Horse owner experiences and observations with the use of SGLT2i for the management of equine metabolic syndrome and hyperinsulinaemia-associated laminitis
Summary
Background
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are being used increasingly in equine practice. While there is emerging clinical evidence of the safety and efficacy of these drugs, there are currently no reports to document owner experiences with treatment.
Objective
The objective of the study was to report owner experiences and observations following treatment with SGLT2i in horses.
Study design
A cross-sectional online survey.
Methods
Horse owners were recruited via social media, online forums and their veterinarians to participate in an anonymous online survey to document their experiences and observations when treating their horses with SGLT2i.
Results
Three hundred forty-two responses met the inclusion criteria. Ertugliflozin was the most commonly prescribed SGLT2i (79.8%), and the most common reasons for treatment were high insulin concentrations (84.2%) and active laminitis (59.7%). 85.3% of owners reported their horses had an improved quality of life after commencing treatment, while 9.4% reported no change and 5.3% reported a worsening of clinical signs. Of owners who had considered euthanasia prior to treatment (n = 77), 80.5% reported their horse's level of pain to be either mild or absent after 30 days of treatment and 94.8% reported their horse's quality of life to be improved. Most owners (n = 220, 64.7%) reported they were either extremely satisfied or somewhat satisfied (n = 72, 21.2%) with treatment. Treatment concerns included safety/side effects, medication cost, availability and long-term efficacy. 114 owners (33.3%) reported one or more initial adverse effects upon induction onto the medication, particularly excessive urination (n = 70, 20.5%), excessive drinking (n = 38, 11.1%), excessive weight loss (n = 34, 9.9%) and dullness (n = 26, 7.6%).
Main limitation
Sampling bias through social media and veterinary practices and reliance on subjective owner reports.
Conclusion
The use of SGLT2i in horses was associated with excellent rates of owner satisfaction and owner-reported improved quality of life for the horse; however, some adverse effects were observed.
INTRODUCTION
Equine metabolic syndrome (EMS) is a collection of risk factors that are linked to an increased risk for the development of hyperinsulinaemia-associated laminitis (HAL) (Durham et al., 2019). EMS is highly prevalent in certain breeds (Carslake et al., 2021) and studies in pleasure horses estimate that between 15% and 23% of horses have suffered at least one episode of laminitis (Menzies-Gow, Katz, et al., 2010; Menzies-Gow, Stevens, et al., 2010; Potter et al., 2017).
Currently, no drugs are registered for the treatment of EMS or HAL, although sodium-glucose co-transporter 2 inhibitors (SGLT2i) are emerging as a promising option (Frank et al., 2023; Kellon & Gustafson, 2022; Kellon & Gustafson, 2023; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023). SGLT2i are human antidiabetic agents that prevent filtered glucose reabsorption in the kidneys, promoting glucosuria (Bays, 2013; Kalra, 2014). As a result, plasma glucose concentrations fall, which leads to a reduced stimulus for insulin secretion from the pancreas (Bays, 2013; Kalra, 2014). The SGLT2i drugs velagliflozin, canagliflozin, and ertugliflozin have been reported to reduce serum insulin concentrations in horses with hyperinsulinaemia (Frank et al., 2023; Kellon & Gustafson, 2022; Meier et al., 2018, 2019; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023) and are being used increasingly in clinical practice to aid recovery from HAL (Kellon & Gustafson, 2022; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023). While these short-term studies demonstrate promising results, side effects including polyuria, polydipsia and hypertriglyceridaemia have been reported (Frank et al., 2023; Kellon & Gustafson, 2022, 2023; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023) and there are anecdotal concerns that adverse effects might limit the use of this drug class in horses.
Currently, there is a lack of information on SGLT2i use in horses and no data regarding horse owners' perceived benefits, concerns and overall satisfaction following treatment with SGLT2i. In human medicine, if patient satisfaction following medication use is low, adherence to treatment decreases, and an effective therapeutic effect may not be achieved (Cramer, 2004; Ishii et al., 2008). Understanding owner experience with a new medication can also provide important directions for future research into safety, for example, by highlighting areas of concern that may have otherwise been missed (Aptekmann & Schwartz, 2011). Additionally, understanding owner attitudes towards treatments can identify barriers to treatment, such as cost or ease of administration, which can be helpful in the ongoing development of treatment strategies and reduce issues with medication adherence (Aptekmann & Schwartz, 2011; Belshaw et al., 2016; Keller et al., 2021).
This study's objective was to further understand the use and responses to SGLT2i in clinical practice and specifically to document horse owner experiences and observations in using these drugs for the management of EMS and HAL.
MATERIALS AND METHODS
Participants
Horse owners were invited to participate in an anonymous online (only non-identifiable data collected) survey (Supplementary Item S1) if their horse had been prescribed an SGLT2i. Participants were recruited via convenience sampling by posting the survey link on veterinary sites, social media and online horse forums between May and July 2023. To be included in the study, an answer to the specific SGLT2i prescribed had to be provided.
Data collection
The survey consisted of 29 questions in total: 4 open-ended questions and 25 closed-ended questions (Supplementary Item S1). Questions included the country of origin, signalment (age, sex and breed), use, diet, PPID status (if known), and concurrent medications. Questions relating to SGLT2i use included which drug was prescribed, the basis for treatment, duration of therapy, response to treatment and the owner's subjective assessment of quality of life and lameness before and after treatment. Owners were also asked if there was any difficulty administering medication, side effects related to treatment and overall satisfaction with the treatment.
Data analysis
Data were collected via QualtricsXM (Qualtrics) and imported into StataMP (StataCorp) for analysis. Survey responses were collated and presented using summary statistics, including mean, standard deviation, median, interquartile range and percentages. Only surveys that were 100% complete were included in the final analysis. Comparisons between reported baseline and Day 30 pain levels were made using the Wilcoxon sign-rank test. Owner satisfaction and perceived quality of life were also presented stratified by the reason for treatment (high insulin, active laminitis, prior laminitis, weight loss and PPID).
Ethical approval
This study was reviewed and approved by the Human Research Ethics Committee at Murdoch University (Permit number: 2023/057).
RESULTS
Between 16 May and 24 June 2023, 354 surveys were commenced. Ten were excluded from the analysis as they were not 100% complete and two were excluded as they had not used an SGLT2i, leaving 342 completed questionnaires.
Characteristics
The majority of respondents were from Australia (n = 185, 54.1%) and the UK (n = 110, 32.2%). However, respondents from the USA (n = 29, 8.5%), Canada (n = 9, 2.6%) and Europe (n = 6, 1.8%) were also recorded. The median age of horses was 16 (IQR: 12, 20), with 189 geldings (55.3%), 150 mares (43.9%), and 3 stallions (0.9%). Ertugliflozin (BOVA Aus; Steglatro, Merck Sharp & Dohme (Australia) Pty Ltd) was the most commonly used medication (79.8%) followed by canagliflozin (Invokana, Janssen UK) (13.5%). The most common reasons for treatment were high insulin concentrations (84.2%) and active laminitis (59.7%) (Table 1). Prior to the commencement of treatment, euthanasia had been considered in 22.5% of cases (n = 77).
| N | % | |
|---|---|---|
| Drug/formulation | ||
| Canagliflozin (Invokana, Janssen UK) | 46 | 13.5% |
| Dapagliflozin (Forxiga, AstraZeneca) | 18 | 5.2% |
| Empagliflozin (Jardiance, Boehringer Ingelheim) | 4 | 1.2% |
| Ertugliflozin liquid | 3 | 0.9% |
| Ertugliflozin paste (BOVA Aus) | 155 | 45.3% |
| Ertugliflozin tablets (Steglatro, Merck Sharp & Dohme (Australia Pty Ltd)) | 115 | 33.6% |
| Velagliflozin (Boehringer Ingelheim) | 1 | 0.3% |
| Reasons for treatment | ||
| High insulin | 288 | 84.2% |
| Active laminitis | 204 | 59.7% |
| Prior laminitis | 100 | 29.2% |
| Weight loss | 65 | 19.0% |
| Diagnosed with PPID | 124 | 36.3% |
| Treated with pergolide | 114 | 33.3% |
| Treated with cabergoline | 8 | 2.3% |
| Breed | ||
| Welsh/Welsh X | 102 | 29.8% |
| Cobs/X | 67 | 19.6% |
| Shetland pony/x | 32 | 9.4% |
| Other pony breeds | 31 | 9.1% |
| Miniature pony/x | 26 | 7.6% |
| Warmblood/x | 22 | 6.4% |
| Arabian/x | 20 | 5.9% |
| Western breeds (QH, Appaloosa, X's) | 16 | 4.7% |
| American breeds (Morgan, Tennessee, Rocky Mountain) | 15 | 4.4% |
| Thoroughbred/Standardbred/x | 8 | 2.3% |
| Discipline | ||
| Pleasure | 146 | 42.7% |
| Companion | 137 | 40.1% |
| Hacking/showing | 96 | 28.1% |
| Dressage | 63 | 18.4% |
| Retired | 57 | 16.7% |
| Eventing/show jumping | 24 | 7.0% |
| Harness/carriage driving | 15 | 4.4% |
| Western riding | 5 | 1.5% |
| Riding school | 4 | 1.2% |
| Breeding | 3 | 0.9% |
| Endurance | 3 | 0.9% |
| Diet | ||
| Low-sugar forage prior to treatment | 282 | 82.5% |
| Reduced pasture access prior to treatment | 280 | 81.9% |
| Duration of SGLT2i treatment when surveyed | ||
| Treatment discontinued | 117 | 34.2% |
| <30 days | 29 | 8.5% |
| 1–3 months | 38 | 11.1% |
| 3–6 months | 46 | 13.5% |
| 6–12 months | 57 | 16.7% |
| Over 12 months | 55 | 16.1% |
Approximately a third of respondents had discontinued SGLT2i use at the time of the survey. The most common reasons for cessation of treatment were a reduction in insulin concentrations (61.5%), laminitis/lameness had resolved (42.7%), and/or weight loss had been achieved (29.9%). Other reasons for discontinuation of treatment included adverse effects (14.5%), treatment costs (10.3%), euthanasia (6.0%), lack of response (5.1%), issues with medication availability (1.7%) and/or difficulty administering the medication (1.7%).
Perceived efficacy
Most owners (n = 290, 85.3%) reported their horses had an improved quality of life after commencing treatment, while 9.4% (n = 32) reported no change and 5.3% reported a worsening of clinical signs. Improvements were also observed in signs consistent with pain, with 57.0% of owners reporting no pain after 30 days of treatment compared with 14.9% at the commencement of treatment (Table 2). Prior to treatment with SGLT2i, 72 horses (21.1%) were being treated with a pain medication (phenylbutazone, firocoxib, paracetamol, meloxicam), while at Day 30, 64 horses (18.7%) were using an analgesic medication. Perceived efficacy did not differ with reason for treatment (Table 3).
| Initial pain levels | Pain at 30 days | p-Value | |||
|---|---|---|---|---|---|
| None | 51 | 14.9% | 195 | 57.0% | <0.001 |
| Mild | 57 | 16.7% | 99 | 29.0% | |
| Moderate | 118 | 34.5% | 22 | 6.4% | |
| Severe | 106 | 31.0% | 11 | 3.2% | |
| Unable to judge | 10 | 2.9% | 15 | 4.4% | |
| High insulin | Active laminitis | Prior laminitis | Weight loss | PPID | |
|---|---|---|---|---|---|
| Number | 288 | 204 | 100 | 65 | 124 |
| Improved quality of life | 245 (85.1) | 184 (90.2) | 87 (87.0) | 55 (84.6) | 110 (88.7) |
| Satisfied with treatment, n (%) | 249 (86.5) | 174 (85.3) | 89 (89.0) | 57 (87.7) | 106 (85.5) |
- Note: Pain scores: 0—no pain, 1—mild pain, 2—moderate pain, 3—severe pain.
- Abbreviation: IQR, interquartile range.
Sixty-two (80.5%) of the owners of the 77 horses who had considered euthanasia of their horses reported their horses' level of pain to be either mild or absent after 30 days of SGLT2i treatment and 73 (94.8%) reported their horses' quality of life to be improved.
Owner satisfaction
The majority of respondents reported they were either extremely satisfied (n = 220, 64.7%) or somewhat satisfied (n = 72, 21.2%) with the treatment. Similarly, 69.6% of respondents (n = 234) would be extremely likely to recommend the use of SGLT2i to other owners, while 17.3% would be somewhat likely to recommend the treatment. While there was some variability in owner satisfaction between the different SGLT2i drugs (dapagliflozin 94.4%, canagliflozin 93.5%, ertugliflozin tablets 84.4% and ertugliflozin paste 83.2%), the difference was not significant. Owner satisfaction with treatment was high regardless of the reason for treatment (Table 3).
Treatment concerns
Treatment concerns were focused on four themes: safety/side effects, medication cost, medication availability and long-term efficacy. Owners (n = 49, 14.3%) had concerns about the safety of SLGT2i and the absence of clear evidence on safety, particularly in terms of triglyceride concentrations and urinary tract infections. Several owners (n = 114, 33.3%) reported one or more initial adverse effects upon induction onto the medication, particularly excessive urination (n = 70, 20.5%), excessive drinking (n = 38, 11.1%), excessive weight loss (n = 34, 9.9%), dullness (n = 26, 7.6%). Some of these issues were resolved when the dose was reduced. Owners (n = 11, 3.2%) also raised concerns about how the use of the medication and the absence of clear long-term safety data may negatively impact their horse's health. The long-term risks were commonly weighed with the short- to medium-term benefits observed with the use of SGLT2i to the health of their horses. One owner reported ‘(the) long term effects (are a concern) but outweighed by pony's quality of life’. Another participant responded they were ‘Scared of the risks but it was this or death from laminitis flares’.
The cost and accessibility of the medication and the cost of veterinary monitoring (e.g., veterinary appointments and regular insulin, triglyceride and hepatic enzyme testing) were identified as a barrier to long-term treatment by 31 respondents (9.1%). Owners stated ‘It's costly and only available after vet visits and bloods’ and ‘The cost. I run a rescue sanctuary for horses and have 3 ponies all on the treatment and it gets very expensive’.
A small number of owners (n = 11, 3.2%) highlighted the long-term efficacy of the medication. For example, one owner stated they were concerned ‘If she will develop resistance to the effect of ertugliflozin and/or intolerance which may lead to having to cease medication’. Six owners (1.8%) had reported that after a prolonged period of treatment, they noticed a gradual return of symptoms and had switched to an alternative SGLT2 inhibitor; however, the therapeutic effects of the second medication were not captured in this survey. Additionally, it appeared unclear to many owners whether the treatment was to be used short-term (used during high-risk periods or when insulin levels were high) or long-term.
Many owners (n = 164, 47.9%) reported no concerns with the use of the medication, explaining they had substantially helped their horse where nothing else had worked. One owner reported that SGLTi were a ‘Game changing medication, my horses are so happy, one retiring sound after almost having to making the near gut-wrenching call to have him put to sleep as we couldn't control his pain before medication’.
DISCUSSION
The results from this study indicate that treatment with SGLT2i in horses is associated with excellent owner satisfaction and perception of improved quality of life for the horse but is also associated with reports of adverse effects in some horses.
The improvement in lameness reported by owners in this study is consistent with previous case series that reported the use of ertugliflozin or canagliflozin being associated with improved lameness grades shortly after commencing treatment in HAL cases refractory to diet and management changes (Kellon & Gustafson, 2022; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023). A previous study (Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023) reported that most horses discontinued NSAID treatment within 14 days of commencing treatment with ertugliflozin, while the results of this study suggested that many horses continued to receive NSAIDs at 30 days. This suggests that veterinarians should consider evaluating lameness in cases treated with SGLT2i at shorter intervals as anti-inflammatory medications may be discontinued earlier in association with their use. In the current study, approximately 20% of owners stated that euthanasia was considered prior to commencing treatment, and of these, 80% reported their horse's level of pain to be either mild or absent within 30 days and almost all reported their horse's quality of life to be improved after starting treatment. Quality of life is an important factor in end-of-life decision-making (Long et al., 2022), and the results of this study suggest that SGLT2i have the potential to improve the welfare of horses affected by HAL markedly. Failure to adequately control pain is one of the most common reasons horses with laminitis are euthanised (Hopster & Eps, 2019) Studies have indicated that 5%–16% of horses died or were euthanised following a diagnosis of laminitis (Cripps & Eustace, 1999; Menzies-Gow, Katz, et al., 2010; Menzies-Gow, Stevens, et al., 2010). The current study therefore provides further (albeit limited) evidence of the ability of SGLT2i to alleviate suffering in HAL and suggests these drugs might potentially be considered as a first-line treatment option alongside diet and management in horses affected by HAL (Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023).
The use of SGLT2i for weight loss was commonly cited in this study, consistent with previous reports highlighting an alarming prevalence of obesity in 24%–50% of horses and ponies (Owers & Chubbock, 2013; Potter et al., 2016). Obesity is a component of many cases of EMS and its management is critical in reducing the risk for the development of HAL (Frank, 2011). Laminitis tends to be more severe in overweight animals and they are more at risk for euthanasia than leaner horses (Menzies-Gow, Katz, et al., 2010; Menzies-Gow, Stevens, et al., 2010). Reports also suggest that once animals are obese (and insulin dysregulated), they are more weight loss-resistant (Argo et al., 2012). Almost one third of owners in this study reported that weight loss occurred in response to SGLT2i use, consistent with previous studies in horses and humans (Janež & Fioretto, 2021; Kalra, 2014; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023). Weight loss is presumed to occur in response to the mobilisation of fat stores (Ferrannini et al., 2014, 2016). This study did not gather objective bodyweight measurements to report the efficacy of SGLT2i in managing obesity.
Approximately one third of the horses in this study were reportedly being treated for pituitary pars intermedia dysfunction (PPID) with oral pergolide or extended-release cabergoline injections before commencing treatment with an SGLT2i. Active laminitis and high insulin concentrations were the most commonly reported reasons for initiating treatment with SGLT2i in this group. Insulin dysregulation reportedly occurs in approximately 30%–60% of PPID cases (Horn et al., 2019; McFarlane, 2011) and those with concurrent PPID and hyperinsulinaemia might be at a higher risk of developing laminitis (Johnson, 2016). More recent studies have demonstrated that the pathological changes in the laminae in both EMS and pituitary pars intermedia dysfunction are consistent with those induced experimentally with hyperinsulinaemia (Karikoski et al., 2015, 2016). Furthermore, reports have indicated that treatment with dopamine agonists does not improve insulin sensitivity (Gehlen et al., 2014; Valencia et al., 2014). The results from this and previous studies (Kellon & Gustafson, 2022; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023) not only suggest that SGLT2i can be used alongside dopamine agonists but suggest they might form an important adjunct therapy to help manage cases of HAL in horses with PPID.
Dietary management is critical to preventing HAL in horses (Durham et al., 2019). 80% of owners stated that their horse was already fed a low-sugar forage and access to pasture was restricted before commencing treatment with SGLT2i. In contrast, previous reports have suggested that owner compliance with dietary restriction is poor (Durham, 2012) and a 2017 study from Australia reported that most owners failed to restrict pasture access to prevent future episodes of laminitis (Potter et al., 2017). The results from the current study, however, suggest that owners are becoming increasingly aware of the importance of implementing preventative measures (such as restricting dietary sugars) in managing horses with EMS or perhaps more likely it indicates a bias in the type of owners that responded to the survey. Anecdotally, concerns have been raised about SGLT2i being prescribed to horses with EMS without attention being paid to optimising diet and management. While the answers pertaining to diet in this survey cannot be verified, they suggest that SGLT2i are being prescribed to horses with EMS and HAL which are generally refractory to diet and management changes.
Owner-reported concerns related to SGLT2i use in this study (excessive drinking and urination) are similar to those reported in recent case series (Frank et al., 2023; Kellon & Gustafson, 2022; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023). Reports of polyuria and polydipsia were common and have been demonstrated previously in horses treated with ertugliflozin and canagliflozin (Kellon & Gustafson, 2022; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023); however, no adverse clinical outcomes have been reported. Studies in people suggest that this is a result of osmotic diuresis induced by glucosuria (List & Whaley, 2011). The potential for volume depletion is higher in elderly human patients treated with SGLT2i (Pollack & Cahn, 2022) Veterinarians should counsel owners on the importance of providing clean, fresh drinking water and monitoring water intake at all times, particularly in older horses. Beyond polyuria and polydipsia, side effects were limited to excess weight loss and dullness. While these were reported commonly (and a number of owners reported risk of adverse effects as their reason for discontinuing treatment) serious sequelae were not reported. Signs of dullness reported by owners in a small number of horses in this study might be attributed to dehydration, hypoglycaemia, caloric restriction or a combination thereof. It was not possible to elucidate the exact cause from the current study, but warrants further investigation. Urinary tract infections have been reported in humans treated with SGLT2i but the risk is no higher than with other classes of diabetic medications (Alkabbani et al., 2022). Urinary tract infections were not reported in this study and have not been observed in studies performed on horses to date (Frank et al., 2023; Kellon & Gustafson, 2022, 2023; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023).
Owner's perceptions of excessive weight loss in a small number of horses and increased triglyceride concentrations are consistent with previous reports of SGLT2i treatment (Kellon & Gustafson, 2022; Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023). Extrapolating from human data, this is thought to result from a shift to fatty acid mobilisation and lipolysis due to increased glucagon secretion from pancreatic alpha cells in response to reduced insulin secretion (Ferrannini et al., 2014, 2016). Emerging evidence from human literature suggests that SGLT2i induce a fasting-like state through metabolic reprogramming (Gao et al., 2022) and severe dietary restriction might need to be avoided while horses are being treated with SGLT2i to prevent excessive weight loss. Given the limited information currently available on SGLT2i use in horses, the significance of elevated triglyceride concentrations is unclear. Previous studies have reported that despite an initial increase in triglycerides, concentrations return to normal after 30 days (Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023) and clinical hyperlipemia has only been reported in one horse with other comorbidities (Kellon & Gustafson, 2023). In human medicine, controversy still exists regarding the clinical significance of changes to the lipid profile during SGLT2i use, and frequent monitoring is recommended (Osto et al., 2023). These results highlight the need for more studies to determine the clinical significance of hypertriglyceridemia. Furthermore, veterinarians should also be cognisant that regular monitoring and dietary management of horses receiving SGLT2i is imperative.
Anecdotally, the authors find that side effects are typically manageable and self-limiting, however they are aware of a small number of horses that have experienced excessive weight loss which is very difficult to reverse. Sarcopenia, a muscle wasting condition, has been reported in humans receiving SGLT2i (Yasuda et al., 2020; Zhang et al., 2023). The exact mechanism by which this occurs is unclear but is thought to be related to increased glucagon secretion which drives hepatic gluconeogenesis and glycogenolysis and accelerates protein breakdown from skeletal muscle (Yabe et al., 2015). This further highlights the need for more studies to investigate the nutritional requirements of horses receiving these drugs and the importance of regular veterinary monitoring.
Cost of medication and laboratory testing, drug availability and long-term effects were other concerns highlighted by participants in this study. Most survey respondents resided in Australia, and almost half of the participants were prescribed ertugliflozin tablets. The timing of this study coincided with the discontinuation of ertugliflozin tablets from the human market in Australia, so it is not surprising that drug availability was frequently cited as a concern. Ertugliflozin has been made available as a compounded paste for horses in Australia and the United Kingdom. The results of this study highlight the need for cost-effective treatment for horses who require long-term medication to prevent any unnecessary suffering from recurrent episodes of HAL. It also suggests that veterinarians need to carefully balance the frequency of follow-up assessments and laboratory testing with what owners can afford.
Some owners reported a gradual return of laminitis symptoms after prolonged use of SGLT2i. While the exact reason for this cannot be determined by this study, it does warrant further investigation. A previous study demonstrated that while insulin concentration was reduced initially following ertugliflozin use in all horses, a small number of cases reported increases in insulin beyond 30 days (Sundra, Kelty, & Rendle, 2023; Sundra, Lester, et al., 2023). Evidence in human medicine suggests SGLT2 inhibition may lead to a compensatory rise in SGLT1 over time (Rieg et al., 2014), which could result in a decreased urinary glucose output, a subsequent increase in insulin concentration and, therefore a return of laminitis in a subset of horses. Another potential explanation is poor long-term owner compliance with medication and/or dietary management (Hague et al., 2021). There are currently no long-term studies to demonstrate the safety or efficacy of SGLT2i in horses and this work is urgently required given the increasing frequency with which these drugs are being prescribed.
Ertugliflozin was the most commonly prescribed SGLT2i in this study (79.8%). As previously mentioned, the majority of respondents originated from Australia, where there are currently no other SGLT2i available with equine-specific data. Canagliflozin was the second most commonly prescribed drug which is not available in Australia but is prescribed in the United Kingdom, USA and Canada. Dapagliflozin and empagliflozin use was reported in 6.4% of participants with similar outcomes and satisfaction rates as ertugliflozin and canagliflozin. Apart from velagliflozin, ertugliflozin and canagliflozin, there is currently no evidence to support the use of other SGLT2i in horses, and caution should be exercised when extrapolating dose rates and results between drugs as inherent differences likely exist between their pharmacodynamic and pharmacokinetic properties (Suzuki et al., 2022). Given the limited options available, further work to investigate the use of other SGLT2i in horses is warranted.
This study had a number of limitations, including the convenience sampling. Owners were recruited through social media and internet forums, and thus, the sample was limited to owners with resources, access and time to participate in an Internet survey. This sampling strategy might have also failed to include owners from broader geographic, social and economic demographics. Respondents were self-selected and it is likely that these owners might have had higher levels of engagement with their veterinary surgeons and horse health in general than non-respondents. Another potential source of bias is the practices that distributed the survey to their clients as these veterinarians might represent a sector that frequently uses SGLT2i. Their clients might be better informed on the use and the potential for adverse effects and may not be representative of clients in broader equine practice. Assessment of lameness in this study was also subjective and based on the owners' interpretation of the lameness grade.
Despite the limitations, this study is the first to report horse owner experiences with the use of SGLT2i for the management of EMS and HAL. The results indicate that treatment with SGLT2i is associated with excellent owner satisfaction, owner-perceived improved quality of life for the horse and few reports of adverse effects. There remains a need for better understanding of the pharmacokinetics, pharmacodynamics, mechanism of action and long-term safety of these drugs in horses. The findings of this study are consistent with previous reports of SGLT2i use in horses and suggest that this class of drug has the potential to alleviate suffering in cases of HAL and might be an important adjunct to the management of horses with EMS.
AUTHOR CONTRIBUTIONS
Tania Sundra: Conceptualization; investigation; methodology; writing – original draft; writing – review and editing. Erin Kelty: Writing – review and editing; writing – original draft; formal analysis. Gabriele Rossi: Conceptualization; writing – review and editing; supervision; project administration; methodology. Guy Lester: Conceptualization; writing – review and editing; supervision; methodology. David Rendle: Conceptualization; writing – review and editing; supervision; methodology.
ACKNOWLEDGEMENTS
The authors would like to thank Edd Knowles from Bell Veterinary Equine Clinic and the Equine Cushings and Insulin Resistance (ECIR) group for their assistance in distributing this survey to horse owners. Open access publishing facilitated by Murdoch University, as part of the Wiley ‐ Murdoch University agreement via the Council of Australian University Librarians.
CONFLICT OF INTEREST STATEMENT
David Rendle provides consultancy services to BOVA who produce a compounded ertugliflozin paste specifically for horses. Tania Sundra has received subsidised travel expenses to CPD events by BOVA.
FUNDING INFORMATION
There are no funders to report for this submission.
