Sweet pee new remedy in feline diabetes

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Insulin resistance is the hallmark of diabetes mellitus in cats, though varying degrees of insulin deficiency also come into play. The chief causes of feline insulin resistance are obesity, aging, acromegaly, and glucocorticoid therapy, while insulin deficiency occurs secondary to diseases like pancreatitis and pancreatic amyloidosis. Glucotoxicity stemming from persistent hyperglycemia can lead to further beta cell damage.¹

Feline diabetes has traditionally been managed by twice-daily insulin shots combined with diet revamps that slash carbs while boosting protein.² These solutions are a big ask for many clients. Not to mention the specter of hypoglycemia, which looms over every diabetic patient being treated with insulin.

A recent upgrade for cats with insulin resistance—type 2 — diabetes takes the form of a pill that lowers blood glucose without threatening hypoglycemia.

“This class of drugs represents a paradigm shift. It’s a whole different approach to glucose control,” said Orla Mahony, MVB, DACVIM, DECVIM, clinical associate professor at Tufts University’s Cummings School of Veterinary Medicine, at the Fetch Coastal conference in Atlantic City, New Jersey.

SGLT2 inhibitors: A new path

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are orally administered drugs that block renal reabsorption of glucose, resulting in its urinary excretion; this occurs independently of any insulin effect.

SGLT2 inhibitors also have natriuretic and diuretic potency. In humans, they have been shown to improve cardiovascular and kidney disease by lowering blood pressure and proteinuria.^3,4 These benefits may hold true for cats as well, Mahony added.

Sodium-glucose cotransporters drive glucose reuptake in the kidneys and gastrointestinal tract. SGLT2, expressed in the early proximal renal tubules, accounts for 90% of the body’s glucose reabsorption.^3,4

Suppressing these compounds reduces blood glucose. At the same time, Mahony said, “There is minimal risk of hypoglycemia, which is an attractive feature.”

Hypoglycemia is mitigated by the simultaneous upregulation of SGLT1, which sops up glucose in the distal segment of the proximal renal tubules and in the small intestine.^4,5

The pivotal study of bexagliflozin

Bexacat (bexagliflozin) is the first SGLT2 inhibitor approved for use in animals. The recently published field study enrolled 84 diabetic cats that lacked significant comorbidities like pancreatitis, ketosis, and kidney and liver disease.⁶

Cats were dosed with one 15 mg tablet once daily. There was immediate improvement in glucose control following the first pill, with minimal glucose curve fluctuations thereafter.

On day 56, 57% of cats achieved blood glucose levels within the reference range (65-155 mg/dl), mean fructosamine had fallen to 301 umol/L (from 545 umol/L, day 0), and mean concentrations of the ketone beta-hydroxybutyric acid (BHBA) had dropped to 2.91 mg/dl (from 13.7 mg/dl, day 0).

On day 180, the mean blood glucose and fructosamine levels were normal, at 144 mg/dl and 306 umol/L, respectively, in cats that had completed the study (n=72). Sixty-eight percent of cats had BHBA levels in the normal range.

In terms of clinical signs, 63% of subjects had improvement in polyphagia, 75% in polyuria, and 81% in polydipsia. Mahony clarified that, while polyuria/polydipsia are reduced despite Bexacat-wrought glycosuria, these cats may be drinking and urinating more than their healthy cohorts.

The most common adverse events—vomiting, diarrhea, and anorexia—were mostly sporadic and self-limited. Serious adverse events, which occurred in some 10% of cats, included diabetic ketoacidosis (DKA), pancreatitis, hepatic lipidosis, weight loss, urinary tract infections, dehydration, anemia, and hypercalcemia.

Approved for cats in December 2022—and people 1 month later—bexagliflozin is labeled for use in otherwise healthy cats with diabetes mellitus not treated with insulin and weighing over 6.6 pounds (3 kg). Given as a 15 mg flavored tablet that can be crushed and mixed into food once daily, it carries a much lower risk of dangerous hypoglycemia when compared to insulin administration.

The big K

DKA is a life-threatening complication that can befall the diabetic cat. “DKA hangs over the head of every diabetic patient, whether they’re on insulin or an SGLT2 inhibitor,” Mahony said.

However, she added, the risk is higher on the latter. The safe use of SGLT2 inhibitors hinges on adequate endogenous insulin secretion, needed for the body to utilize glucose and suppress ketone formation.

“Not all of our type 2 diabetic cats can produce enough insulin to prevent them from becoming ketoacidotic,” she explained.

While DKA typically is attended by uncontrolled glucose levels, cats that develop DKA on SGLT2 inhibitors are generally euglycemic. This normalcy, which can persist for over a week following drug discontinuation in sick cats, can make DKA easy to miss.

“If they’re on an SGLT2 inhibitor, we need to think about DKA, no matter what the blood glucose is,” she said.

DKA is diagnosed by documenting hyperglycemia (or euglycemia on SGLT2 inhibitor), high anion gap metabolic acidosis, and ketonemia or ketonuria.

Ketone bodies take the form of acetone, acetoacetic acid, and BHBA; the latter is the predominant ketone in DKA. Since urine dipsticks only detect the first 2 types, a negative urine ketone test does not rule out DKA.

Mahony advocates checking BHBA levels using a handheld portable blood ketone meter, or by sending serum samples out for laboratory analysis. A cutoff value of 25 mg/dl has shown 100% sensitivity and 87 percent specificity for diagnosing DKA7.

Most occurrences of DKA happen in the first 2 weeks of SGLT2 therapy, so careful monitoring at this time is crucial.

If BHBA is not dropping or if weight loss or other signs of illness develop, Mahony recommends discontinuing Bexacat, testing for DKA and switching to insulin. Supplementation with 5-10% dextrose is advised to balance out the insulin dose the cat requires to chase ketones.

“If we can get the cats to eat,” she explained, “that can also be helpful in augmenting their glucose and allowing us to give them the insulin they need to stop the ketoacidosis.”

Identifying the “Bexa” cat

The labeling for Bexacat includes a boxed warning calling for appropriate patient selection and highlighting the potential for adverse reactions.

No, Bexacat is not for every cat! Mahony described the ideal candidate as having uncomplicated diabetes, with no prior insulin treatment. The cat should also be eating and drinking normally, and not lethargic. Baseline testing includes a complete blood count (CBC), chemistry profile, T4, BHBA and fructosamine levels, fPLI (and/or snap PSL), urinalysis, and urine culture.

Cats with BHBA >37 mg/dl, or >25 mg/dl with kidney disease should be excluded from treatment. So too, Bexacat should not be used in cats with IRIS stage 3 or 4 kidney disease, liver enzymes over 3 times normal, or evidence of pancreatitis.

Monitoring cats on Bexacat

DKA, whether hyper- or euglycemic, is most apt to happen within a few weeks of starting on Bexacat. During this time, Mahony said, clients should watch closely for decreased appetite, lethargy, and other signs of illness. They should also bring their cat to the hospital 3-5 days after treatment has begun for a physical exam, weight check, and measurement of blood glucose and BHBA.

At weeks 2, 4, and 8, and then every 90 days thereafter, she added, patients on Bexacat should be weighed and have the following testing: CBC, chemistry panel, blood glucose, fructosamine, BHBA and fPLI/snap PSL.

Mahony advised informing owners that over time, these patients can become hyperglycemic again due to progressive loss of pancreatic beta cells. Any loss of glycemic control, hyperlipidemia, ketonemia, hyporexia, anorexia, weight loss or dehydration calls for a switch from Bexacat to insulin.

Despite its potential drawbacks, she concluded, “Bexacat is a promising novel treatment, and this is an exciting time for those of us who manage diabetic cats.”

References

1. Niessen SJM, Bjornvad C, Church DB, et al. Agreeing Language in Veterinary Endocrinology (ALIVE): Diabetes mellitus - a modified Delphi-method-based system to create consensus disease definitions. Vet J. 2022;289:105910. doi:10.1016/j.tvjl.2022.105910
2. Sparkes AH, Cannon M, Church D, et al. ISFM consensus guidelines on the practical management of diabetes mellitus in cats. J Feline Med Surg. 2015;17(3):235-250. doi:10.1177/1098612X1557188
3. Vallon V, Sharma K. Sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Curr Opin Nephrol Hypertens. 2010;19(5):425-431. doi:10.1097/MNH.0b013e32833bec06
4. Idris I, Donnelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes Metab. 2009;11(2):79-88. doi:10.1111/j.1463-1326.2008.00982.x
5. Kurosaki E, Ogasawara H. Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data. Pharmacol Ther. 2013;139(1):51-59. doi:10.1016/j.pharmthera.2013.04.003
6. Hadd MJ, Bienhoff SE, Little SE, et al. Safety and effectiveness of the sodium-glucose cotransporter inhibitor bexagliflozin in cats newly diagnosed with diabetes mellitus. J Vet Intern Med. 2023;37(3):915-924. doi:10.1111/jvim.1673
7. Weingart C, Lotz F, Kohn B. Measurement of β-hydroxybutyrate in cats with nonketotic diabetes mellitus, diabetic ketosis, and diabetic ketoacidosis. J Vet Diagn Invest. 2012;24(2):295-300. doi:10.1177/1040638711428332