Topical questions on treating feline diabetes mellitus

Introduction

Diabetes mellitus (DM) is one of the most common endocrinopathies, usually resulting from impaired or absent insulin secretion from the pancreatic β-cells alongside peripheral insulin resistance (IR). Various factors can contribute to the pathogenesis in cats, but the final common step in DM development is failure of pancreatic β-cells to secrete adequate insulin to maintain normoglycemia (1). Many cases of feline diabetes share similarities with Type 2 DM in people; these include similar risk factors (such as obesity, increasing age, physical inactivity) and a likely polygenic inheritance pattern (2,3). However, many cases in cats result from other causes, especially endocrine influences that cause IR, such as hypersomatotropism (HS, commonly referred to as “acromegaly”), naturally occurring hyperadrenocorticism (HA), and cats receiving exogenous steroid treatment. These have previously been referred to as “Other Specific Types of Diabetes”. Diabetes pathogenesis can, therefore, differ substantially between individual cats (Figure 1) (1), and it is vital that veterinarians appreciate the likely cause(s) of DM when a cat is diagnosed, because addressing these factors during treatment will encourage good diabetic control. Some diabetic cats experience resolution of their clinical DM during treatment and can discontinue medical anti-hyperglycemic therapy without hyperglycemia recurring; this is referred to as “diabetic remission”. 

Figure 1. Three diabetic cats with likely different etiologies to their diabetes mellitus (DM). (a) An overweight diabetic cat in which obesity-associated insulin resistance likely contributes to DM development; (b) A diabetic cat with underlying hypersomatotropism (HS). Note the phenotypical changes associated with acromegaly, such as prognathism inferior and paw enlargement; (c) A diabetic Burmese cat; the breed has a well-documented predisposition for DM in Europe and Australia. 
© Ruth F. Gostelow

 

Until recently, insulins were the only licensed medication type for diabetic cats, but sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as velagliflozin, are now licensed in many countries as an alternative treatment (Figure 2). These drugs decrease hyperglycemia by antagonizing the SGLT2 protein in the renal tubules, causing urinary loss of glucose. This initial improvement in hyperglycemia is thought to provide a period of β-cell rest and recovery, and in patients where SGLT2 inhibitor therapy is successful, ongoing DM control is, therefore, largely maintained by endogenous β-cell function (4). Although SGLT2 inhibitors have been licensed in many countries for several years, aspects of their use may still cause uncertainty among both veterinarians and pet owners, and this article aims to increase the clinician’s confidence with SGLT2 inhibitor treatment by discussing questions that might arise during their use.

Figure 2. Insulin (a) and sodium-glucose cotransporter-2 inhibitors (b), such as those shown here, offer two alternative licensed treatment options for diabetic cats. 
© with kind permission from Boehringer Ingelheim

 

How do I choose between an SGLT2 inhibitor and insulin?

Whether an SGLT2 inhibitor or insulin is best suited to an individual cat must be decided based on clinical findings and discussion with the cat’s owner. SGLT2 inhibitors provide effective glycemic control in many diabetic cats, but they are contraindicated in some instances; these include animals with ketosis, those with clinical pancreatitis or who are clinically unwell, and they must be used with care in cats with chronic kidney disease. Insulin therapy is more appropriate in such cases (4). 

The dilemma whether to use a SGLT2 inhibitor or insulin is, therefore, most likely to occur when faced with clinically well, newly diagnosed diabetic cats with no obvious comorbidities and no current evidence of ketosis, because either treatment option would be suitable in such patients. In this scenario, the decision between these two therapies will likely be based on a discussion around features of these two options with the cat’s owner. Box 1 shows points that might be raised during a discussion with owners on which treatment is preferable. Potential benefits of SGLT2 inhibitors, as compared to insulin, include their once-daily, oral administration, standard dosage based on body weight, and negligible risk of clinical hypoglycemia (4). These features are likely to be attractive for many owners of diabetic cats, especially as worries about hypoglycemia, the possible impact on an owner’s social life, and concern around leaving their pet with carers are known to be some of the commonest concerns (5). However, a notable distinction between the two therapies, which might be less apparent to pet owners, is their differing association with diabetic remission. This subject will, therefore, require guidance from veterinary surgeons and is discussed in greater detail afterwards.

 

Box 1. Checklist of recommended items to consider when deciding between insulin and SGLT2 inhibitor therapy in an otherwise-healthy, newly diagnosed diabetic cat without ketosis.

Does owner have a strong preference for a once-daily, oral therapy (SGLT2 inhibitor) compared to twice-daily insulin injections? Could be influenced by owner and cat lifestyle, cat temperament, owner’s attitude to needles Is owner aware of potential side effects of both SGLT2 inhibitors (diabetic ketoacidosis (DKA), including euglycemic DKA) and insulin (hypoglycemia, including clinical hypoglycemia) and does this influence their preference for treatment? Is the owner interested in diabetic remission as an outcome of their cat’s diabetic management? If so, insulin could be advisable. Particularly relevant in cats with reversible causes of insulin resistance (e.g., obesity, recent glucocorticoid therapy) or other factors associated with remission (e.g., Burmese breed) in which remission might be more likely to occur. Is long-term suitability of treatment important to the owner? Treatment expectations over the very long term are better understood for insulin compared to SGLT2 inhibitors.

 

How might the possibility of remission affect choice of therapy? 

Box 2 gives a typical definition of diabetic remission in cats. The precise mechanisms leading to diabetic remission are poorly understood. However, remission is likely encouraged by factors that either: 

1. improve endogenous β-cell function, 
2. improve insulin sensitivity, 
3. decrease a patient’s glucose load or 
4. a combination of these mechanisms, allowing the patient to return to a state whereby endogenous β-cell function can maintain normal glucose tolerance again (1).

 

Box 2. Typical definition of diabetic remission in cats (adapted from 6).

A previously diagnosed diabetic cat is able to discontinue exogenous anti-hyperglycemic therapy and shows no evidence of diabetes mellitus recurrence after 4 weeks. Note that receiving a therapeutic diabetic diet is not classified as an “anti-hyperglycemic therapy” for the purpose of this definition.

 

There is no patient characteristic or diagnostic test which accurately predicts which diabetic cats will achieve remission, but several factors have been associated with greater chance of remission. These include overweight diabetic cats that undergo planned weight loss, cats in which previous steroid therapy might have contributed to DM development, and Burmese cats (7,8). Cats with HS-associated DM also frequently achieve remission if their underlying endocrinopathy is adequately treated (9). 

While remission is a well-documented outcome in insulin-treated diabetic cats, the likelihood of remission in animals treated with a SGLT2 inhibitor has yet to be assessed, and none of the initial trials into SGLT2 inhibitor use evaluated remission as an outcome (10,11). It is highly likely that diabetic cats treated with SGLT2 inhibitors can achieve remission, especially because cats that respond well to the medication are assumed to have endogenous β-cell function, which is an absolute requirement for maintaining normoglycemia. However, the stronger association of remission with insulin could make this option more advisable for a diabetic cat, especially if the owner is particularly interested in pursuing remission as a possible treatment outcome. This is especially relevant for cats where the chance of remission is reasonable (e.g., in overweight cats whose obesity can be treated). It is, therefore, vital for veterinarians to be familiar with factors associated with remission, and to introduce the concept of remission to owners as a potential outcome for a diabetic cat at the time of diagnosis. 

In addition to remission being a more frequent outcome with insulin, remission might also be easier to identify in individuals treated with insulin than those receiving SGLT2 inhibitors. In insulin-treated cats, possible indicators of remission can include hypoglycemia or persistent normoglycemia during glucose monitoring*, a lack of glucosuria, or episodic clinical signs that suggest hypoglycemia. These indicators may not help in identifying cats on SGLT2 inhibitor treatment that can stop therapy, because such individuals can show near-normal glucose concentrations throughout the day, and they have a low risk of hypoglycemia and negligible risk of clinical signs of hypoglycemia; in addition, they often have persistent glucosuria (10,12). Potential indicators of possible remission in SGLT2 inhibitor-treated diabetic cats, therefore, warrant further investigation.

* https://academy.royalcanin.com/en/veterinary/continuous-glucose-monitoring-in-diabetic-cats

Can SGLT-2 inhibitors be used in a cat with concurrent endocrinopathies?

Diabetic cats are often affected by concurrent endocrinopathies, including hyperthyroidism, HS or naturally occurring HA (13,14). These concurrent endocrinopathies can contribute to the development of a cat’s DM, especially in the case of HS or HA, and can greatly impair a cat’s response to insulin therapy (14,15). SGLT2 inhibitors could, therefore, offer an attractive treatment alternative for these cases, as long as there are no contraindications, such as ketosis. 

In particular, the ability of SGLT2 inhibitors to provide glycemic control in cats with HS-associated DM has generated specific interest, likely because these cats account for an estimated 15-25% of feline DM cases (13,16). In addition, cats with HS-associated DM typically show a very poor response to insulin therapy, and treatments targeting their underlying HS – such as trans-sphenoidal hypophysectomy (Figure 3) – are costly and have limited availability (17). An accessible, well-tolerated treatment that provides good diabetic control in cats with HS-associated DM would, therefore, be extremely valuable. Cats with HS appear to often retain viable β-cells, despite inevitably developing DM. This is supported by how many affected cats achieve diabetic remission once their underlying HS is treated (9). In addition, clinical experience suggests that cats with HS-associated DM have a low likelihood of diabetic ketoacidosis (DKA) development. Together, these factors could make cats with HS-associated DM well suited to SGLT2 inhibitor treatment, so although there is still little research on SGLT2 inhibitor use in acromegalic diabetic cats, current evidence suggests that these patients can achieve good glycemic control with this therapy. One large cohort study, examining the effectiveness of velagliflozin monotherapy for control of feline DM, included 23 cats with a serum insulin-like growth factor-1 (IGF-1) concentration supportive of underlying HS (11); 16/23 (67%) of these cats completed the study, although describing their diabetic control was not a study aim. Furthermore, a recent case series assessed glycemic control when using velagliflozin as an adjuvant treatment to insulin in eight cats with HS-associated DM (18). The cats showed a significant decrease in both interstitial glucose concentrations and insulin dose after approximately one month of treatment, and two cats were able to stop insulin therapy and be treated with velagliflozin alone. No clinical hypoglycemic episodes were noted, but one cat developed DKA after 143 days of treatment. Considering the historical challenges in treating HS-associated in DM cats, these promising results suggest that SGLT2 inhibitors could be effective anti-diabetic therapies in these patients, although further work is needed into their safety and how they should be dosed when used alongside insulin.

Figure 3. A cat with hypersomatotropism (HS)-associated diabetes mellitus positioned prior to transphenoidal hypophysectomy. This procedure is curative for HS in over 80% of cases, and approximately 70% of cats undergoing successful surgery also achieve diabetic remission (9). 
© Ruth F. Gostelow 

 

What is the optimum dietary management for diabetic cats?

Typical recommendations are that diabetic cats should be fed a diet high in protein and low in digestible carbohydrate, unless they have a comorbidity that requires alternative specific dietary management (19). Current evidence, although limited, supports the notion that dietary digestible carbohydrate restriction is associated with improved glycemic control and a greater chance of diabetic remission (20); total carbohydrate content should be limited as much as possible, with a target of ≤ 12% of metabolizable energy proposed (19). However, these recommendations pre-date the licensing of SGLT2 inhibitors, and to date there has been no research into the ideal diet for diabetic cats receiving SGLT2 inhibitors. Carbohydrate restriction has been linked to greater risk of ketosis in people receiving SGLT2 inhibitors (21), but this might not be replicated in cats, as they are obligate carnivores and, therefore, better adapted to a low carbohydrate diet (22). In a trial comparing velagliflozin therapy to lente insulin treatment in diabetic cats, 20% of the former group were being fed a low-carbohydrate, high-protein diet, but evaluating safety in this subgroup was beyond the trial’s remit (10). Overall, there are no clear contraindications to feeding a low carbohydrate, high-protein diet in cats prescribed SGLT2 inhibitors, although it has been recommended that any dietary change should be carried out 1-2 weeks after starting treatment so that any changes in fecal consistency and appetite, secondary to SGLT2 inhibitor therapy, can be reliably recognized and addressed (4).

There is reasonable evidence that planned weight reduction in overweight diabetic cats leads to improved diabetic control and increased chances of remission (1). Obesity is a widely recognized cause of IR in cats, and reversal of obesity-induced IR during planned weight reduction could, therefore, lead to improved glycemic control (23). However, a recent study demonstrated that caloric restriction, rather than weight loss, was associated with a significant increase in remission and improved DM control in overweight diabetic cats fed a therapeutic weight-loss diet (24). Caloric restriction can lead to rapid diabetic remission in overweight people with Type 2 DM; in these individuals it is thought that calorie restriction causes a rapid decrease in hepatic and pancreatic fat deposition, leading to improvements in hepatic insulin sensitivity and β-cell function (25). The benefits of caloric restriction, and the possible mechanism involved, in overweight diabetic cats requires further study. However, if caloric restriction has a benefit independent of weight loss, it could result in some overweight diabetic cats achieving remission very early during weight loss programs, i.e., before significant weight loss occurs (Figure 4). Owners of diabetic cats undergoing a planned weight loss program must, therefore, be educated on the possibility of remission, and how to monitor for it. It is also prudent to slightly reduce the insulin dose for diabetic cats who are transitioning to a low carbohydrate, high-protein diet, or starting caloric restriction, in case these dietary changes lead to increased insulin sensitivity and a heightened risk of hypoglycemia. Finally, caloric restriction and planned weight reduction should only be pursued in diabetic cats with overweight (BCS > 5/9), and must be carried out using diets suitable for weight loss, to ensure that essential nutrient requirements are still met.

Figure 4. A diabetic cat before (a), and after (b) successful planned weight loss through calorie restriction using a reduced-carbohydrate, prescription weight loss diet. The cat was able to stop insulin therapy, prior to successful remission, three weeks after starting caloric restriction despite having only lost 3% of its initial body weight at this point. 
© Reproduced with kind permission of owner

 

Conclusion

The pathogenesis of feline diabetes can differ substantially between affected cats, and wherever possible the clinician should determine the likely cause in an individual cat, as addressing the underlying reason can assist in achieving good diabetic control. The advent of SGLT2 inhibitors now offer an alternative to insulin treatment for affected cats, but the choice of therapy must be made based on clinical findings and in discussion with the cat’s owner. SGLT2 inhibitors provide effective glycemic control in many diabetic cats, but they are contraindicated in some instances, and whilst remission is not uncommon in insulin-treated individuals, the likelihood of remission in cats treated with SGLT2 inhibitors has yet to be assessed. Furthermore, to date there has been no research into the ideal diet for diabetic cats receiving SGLT2 inhibitors, but there is no doubt that they add another therapeutic option to the clinician’s pharmacy. 

References

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