Diagnosis & Treatment of Feline Diabetes Mellitus

The author and Clinician’s Brief editorial team acknowledge the prior contribution of Alice Huang, VMD, DACVIM.

Overview

Diabetes mellitus (DM) is a treatable condition caused by insulin deficiency or insulin resistance. Most diabetic cats are insulin resistant, similar to type II diabetes in humans.¹ Insulin deficiency, the hallmark of human type I diabetes, is less common in cats. Diabetic remission, in which the patient no longer requires exogenous insulin administration, is more likely with type II disease.

Epidemiology

Prevalence

• Occurs in an estimated up to ≈0.5% to 1% of domestic cats in many countries (range varies by population/study)^2,3

Signalment

Breed Predisposition

• Burmese cats are overrepresented.^4,5

Age

• Most common in middle-aged cats (4-12 years of age)^2,5

Sex

• Males are affected ≈1.6 times more frequently than females.^2,5

Risk Factors

• Obesity

• Male

• Chronic glucocorticoid administration

Pathophysiology

Insulin resistance and insulin deficiency can lead to hyperglycemia secondary to uninhibited hepatic glucose production and reduced glucose transport into cells. Insulin deficiency is a lack of endogenous insulin production and requires administration of exogenous insulin. Insulin deficient diabetes is more common in dogs, as well as in geriatric cats newly diagnosed with diabetes that may be secondary to infiltrative disease of the pancreas.

Insulin resistance (ie, decreased sensitivity to insulin) is more common in cats. Pancreatic beta cells produce insulin, but the insulin is less effective (creating a hyperglycemic state) because of obesity, inflammation, or excess endogenous or exogenous corticosteroid levels.

Persistent hyperglycemia can result in glucosuria when the renal tubular threshold for glucose excretion exceeds 200 to 300 mg/dL in cats. Endothelial damage, immunosuppression, and glucose toxicity can occur. Glucose toxicity, defined as the cellular damage resulting from persistent hyperglycemia, is initially associated with suppressed insulin secretion but can eventually lead to permanent beta-cell loss, perpetuating diabetic disease. Increased proteolysis secondary to hyperglycemia can lead to muscle wasting. As accelerated lipid catabolism persists, hepatic lipidosis can develop. Ketoacidosis is a metabolic acidosis that can occur secondary to enhanced ketone production.

Clinical Presentation

• Polyuria, polydipsia, polyphagia, weight loss

• Lethargy

• Unkempt hair coat

• Plantigrade stance

• Hepatomegaly

• Signs of concurrent disease or diabetic ketoacidosis (DKA)

  • Anorexia

  • Dehydration

  • Depression

  • Vomiting

Differential Diagnoses

• Chronic enteropathy

• Chronic kidney disease

• Exocrine pancreatic insufficiency

• Hyperthyroidism

• Neoplasia

• Stress hyperglycemia

Diagnostics & Diagnostic Findings

Definitive Diagnosis

• Persistent fasting hyperglycemia and glucosuria with concurrent clinical signs of polyuria/polydipsia/polyphagia and weight loss

• Stress hyperglycemia can complicate diagnosis, suggesting consideration of serum fructosamine measurement for possible confirmation of chronic hyperglycemia.

  • Normal serum fructosamine, 200 to 350 mmol/L

  • Fructosamine levels may be within the normal reference interval in cats with mild persistent hyperglycemia.

  • Fructosamine levels may be artificially low in cats with decreased serum protein levels.

  • At-home urine collection and testing with urine glucose strips can be considered to evaluate for persistent glucosuria.

• Concurrent diseases that cause insulin resistance can complicate diagnosis and regulation. Screening may be necessary.

  • Hypersomatotropism⁶

  • Hyperthyroidism

  • Hyperadrenocorticism

Relevant Laboratory Tests

• CBC

  • May be normal or reflect a mild, nonregenerative anemia

• Serum chemistry profile

  • Hyperglycemia

  • Hypercholesterolemia/hypertriglyceridemia

  • ALT/ALP elevations possible

  • In patients with DKA, hypokalemia and hypophosphatemia may be present.

• Urinalysis

  • Glucosuria

  • Possible ketonuria

  • Urine culture only indicated if bacteriuria occurs with pyuria and clinical signs consistent with UTI⁷

• Abdominal ultrasonography and radiography may help identify hepatic changes, concurrent small intestinal disease, or pancreatitis.

Treatment

The goal of treatment is to control clinical signs, improve quality of life for the patient and pet owner, prevent ongoing hyperglycemia and potential long-term complications of diabetes, and avoid hypoglycemia. Treatment may be lifelong.

Because most cats with diabetes are likely to be insulin resistant, sodium glucose cotransporter 2 (SGLT2) inhibitors are likely a good first option for many cats. SGLT2 inhibitors may be the ideal choice for otherwise healthy cats newly diagnosed with diabetes because of the medication’s safety margins and ease of administration; close monitoring is needed during the first 2 weeks of treatment.⁸

Inpatient/Outpatient

Most newly diagnosed diabetic cats are treated on an outpatient basis. Patients with clinical DKA or significant concurrent disease may need initial hospitalization.

Medical

Sodium Glucose Cotransporter 2 Inhibitors

• Overview/mechanism

  • Patient selection is imperative. Successful use of an SGLT2 inhibitor requires the ability to maintain endogenous insulin production.

  • SGLT2 inhibitors are not oral insulin.

  • SGLT2 inhibitors block renal glucose reabsorption at the proximal tubule, resulting in increased glucosuria and lower blood glucose.

  • SGLT2 inhibitors eliminate the risk for severe, clinical, life-threatening hyperglycemia.

• FDA-approved veterinary agents

  • SGLT2 inhibitors are FDA approved for use in newly diagnosed, otherwise healthy diabetic cats.

  • Bexagliflozin (15 mg/cat PO every 24 hours)

  • Velagliflozin (1 mg/kg PO once every 24 hours)

• Efficacy

  • Field trials have shown substantial improvements in glycemic control and clinical signs with SGLT2 inhibitor monotherapy every 24 hours in newly diagnosed, otherwise healthy diabetic cats.⁴

  • Successful diabetic control occurs in >80% of cats.^9,10

• Indications/patient selection

  • Indicated for newly diagnosed diabetic cats that are otherwise healthy

  • Patients should not have previously received insulin.

  • Not for use in cats with insulin‑dependent diabetes or those currently receiving insulin

  • Careful selection and screening are required prior to treatment initiation.

  • Patients must be screened for the presence of ketones prior to initiation of an SGLT2 inhibitor.

    • Beta-hydroxybutyrate (BHB) is the earliest and most predominant ketone body produced during DKA in cats.¹¹

    • Point-of-care ketone meters are inexpensive and allow for rapid measurement of BHB in blood.

    • Urine ketone measurement (acetoacetic acid) is available but less quantitatively accurate and sensitive than BHB measurement.¹²

    • BHB measurement is the recommended and preferred method for accurately determining ketosis.

    • If BHB is elevated (>3.6 mmol/L), ketonemia is significant, and insulin should be used instead of SGLT2 inhibitors. In some cases of BHB elevation in cats that are not clinically ill, SGLT2 inhibitors may still be considered by experienced clinicians.^1,8

• Contraindications and cautions

  • Contraindicated or not recommended in cats with prior insulin therapy, DKA, anorexia, dehydration, lethargy, significant hepatic or renal disease, or clinical pancreatitis or in cats that are not eating or are clinically unstable⁴

• Important adverse effects and safety signals to monitor

  • Cats that develop DKA while receiving an SGLT2 inhibitor may be presented with euglycemia (blood glucose <250 mg/dL).

  • Euglycemic DKA (eDKA) is not caused by SGLT2 inhibitors but can develop in the absence of endogenous insulin production.

  • DKA/eDKA signs include vomiting, inappetence, dehydration, weight loss, depression, and concurrent UTI.

    • Early recognition and prompt treatment (ie, stopping the SGLT2 inhibitor, starting insulin, providing carbohydrate and supportive care) are essential.

  • Adverse effects (eg, diarrhea, vomiting, weight loss) of SGLT2 inhibitors are usually self-limiting and resolve within the first 2 weeks of treatment.

• Monitoring recommendations

  • Baseline: CBC, serum chemistry profile, urinalysis (with urine culture if indicated), fructosamine, baseline BHB or urine ketone measurement if BHB is not available

  • Early follow‑up: frequent checks during the first 1 to 4 weeks

    • Rechecks should minimally include measurement of serum BHB, weight, and blood glucose on days 3, 7, and 14.

    • Blood glucose curves are not indicated.

    • Considerations for transitioning to insulin include persistent hyperglycemia, development of persistent ketonemia, eDKA, and persistence of adverse effects.

• Practical points for clinicians and owners

  • With appropriate patient selection, SGLT2 inhibitors may be a safer option than insulin because of the eliminated risk for hypoglycemia.

  • Owners should be advised to stop the drug and seek immediate veterinary care if anorexia, lethargy, vomiting, and/or weakness occur, as these may be signs of DKA/eDKA.

  • Insulin should not be withdrawn to start SGLT2 inhibitors in cats previously treated with insulin.

  • Cats that are not responding to treatment or develop ketonemia or ketonuria while receiving an SGLT2 inhibitor should be transitioned promptly to insulin therapy.

  • If clinical signs or glycemic control do not improve within 1 month of SGLT2 inhibitor therapy, it is important to ensure the medication is being consumed and/or administered correctly. If the dose is being administered and consumed correctly with no improvement, causes of insulin resistance should be assessed. The SGLT2 inhibitor should be discontinued and the patient transitioned to insulin.

Insulin

• Short-acting insulin (eg, regular insulin) is primarily used in the hospital for clinically ill diabetic patients or patients with DKA, as increased potency increases the risk for hypoglycemia.

• Long-acting insulin is the mainstay of insulin therapy.

• Protamine zinc insulin (PZI) and insulin glargine are the recommended insulin choices for cats.

• PZI and insulin glargine result in similar glycemic control and can aid in achieving remission.

  • Administration in conjunction with a low-carbohydrate, high-protein diet may comparatively increase the likelihood for diabetic remission.

  • PZI U-40

    • FDA approved for cats

    • U-40 syringe

  • Insulin glargine U-100

    • U-100 syringe

• Other insulin choices for cats

  • Porcine lente insulin U-40

    • Available and approved for cats

    • Duration of action may not be long enough for ideal glycemic control in cats¹

  • Insulin glargine U-300

    • May be effective and safe for treatment of feline diabetes, but more long-term and comparative clinical trials are needed

  • Degludec U-100, U-200

    • Basal insulin

    • Not approved for cats

    • Can be considered when there is poor response/glycemic control with insulin glargine or PZI

  • Detimir U-100

    • Long-acting insulin analog

    • Similar duration of action as insulin glargine U-100

    • Can be considered when there is poor response/glycemic control with insulin glargine or PZI

• Neutral protamine Hagedorn insulin should not be used in cats due to its very short duration of effect (<8 hours).¹

• Future options may include automatic insulin delivery systems and ultra–long-acting insulin preparation administered weekly.^13,14

Nutrition

• Low-carbohydrate, high-protein diets have been associated with higher diabetic remission rates when used with insulin but may be used with SGLT2 inhibitor therapy as well.¹⁵

• BCS optimization; obesity can exacerbate insulin resistance.^10,16

• Most cats require timely intervention for persistent hyperglycemia. In cases in which owners are resistant to medical intervention, dietary therapy alone has been used. If managing diabetes with diet alone, close monitoring is imperative. Medical intervention is required if hyperglycemia fails to improve after 2 to 4 weeks.

Monitoring & Follow‑up

• Blood glucose curves are no longer recommended for monitoring cats receiving insulin.¹

• Continuous glucose monitors measure interstitial glucose and may be helpful for monitoring overall blood glucose trends.¹⁶

  • At-home blood glucose monitors are helpful but only provide information about the blood glucose at that particular moment. These monitors may be most helpful when used to ensure absence of hypoglycemia prior to insulin administration or in patients with consistent clinical signs of hypoglycemia.

• Weight and clinical signs should be monitored in conjunction with laboratory findings to evaluate control of diabetes.

• Fructosamine measurement every 4 to 6 months may be helpful for broad glycemic control.

• CBC, serum chemistry profile, and urinalysis are recommended every 6 months for cats with well-controlled diabetes.

• Urine culture is indicated if there are signs of cystitis (ie, dysuria, pollakiuria) and an active urine sediment. Antimicrobial sensitivity results should guide therapy.⁷

• A clinical scoring system developed by the European Society of Veterinary Endocrinology may be considered to help evaluate individual diabetic control.^16-18

Complications

• Iatrogenic hypoglycemia (with insulin treatment)

• DKA

• Hepatic lipidosis can occur if dietary changes are resisted by the patient or caloric restriction is overly aggressive.

• Polyneuropathy (often reversible with good control)

Prognosis

Prognosis is good with diligent care and monitoring. Diabetic remission, defined as euglycemia without administration of exogenous insulin or oral hypoglycemic agents for at least 4 weeks, is possible. Following resolution of persistent hyperglycemia, insulin resistance and glucose toxicity resolve, allowing restoration of pancreatic beta-cell function.

Historically, remission was suspected in cats receiving insulin therapy because of a hypoglycemic episode, which may occur after resolution of comorbidities, discontinuation of corticosteroid therapy, or improved BCS. Insulin should be discontinued, and the patient should be monitored for recurrence of diabetic signs and hyperglycemia.

With SGLT2 inhibitor therapy, there is no risk for clinical hypoglycemia and subsequently no outward indicator of remission. Although attempted discontinuation of SGLT2 inhibitors is not required, administration may be stopped when overall diabetic risks have been reduced (eg, weight loss, corticosteroid administration discontinued, concurrent diseases resolved), with close monitoring for recurrence of diabetic clinical signs (eg, polyuria/polydipsia) and hyperglycemia. After this short discontinuation, SGLT2 inhibitors can be restarted if necessary in cats that were previously well regulated.

Improvement of BCS and elimination of other diabetic risk factors may improve chances of diabetic remission. Many cats can do well for many years.

Prevention & Owner Education

• Maintaining optimum body condition

• Minimizing medications that contribute to insulin resistance¹

• Environmental enrichment to reduce the risk for diabetes^19-22