fully explain the beneficial effects of these drugs.
Therefore, further studies – particularly into their mechanism of action and into the potential deleterious effects of treatment-associated hypertriglyceridaemia in the long term – are required.
