Figure 3: FreeStyle Libre sensor placed on the neck of a diabetic cat. Courtesy Dr. Heather Kvitko-White.

These values are not identical to BG, but provide a fair approximation, unless BG is increasing or decreasing rapidly. The sensor does not need to be calibrated, is read by an app on most smartphones, and provides up to 14 days of data. When scanned, the sensor provides an instant reading, along with a graph of the previous eight hours. Information can be downloaded to a computer, or uploaded to the cloud and accessed remotely by the veterinarian. It is always prudent to initially compare a couple of AlphaTRAK measurements to the readings provided by Libre to be sure it seems to be reliable in this particular individual.

In stable patients, defined by an appropriate body weight, no signs of hypoglycemia, and minimal clinical signs of DM, a serum fructosamine may be used to provide a more global assessment of glycemic control over the previous seven to 10 days. A fructosamine concentration below the reference range indicates significant insulin overdose and merits an immediate dose reduction. A value above the reference range simply means the patient is poorly regulated, but does not provide enough data to safely increase the insulin dose. It is important to bear in mind the fructosamine reflects the average BG; brief periods of hypoglycemia followed by sustained hyperglycemia will, therefore, result in increased fructosamine concentrations.

Diabetic remission

Most experienced practitioners have witnessed the phenomenon of feline diabetic remission, in which the patient is able to maintain euglycemia without exogenous insulin. This usually occurs within the first three months, but can occur after prolonged dependence on exogenous insulin. Now there is a greater understanding of the processes that drive a cat to become diabetic, and the influence of factors such as body weight and diet on insulin responsiveness, it is reasonable–in carefully selected cats–to regard diabetic remission as a treatment goal.¹⁸ Not all cats are realistic candidates for remission, but studies suggest a sizeable proportion of suitable patients will become insulin independent within four months with protocols designed with this goal in mind.¹⁹ However, there is still significant uncertainty about the factors that influence diabetic remission and the current literature on this subject makes it difficult to create solid recommendations.²⁰

The ideal candidate for remission is an overweight and sedentary cat on a high CHO diet, recently given a long-acting steroid injection. There is an excellent chance this cat will undergo remission following effective control of BG with exogenous insulin, combined with a low CHO diet and appropriate weight loss. Interestingly, an episode of diabetic ketoacidosis does not preclude the possibility of remission.

Identifying a cat with a strong likelihood of remission is generally based on the physical examination, patient history (e.g. episodes of prior illness, current medication use, body weight changes, etc.), and standard laboratory evaluation. A complete blood count, chemistry panel, urine analysis, thyroid evaluation, retroviral testing, and measurement of feline pancreatic lipase immunoreactivity should be performed on all newly diagnosed diabetic cats, so concurrent or underlying issues can be promptly identified and addressed.

Transient or reversible causes of insulin resistance include obesity, exogenous steroids, and dental disease; all of these should be addressed. If a cat has chronic stomatitis, inflammatory bowel disease, asthma, heart disease etc., it is much less likely to achieve a sustained remission. Under these circumstances, it is generally unhelpful to propose this as a treatment goal.

If the patient's history suggests a sustained period of preclinical diabetes, in which BG was routinely above 200 mg/dl but below the renal threshold, remission is unlikely. A big clue pointing toward this circumstance is the presence of a peripheral neuropathy, as this finding strongly indicates chronic hyperglycemia. All nerves can be affected, but those supporting function in the rear limbs are predictably impacted. The cat may be noted to have an overtly plantigrade stance, or the owner may report difficulty getting up on to furniture.

However, the signs of a peripheral neuropathy may be subtle and can be overlooked during a routine physical examination unless the cat is able to move freely and encouraged to jump. The other way to identify subtle changes in rear limb function is by scratching the base of the tail and seeing if the cat "tip toes" in response.

Remission is also unlikely if the patient's physical examination suggests hyperadrenocorticism; many cushingoid diabetic cats can be successfully managed, but diabetic remission is very uncommon.¹⁰ Definitive treatment of hypersomatotropism (acromegaly) with hypophysectomy often results in diabetic remission, but it is a costly option with limited availability in the U.S.²¹

The most effective way to support diabetic remission is to begin appropriate insulin therapy, with the intent to keep the BG below about 220 mg/dL. This is best achieved with long-acting insulins such as insulin glargine, insulin detemir, or protamine zinc insulin. Intermediate products such as pork lente or neutral protamine hagedorn insulin are widely regarded as less-suitable first choices for cats.^1,2 Practitioners are encouraged to access current recommendations regarding appropriate starting doses or to consult with an internal medicine specialist for advice before using an unfamiliar insulin type.

If the owner wishes to try for remission, BG must be carefully monitored so insulin doses can be adjusted as necessary. As a general rule, the dose should not be increased until a full 72 hours have elapsed on a new regimen, as it can take a few days to see the full effects. Owners need to be able to check BG at home so insulin therapy can be adjusted promptly. The goal is to keep blood glucose concentrations between 65 and 220 mg/dL. As insulin sensitivity improves and β/beta cell function is restored, the patient is likely to have BG values that stay consistently below 120 mg/dL. At this point, the insulin dose should be gradually decreased. It can be technically challenging to do this if the cat is only on one unit of insulin, as it can be difficult to reliably draw up smaller amounts.

Remission can be transient, particularly if the cat regains weight. Careful long-term monitoring is essential, and triggers for DM such as glucocorticoids should be avoided.

'Loose control' approach

This philosophy regarding the management of feline diabetics is in stark contrast to the idea of trying to induce diabetic remission. Instead, this strategy is designed to ease the psychological and financial burden on the owner by negating the need for close monitoring and frequent adjustments of the insulin dose. Essentially, the cat receives enough insulin to be a functional pet; this minimizes the risk of hypoglycemia, but does mean the cat is likely persistently polyuric and polydipsic. A recent report of 185 cats managed in a private practice setting with minimal monitoring suggests many cats may do well with this approach.²² These cats were primarily monitored on the basis of clinical status (weight, thirst, appetite) and pre-insulin BG levels, with the goal of keeping these over 300 mg/dL. All cats were on protamine zinc insulin, given every 12 hours, and most were fed a low CHO diet. Median survival time was over four years and both clinical hypoglycemia (<6% of cats) and diabetic ketoacidosis (less than four percent) were rare. This approach provides a useful option for owners with limited interest in more intensive monitoring, and emphasizes the importance of evaluating the patient's clinical status when managing a feline diabetic.  

What lies ahead?

Once weekly insulin. Preliminary data describing the effect of an insulin designed for once-weekly administration in cats was reported at the 2020 ECVIM Forum.²³ This product combines a recombinant feline insulin molecule with the crystallizable fragment portion of immunoglobulin G via a linkage protein. After injection into the subcutaneous space, the insulin-crystallizable fragment unit is very slowly released due to its large size. When it does leave the subcutaneous space, the insulin-Fc unit is taken up by antigen presenting cells. The insulin is then subsequently released very slowly back into the circulation.

In this pilot study, five cats with DM were transitioned to this product and the dose was then titrated using continuous glucose monitoring systems. After seven weeks of once-weekly injections, there were no changes in clinical signs, body weight, or fructosamine concentrations compared to baseline values. Once-weekly therapy would bring enormous benefits to both owners and cats, so it is hoped this product continues to move forward.

Incretin analogues. Synthetic GLP-1 analogues (a.k.a. incretin analogues) are now licensed for use in people with Type 2 DM. In addition to improving insulin sensitivity, these therapeutic agents actually promote the growth of new β/beta cells. These drugs also suppress food intake and support gradual weight loss; similar effects have been reported in nondiabetic cats, along with the potentiation of insulin secretion.^24,25 There is limited information about the effect of these drugs on cats with DM, although one placebo-controlled study looking at exenatide-extended release in newly diagnosed diabetic cats. All cats received insulin glargine and low CHO diet for the 16 weeks of the study; the cats in the treatment group were also given exenatide-extended release by injection once weekly.

The results suggested exenatide may improve glycemic control (89 percent vs. 58 percent) and increase rates of remission (40 percent vs. 20 percent). However, the number of cats in each arm of the study was small (n=15 for each group), and the findings did not achieve statistical significance.²⁶ In addition, glycemic variability (defined by the dispersion of BG values around the mean) was lower in the treated cats at various time points. This finding is tied in with an increased likelihood of remission.²⁷ In another small study, short-acting exenatide was combined with insulin glargine; the combination was associated with improved weight loss and decreased insulin requirements.²⁸

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors. More than 90 percent of the glucose reclaimed from the filtrate in the proximal convoluted tubules of the kidney is pulled back into the body by special proteins called SGLT-2s. Drugs that inhibit these specialized transporters are called SGLT-2 inhibitors or gliflozins, and several are now approved for the management of Type 2 DM in people. These drugs are given orally and lower BG by promoting glucose loss through the kidneys; they have also been shown to improve other parameters, such as body weight and blood pressure.²⁹

Side effects include urinary tract infection and euglycemic ketoacidosis. One recent report described the effect of an SGLT-2 inhibitor–velagliflozin–in normal cats; as expected, the drug increased water intake and urinary glucose excretion. Cats receiving velagliflozin also showed a tendency toward improve insulin sensitivity.³⁰ In addition, bexagliflozin has been used in combination with insulin in five client-owned cats with poorly regulated DM. All cats had a significant reduction in their insulin needs, and two cats went into remission. Adverse effects were mild and hypoglycemia was not reported.³¹ More studies are needed, but this drug class certainly shows significant promise in managing feline DM.

Audrey Cook, BVM&S, MRCVS, MSc Vet Ed, Dip ACVIM (SAIM), Dip ECVIM (CA), Dip ABVP (feline practice) is professor of Small Animal Internal Medicine at Texas A&M University. She is chief of the Internal Medicine Section, and currently divides her time between the Internal Medicine Service and the Interventional Radiology and Endoscopy Service.

Additional resources

• ISFM Consensus Guidelines on Feline Diabetes Mellitus

https://journals.sagepub.com/doi/pdf/10.1177/1098612X15571880

• AAHA Guidelines on Diabetes Mellitus in Dogs and Cats

https://www.aaha.org/globalassets/02-guidelines/diabetes/diabetes-guidelines_final.pdf

• AAFP Diabetes Educational Toolkit for Feline Diabetes Mellitus

https://catvets.com/diabetes-toolkit/

• Pet Nutrition Alliance Food calculator

https://petnutritionalliance.org/

• BalanceIt Guaranteed Analysis Converter

https://secure.balanceit.com/tools/_gaconverter/index.php? 

References

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