Info New Treatments for Feline Diabetes

Many of our members have raised questions about newer forms of treatment for their cats. Below is information on several of the types of treatments and what we have been able to find in the research literature. Our goal is to help FDMB members make informed decisions.

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT-2 Inhibitors): BEXACAT & SENVELGO

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors developed for human use have garnered considerable attention in the last few years. Two of the drugs that have been widely publicized were both initially released for Type 2 diabetes treatment but have since been found to be effective for treating other conditions (e.g., heart failure, kidney disease) and have become very popular for helping with weight loss. These include Farxiga (dapaglifozin) and Jardiance (empaglifozin).

In December 2022 the FDA approved a new oral medication for the treatment of diabetes in cats. Bexacat (bexaglifozin) is an SGLT-2 inhibitor that prevents the kidneys from reabsorbing glucose allowing excess blood glucose to be excreted in the urine. The following August, the FDA also approved Senvelgo (velaglifozin) which is an oral liquid that is also an SGLT-2 inhibitor for the treatment of feline diabetes.

What is important to consider regarding Bexacat and Senvelgo is they are NOT indicated for cats that have already been treated with insulin. These are not drugs meant for treating cats who are insulin-dependent diabetics and are neither drug is indicated if your cat has symptoms of diabetic ketoacidosis (DKA). Both drugs increase the risk of DKA as well as euglycemic DKA in cats. Just like DKA, euglycemic DKA is a life-threatening emergency that is characterized by euglycemia (normal range blood glucose), metabolic acidosis, and ketoacidosis. Unlike DKA, euglycemic DKA may be overlooked due to the absence of hyperglycemia.

There were two 6-month field studies that demonstrated that Bexacat was over 80% effective in improving glycemic control in cats with diabetes. While these are very optimistic results, there were notable safety concerns.

• Very careful screening of cats who are being considered for treatment with either of these drugs is imperative. Prior to initiating treatment with either Bexacat or Senvelgo, the veterinarian should ensure the cat is alert, active, eating, and drinking.
• The veterinarian should conduct a physical examination, obtain a medical history, CBC, serum chemistry, serum fructosamine, and urinalysis including evaluation for ketonuria.
• Laboratory values or physical assessment that indicates the presence of ketones, DKA, kidney or liver disease, or recurrent urinary tract infection (UTI) would preclude the use of either of these medications.
• If there is a delay of more than a week between diagnosis of diabetes mellitus and initiation of either of these medications, the veterinarian should re-evaluate the cat with a full physical examination and updated history to ensure the cat still meets the criteria described above. A delay of more than a week between diagnosis and starting either Bexacat or Senvelgo may increase the risk of developing diabetic ketoacidosis since the cat’s diabetes would be untreated during this period.
• Also crucial is diligent monitoring regardless of the duration of or the response to treatment, and the ability to and how to promptly recognize and intervene if there are serious and life-threatening adverse reactions.
• Sudden onset of loss of appetite, anorexia, lethargy, dehydration, or weight loss should indicate the medication should be immediately discontinued and the cat should be assessed for DKA.

Administration

Both Bexacat and Senvelgo are orally administered.

• Bexacat is a 15 mg tablet available in bottles containing 90 tablets. The same dose is administered regardless of blood glucose level.
• Senvelgo is a clear to slightly yellow to brown liquid. The dose of Senvelgo is 0.45 mg/lb (or 1 mg/kg) of body weight regardless of blood glucose level. It should not be mixed into food. If a dose of Senvelgo is missed, it should be given as soon as possible on the same day. If a cat vomits within 30 min of dosing, the dose can be repeated. Senvelgo needs to be administered using the dosing syringe provided in the package. The dose should be rounded down to the nearest pound.

What are the Positives?

• Both medications are taken orally.
  • Bexacat is a tablet and it can be crushed and mixed into food.
  • Senvelgo is a liquid and should NOT be mixed into a cat’s food.
• They are administered once daily.
• For caregivers who are uncomfortable with needles, it is an alternative treatment.
• It is easier to find someone willing to care for you cat if an insulin injection is not involved or blood glucose testing is not needed. (The need for home testing is not mentioned in any of the manufacturer's materials. We would encourage home testing.)
• The cost appears to be less expensive than insulin (although insulin prices have been changing).
• Dosing:
  • There is only one dose of Bexacat so there is not the issue of correct dosing as when drawing insulin into a syringe.
  • This is not the case with Senvelgo since the dose is based on the cat’s weight. Changes in weight could necessitate a change in dose.
• Caregivers have greater schedule flexibility although either medication should be given at approximately the same time of day.
• There appears to be a lower potential for hypoglycemia.

What are the Negatives?

• Cats who are 13 or older and, especially if not overweight prior to diagnosis, are more likely to be insulin dependent or have other medical problems. They are likely not good candidates.
• This is not a medication recommended for an insulin-dependent diabetic cat.
• Bexacat and Senvelgo should not be used in cats that have either liver disease or reduced renal function.
• Cats with symptoms of loss of or no appetite, weight loss (i.e., anorexia), dehydration, or lethargy at the time diabetes is diagnosed need to be very carefully screened. The presence of these symptoms require immediate discontinuation of Bexacat or Senvelgo and assessment for DKA regardless of blood glucose levels.
• Cats need to be monitored for urinary tract infections (UTI) as Bexacat may increase the risk of UTIs. The long-term use of Bexacat may increase the risk of urothelial carcinoma.
• During treatment with Bexacat or Senvelgo, blood glucose, fructosamine, serum β-hydroxybutyrate (BHBA), serum feline pancreas-specific lipase (fPL), liver parameters, serum cholesterol and triglycerides; and body weight and clinical signs should be routinely monitored. (Note that the lab values below are US based and may involve different metrics in other countries.)
  • fPL or liver tests require prompt evaluation for pancreatitis and/or liver disease. Discontinuation of Bexacat or Senvelgo may need to be considered.
  • fPL > 5.3 mcg/L, diagnostic imaging consistent with pancreatitis, a history of pancreatitis, or current clinical signs of pancreatitis need to be ruled out.
  • BHBA is the predominating ketoacid in DKA. Bexacat should be stopped if BHBA is not notably reduced after initiating treatment or if BHBA levels persistently rise after an initial reduction. BHBA > 37 mg/dL or if BHBA > 25 mg/dL in a cat with a history of renal disease or metabolic acidosis indicates the cat is not a good candidate for Bexacat or Senvelgo.
  • Cats with persistently elevated cholesterol and triglyceride levels may be at an increased risk for developing DKA or euglycemic DKA.
• During the first 8 weeks after starting Bexacat or Senvelgo, glycemic control and clinical improvement needs to be assessed.
  • A vet needs to complete a thorough physical examination, at least an 8-hour blood glucose curve, and a fructosame level. Glucose levels over 350 mg/dL or a fructosamine level indicating poor glycemic control suggests the SGLT-2 should be discontinued.
• Bexacat and Senvelgo may cause increased serum calcium concentrations. These levels need to be monitored.
• Diarrhea is the most common adverse reaction to both drugs. Bexacat or Senvelgo should be discontinued in cats that develop diarrhea that is unresponsive to conventional treatment.
• Inappropriate urination may occur.
• Approximately 20 – 30% of cats have persistent excessive urination and/or water intake due to Bexacat-induced osmotic diuresis. This can be a risk factor for dehydration-induced DKA.
• Cats should be evaluated for concurrent disease including pancreatitis, infectious disease, urinary tract infection, neoplasia, and hypersomatotropism (acromegaly) before initiating and while receiving either Bexacat or Senvelgo.
• Cats with baseline creatinine between 1.6 and 2 mg/dL at treatment initiation should be closely monitored for signs of dehydration and weight loss. Renal function should be closely monitored.
• Persistently low or worsening serum chloride values compared to pre-treatment levels may be indicative of DKA or euglycemic DKA.
• When stopping either drug, cats should be closely monitored for the development of DKA or euglycemic DKA.

Research

• 84 cats with newly diagnosed diabetes were enrolled in a 180-day multicenter effectiveness and safety study. 72 cats completed the study. The most common adverse reactions included elevated blood urea nitrogen (BUN), vomiting, elevated urine specific gravity (USG), elevated serum fPL, diarrhea, anorexia, lethargy, and dehydration. Nine serious adverse events occurred including three cats who died or were euthanized.
• 89 cats with newly diagnosed diabetes were enrolled in a 56-day multicenter pilot field effectives and safety study with continued use up to 180 days. The most common adverse reactions included elevated blood urea nitrogen (BUN), elevated urine specific gravity (USG), elevated serum feline pancreas-specific lipase, vomiting, diarrhea/loose stool, hyporexia/anorexia, lethargy, elevated serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), and urinary tract infections. Twenty cats (22%) had at least one blood glucose value < 65 mg/dL recorded during 8-hour blood glucose curves. No clinical signs of hypoglycemia were observed and bexagliflozin dosing was not adjusted in any cat due to documented hypoglycemia. Nine serious adverse reactions associated with bexagliflozin administration occurred during the study, including six cats who died or were euthanized. Of the six cats who died or were euthanized, five became clinically ill within receiving 5 doses of bexagliflozin (range 1 to 5 doses).
• One hundred twenty-five cats with diabetes mellitus that had previously completed a bexagliflozin field study were enrolled in a multicenter extended use field study. Cats were enrolled in the study for a range of 7 to 1064 days, with a mean of 329 days. Safety data were evaluated for all 125 cats. Forty-nine of the 125 enrolled cats were withdrawn from the study due to adverse reactions, serious adverse reactions, death/euthanasia, lack of effectiveness, suspected diabetic remission, withdrawal of owner consent, or lost to follow up. The most common adverse reactions were similar to those noted in the previous field studies. Twenty serious adverse reactions associated with Bexacat administration occurred during the study, all resulting in death or euthanasia.
• There are few published studies using velaglifozin in cats. A 2014 study focused on six non-diabetic obese cats that were otherwise healthy. A 2022 conference presentation involving 26 cats, half of which received velaglifozin and half insulin indicated that the cats receiving the SGLT-2 had a positive response. Any other references were the proprietary property of the drug manufacturer, Boehringer Ingelheim Vetmedica.

Thoughts for consideration:

• While there are advantages to using a drug that does not involve an injection, the lack of emphasis on home testing leaves caregivers at a loss as far as knowing how their cat is responding to treatment.
• There is a clear need for thorough assessment both prior to starting an SGLT-2 drug and throughout the course of treatment. Medical problems common in diabetic cats such at UTIs or pancreatitis can be potentially more of an issue. Of particular concern is the use of either Bexacat or Senvelgo in cats that are prone to developing ketones. The use of either of these medications could be dangerous. The cost for veterinary appointments and regular monitoring and lab tests let along hospitalization for DKA can be prohibitive.
• The lack of long-term studies makes the outcomes difficult to assess. There is no indication of whether doses are reduced especially if the cat is approaching remission. And without home testing, there is a limited means of knowing whether a cat is approaching remission.
• There is no mention of keeping cats below renal threshold. Since the mechanism of action is that glucose is eliminated in the urine, it would seem this is a concern that needs to be further investigated.
• SGLT-2 inhibitors can induce diuresis and lead to clinical polyuria. While this condition can be transient, it can also indicate the drug needs to be discontinued. If SGLT-2 inhibitors induce significant polyuria and polydipsia, it may limit their therapeutic potential since these are clinical signs of diabetic regulation (or lack thereof).
• A 2023 article in Veterinary Clinics in North America underscored the need for further research into these treatments for feline diabetes.

A cautionary note: These are new medications. There is very limited research and even less research supporting their long-term use. There is more research on the use of Senvelgo in ponies than in cats. In addition, most of the research has been underwritten by the drug manufacturers, Elanco or Boehringer Ingelheim.

American Animal Hospital Association information regarding Bexacat

ULTRA-LONG-ACTING INSULINS: TRESIBA & TOUJEO

This group of insulins has a duration of action greater than 24 hours in humans and is often used for basal-bolus treatment. The basal-bolus approach may not be practical for cat given the need for frequent BG measurements and multiple daily injections. They may, however, be useful as a single-agent therapy.

Two ultra-long-acting insulins have been investigated in cats (and dogs): insulin glargine U300 (Toujeo) and insulin degludec (Tresiba). Insulin glargine is the same insulin as glargine U100 but is three times more concentrated. Due to the increased concentration, it forms a denser subcutaneous depot which slows insulin release. Insulin degludec is a human insulin which facilitates the formation of a subcutaneous depot and increases protein binding. This method of action delays absorption, provides a flatter time-action profile, and reduces day-to-day variability in glucose concentrations.

The potential advantage of an insulin that requires a once a day or even less frequent dosing includes improved treatment compliance and quality of life for both diabetic cats and their caregivers. The concern is that despite ultra-long-acting insulin having been on the market for some time, there is limited research available. From the questions on FDMB, there does not appear to be many members who have cats that are prescribed either insulin.

Tresiba has a duration of 40 hours in humans. It has been studied in a small number of healthy cats and seems to have a considerably shorter duration (approximately 11 hours). The results of one study (Gilor et al., 2019) suggests that degludec is not adequate for once a day dosing. Toujeo has a longer duration – about 16 hours) along with a relatively flat curve, much like Lantus. However, the drawback to Toujeo is that it is not very potent causing the need for a higher daily dose making it cost prohibitive for some caregivers. There is a need for more research investigating the efficacy and effectiveness of the ultra-long acting insulins.

At present, there is no U300 syringe available. As a result, you must use the insulin pen in order to give an injection. One consideration is whether these insulins would be best suited for cats that need a large dose of insulin such as cats with acromegaly.

GLUCAGON-LIKE PEPTIDE 1-BASED THERAPIES: EXENATIDE ER (Bydureon)

Glucagon-like peptide 1 (GLP-1) is an incretin hormone secreted by L cells in the intestines in response to luminal nutrients, bacterial products, and secondary bile acids. GLP-1 acts as an “early warning system” to prepare the body for the nutrient load, particularly glucose that is about to arrive. It increases insulin secretion by sensitizing beta cells in the pancreas to glucose stimulation and decrease glucagon release by alpha cells. GLP-1 analogs have the highest therapeutic potential in diabetic cats however, the effects of GLP-1 analogs have been documented primarily in rodent models. The concern is that with GLP-1 analogs, diabetes is detected with the onset of clinical signs and symptoms which occur after there is widespread beta cell loss. Since GLP-1 maximized the function of the remaining beta cells, the use of this therapy may be limited to cats whose FD has been detected quite early. Based on the existing research, these drugs need to be combined with insulin to achieve glycemic control in cats.




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