14 Sept
David Rendle BVSc, MVM, CertEM(IntMed), DipECEIM, FRCVS provides an update on the diagnosis on two commonly seen conditions, as well as their treatment and management.
Figure 1. Metabolic disease that occurs as a consequence of obesity is the most common endocrinopathy in horses and has huge implications for equine welfare.
Endocrine dysfunction associated with obesity is a daily challenge in equine ambulatory practice, and obesity-related laminitis is frequently cited as the greatest threat to equine welfare in the UK (Figure 1).
Equine metabolic syndrome (EMS) describes the conflation of obesity, hyperinsulinaemia and laminitis, and accounts for most cases of laminitis in the UK.
Studies demonstrating that laminitis can be induced by protracted increases in insulin concentration1,2 were pivotal in understanding that hyperinsulinaemia is central to the development of laminitis. These have been followed by work in field cases demonstrating that the pathological changes that occur in both EMS and pituitary pars intermedia dysfunction (PPID) are consistent with those that occur in laminitis that is induced experimentally with hyperinsulinaemia3,4.
PPID (Figure 2) has historically been associated with laminitis; however, its importance as a cause of laminitis remains to be fully elucidated, as does the mechanism that might link the two conditions.
While the link between PPID and laminitis may have been overstated in the past, PPID remains a very common endocrinopathy of ageing horses and can result in a range of clinical signs that have the potential to compromise quality of life.
Relative to EMS and PPID, other equine endocrinopathies are rare. Benign adenomas of the thyroid gland are seen occasionally, but beyond this condition other disorders of the thyroid, parathyroid or adrenal glands are very rare.
EMS is a collection of risk factors for endocrine laminitis, with insulin dysregulation being the central feature. Specifically, it is persistent hyperinsulinaemia that is thought to result in laminitis, and investigation of EMS focuses on assessment of insulin concentrations.
Laboratory investigation may not be necessary – it is reasonable to assume that a young, fat native pony with laminitis is suffering from EMS and a laboratory diagnosis is unlikely to change the treatment recommendations made at the outset.
However, not all horses with EMS exhibit the typical obese phenotype – and assessment of hyperinsulinaemia, as well as measurement of adiponectin and triglyceride concentrations, may provide clinically useful information that can guide management and treatment decisions.
Insulin concentrations can be assessed following a period of fasting, following feeding, following oral ingestion of a known quantity of sugar, or following IV infusion of glucose and/or insulin. These different tests have advantages and disadvantages, and are discussed in detail elsewhere5,6.
IV tests are less convenient and, therefore, are unlikely to be performed in ambulatory practice, but can be helpful in demonstrating tissue insulin resistance that may not be demonstrable using other tests.
Measurement of serum insulin concentration without any form of sugar challenge is the most straightforward test in practice, but false negative results are common. Unexpected negative results when measuring basal insulin concentration should be followed up with some form of sugar challenge test.
Measurements taken following feeding with forage are more variable, but more sensitive – and potentially more helpful as they give an indication of the insulin concentrations (and hence laminitis risk) that are occurring under normal management conditions.
Surveillance data would suggest at least 50% of UK horses are overweight or obese. The increasing prevalence of obesity has paralleled rises in obesity in other domestic species – and, indeed, our own species – as we live in an increasingly obesogenic environment.
Dietary management and increased exercise (where appropriate) should be the focus of efforts to improve tissue sensitivity to insulin and hence reduce the risk of laminitis, with pharmaceuticals being a secondary, but important, consideration.
It should, in theory, be straightforward to manage the weight of our domestic animals by manipulating their dietary intake; however, this overlooks the complex behavioural and psychological factors that influence the relationships we have with our pets. Therefore, strategies are often required that can accommodate some of the barriers that cannot be broken down, and would otherwise prevent weight loss and reduction in laminitis risk.
The use of pharmaceuticals as a treatment for obesity and insulin dysregulation has traditionally been a last resort, but as evidence increases for the potential welfare benefits of accelerated weight loss and reduced laminitis risk, so the use of these drugs has increased.
In a recent study of native ponies, the risk of laminitis occurring within three years was 9.9%7; the risk in those that had a fed insulin greater than 21.8u/L was a staggeringly high 21.5%.
With the risk of laminitis being so high in certain populations, it seems entirely appropriate that a more proactive approach to management is taken to prevent unnecessary suffering. If insulin cannot be reduced within a couple of months through management alone then the use of pharmaceuticals to reduce insulin concentrations (and potentially adiposity) should be considered (Figure 1).
Anecdotal reports also exist of the benefits of insulin‑sensitising drugs in horses with acute laminitis and hyperinsulinaemia, and it is logical that a reduction in circulating insulin concentrations would be associated with improved recovery.
Sodium glucose co-transport-2 (SGLT2) inhibitors have become a popular treatment for human type-two diabetes mellitus, and show considerable promise as a means of limiting hyperinsulinaemia and reducing laminitis risk in horses.
Through inhibiting reuptake of glucose in the kidney – and thereby promoting the excretion of glucose in urine – circulating insulin concentrations are lowered.
The risk of laminitis has been shown to reduce following the administration of velagliflozin8,9. Canagliflozin has also been shown to be effective in reducing insulin concentrations in horses with insulin dysregulation10.
Ertugliflozin is available in the UK as an extemporaneous paste formulated for horses. Like velagliflozin and canagliflozin, ertuglflozin has been shown to reduce insulin concentrations rapidly in horses with EMS (Tania Sundra, unpublished data), and has been associated with rapid reductions in insulin concentrations and rapid clinical improvement in ponies with acute laminitis.
Larger clinical field trials are required, but all of the work performed to date suggests the SGLT2 inhibitors could be very useful in both preventing and treating laminitis associated with hyperinsulinaemia. Ertugliflozin has been used at 0.05mg/kg orally once daily.
With the availability of a suitable palatable paste for horses in the UK, levothyroxine has rapidly become a popular treatment for obese horses that are refractory to weight loss through diet and management alone.
The administration of levothyroxine to obese horses with a history of laminitis results in both weight loss and improvements in insulin sensitivity compared to controls11. In healthy horses, levothyroxine administration is associated with a reduction in insulin concentrations, a doubling of insulin sensitivity, an increase in insulin disposal rate, a decreased insulin response to glucose and an increase in insulin receptors on adipocytes12-13.
The effects on insulin dynamics, coupled with the promotion of weight loss, make levothyroxine a compelling treatment option for obese horses that are suffering from, or are deemed to be at risk of, laminitis. In the US, where levothyroxine has been widely available at a more reasonable cost, the drug has been used safely and effectively in the management of EMS for decades.
In the UK an increasing tendency exists to use levothyroxine in the treatment of acute laminitis in overweight horses with hyperinsulinaemia, in addition to using it as a treatment for obesity. While evidence is lacking, this is logical considering the drug’s effects on insulin dynamics14.
Several investigations have now demonstrated that levothyroxine is safe and well tolerated, even when used for very long periods or at extremely high doses13,15,16.
Levothyroxine is typically used at 0.1mg/kg orally once daily; however, anecdotally lower doses may be effective.
Historically, three to six months of treatment has been recommended, but this is an arbitrary figure and the drug should be used until target weight is reached, at which time the dose should be reduced gradually over a few weeks.
Where finances do not permit three to six months of treatment, shorter courses can be helpful in promoting weight loss and in encouraging owners that it is possible to effectively reduce the weight of their horses.
The author tends to treat for one month at a time, reassessing the clinical response before prescribing a further month of treatment if appropriate.
Monitoring of body condition is important as responses are variable – some horses will lose weight rapidly, while others may not lose weight if management recommendations are not complied with.
When target weight is reached, it is helpful to assess insulin concentrations to determine whether persistent insulin dysregulation is present that may need to be managed indefinitely.
Metformin became a popular treatment for horses with recurrent “pasture-associated” laminitis prior to other alternatives becoming available in the UK17. Its popularity has waned with the availability of levothyroxine and with a growing perception that it does little to reduce the risk of laminitis.
Evidence generated to date suggests that metformin acts at an intestinal level, inhibiting the absorption of monosaccharides, and in doing so reduces the subsequent secretion of insulin from the pancreas.
In an experimental investigation, metformin significantly reduced circulating concentrations of glucose and insulin following the administration of a bolus of dextrose by nasogastric tube18. Some evidence exists that metformin may reduce insulin concentrations in ponies with EMS, but it does not appear to reduce adiposity11.
Whether metformin makes a clinically relevant difference to insulin concentration or laminitis risk in the field has not been adequately determined.
Levothyroxine is probably a better alternative for horses with hyperinsulinaemia that need to lose weight – and for those that do not need to lose weight, but have high insulin concentrations, ertugliflozin is likely to be more effective.
If metformin is being used, it is generally administered at 15mg/kg to 30mg/kg two to four times per day. It is likely to be more effective if it can be administered little and often.
A high adrenocorticotropic hormone (ACTH) concentration in association with clinical signs provides a diagnosis of PPID.
The use of ACTH concentration in the absence of clinical signs is not recommended – and if clinical signs are not evident then ACTH concentration should be assessed following the administration of thyrotropin‑releasing hormone to increase the accuracy of diagnosis.
ACTH concentration can increase in response to many physiological – as well as pathological – processes, and slight increases above normal reference intervals should be interpreted with scepticism and prompt further confirmatory testing.
Recent publications have reviewed the diagnosis of PPID6,19.
Pergolide has been used widely for the treatment of PPID for more than 20 years. Most horses exhibit a good improvement in clinical signs and a reduction in ACTH concentration, even though in the majority ACTH does not return to normal.
Good preventive medicine, farriery, nutrition, dentistry and parasite control are essential in the management of PPID, and are as important as pharmaceuticals.
Anecdotally, pergolide seems to reduce the incidence of laminitis, although recent evidence indicates that dopamine agonists do not improve insulin dynamics20 and no evidence exists that pergolide reduces the risk of laminitis in horses with PPID21.
PPID and obesity are common comorbidities, and how (or indeed whether) PPID contributes to insulin dysregulation and laminitis risk is not known. A recent study indicated that insulin dysregulation is refractory to treatment in horses with PPID, even when they are treated with pergolide (McGowan and Hertzel, unpublished data).
If concern exists over laminitis then it is essential that horses with PPID have insulin concentrations assessed and that treatment of concurrent EMS is considered.
The registered form of pergolide is a tablet that some horses are reluctant to ingest. A survey that compared the amount of pergolide used with the amount that should have been dispensed demonstrated that compliance was very poor, with only 48% of horses receiving the amount they should have22. This may have implications for the control of clinical signs, even though it did not appear to be associated with any difference in laboratory control.
An extemporaneous pergolide paste preparation has been shown to be safe and effective in horses that are refractory to treatment with the registered tablets23, and in a recent field trial the extemporaneous paste resulted in better suppression of ACTH concentrations than the registered tablet (Luoda pharma, unpublished data).
The use of pergolide in the treatment of PPID was the subject of a recent systematic review24.
Cabergoline is a dopamine agonist that has the same mechanism of action as pergolide, but is used as a long-acting IM injection.
It is being used as an alternative to pergolide in the US as a fortnightly injection and has the potential to facilitate treatment in PPID cases that are difficult to treat daily with an oral medication.
Clinical data on the efficacy of cabergoline in the treatment of PPID is lacking, but anecdotal reports are promising and evidence exists that it is effective in suppressing the output of the pars intermedia (Luoda pharma, unpublished data).
EMS and PPID are two of the most common conditions in equine practice, and can have a devastating effect on equine welfare.
Interest in both conditions has increased markedly – and that interest has been associated with improvements in diagnostic testing and the development of novel treatments that have the potential to improve the control of both conditions.
Diet and exercise will always be the mainstay of effective management of EMS and prevention of laminitis; however, ertugliflozin and other insulin‑sensitising drugs have the potential to reduce insulin concentrations and the incidence of laminitis. They may also promote recovery from laminitis.
Levothyroxine offers the additional benefit of promoting weight loss, as well as reducing insulin concentrations.
In the management of PPID, pergolide remains the mainstay of treatment and the paste preparation provides an alternative where the registered product is not suitable. Cabergoline offers an interesting alternative, but clinical data from horses with PPID is limited.