Abstract
Case summary
A 13-year-old castrated male domestic shorthair cat was diagnosed with diabetes mellitus based on hyperglycaemia, glucosuria and an elevated plasma fructosamine concentration. The diagnosis followed a 1-month history of lethargy and weight loss, along with a 1-week history of polyuria and polydipsia, which developed after the patient received a long-acting methylprednisolone injection from the referring veterinarian for pruritus. Treatment with velagliflozin was initiated, resulting in excellent glucose control, weight gain and resolution of clinical signs. However, the owner reported diarrhoea that did not improve with dietary modifications, symptomatic treatments or dose reduction of velagliflozin. Consequently, velagliflozin was discontinued after 64 days. Despite discontinuation, the cat remained euglycemic, with plasma fructosamine levels within the reference interval throughout a 175-day follow-up period. According to the Agreeing Language in Veterinary Endocrinology consensus definition, diabetes mellitus remission was confirmed.
Relevance and novel information
This case report highlights that diabetic remission is achievable in cats treated with SGLT2 inhibitors, as described in human patients with type 2 diabetes mellitus.
Plain language summary
A 13-year-old male castrated domestic shorthair cat was diagnosed with diabetes after showing high blood sugar, sugar in the urine and elevated fructosamine levels. The cat had been lethargic and losing weight for approximately 1 month and was drinking and urinating more than usual for 1 week, which started after receiving a long-acting steroid injection for skin itching. The cat was treated with velagliflozin, a medication that helps lower blood sugar, which led to excellent glucose control, weight gain and disappearance of clinical signs. The cat developed diarrhoea that did not improve with diet changes, supportive treatments or lowering the velagliflozin dose, so the medication was stopped after 64 days. Despite stopping the drug, the cat’s blood sugar stayed normal, and fructosamine levels remained within the normal range during 175 days of follow-up. According to veterinary guidelines, this means the cat achieved diabetes remission. This case shows that remission of diabetes is possible in cats treated with SGLT2 inhibitors, similar to what has been observed in humans with type 2 diabetes.
Case description
A 13-year-old castrated male domestic shorthair cat was referred with a 1-month history of lethargy and weight loss, and a 1-week history of polyuria and polydipsia (PU/PD). The cat had a previous history of pruritus and received a subcutaneous injection of long-acting methylprednisolone (Depomedrol; Zoetis) 1 month earlier (day -34; body weight [BW] 4 kg) (Figure 1). One week after the injection (day -27), lethargy was reported by the owner (Figure 1). No abnormality was found by the referring veterinarian during the physical examination, and serum biochemistries revealed moderate hyperglycaemia, mild hypercholesterolemia and a moderate decrease in plasma total calcium concentration (Table 1). Plasma fructosamine and total thyroxine concentrations were within the reference interval (RI) (Table 1). One week later (day -20), the cat lost 700 g of weight and remained lethargic (Figure 1). Abdominal ultrasound suggested bilateral loss of renal corticomedullary distinction. Urinalysis revealed a concentrated urine (urine specific gravity [USG] 1.068), with a pH of 7, glucosuria (4+), proteinuria (2+) and haematuria (2+). Biochemistry did not reveal significant abnormalities (Table 1).
Illustration of key events, including diagnosis, treatment (with therapeutic diet trial), velagliflozin (VELA)-related complications, remission of diabetes mellitus, pulmonary nodule surgery and follow-up. The thin blue line at the top of the figure represents changes in the cat’s body weight. In the middle of the figure, the bold orange line depicts plasma fructosamine concentrations (reference internal [RI] 191–350 µmol/l), while the bold blue line represents plasma glucose concentrations (RI 70–160 mg/dl). This figure was created with Microsoft Excel and ChatGPT
Haematological and serum biochemical findings in a cat with diabetes mellitus treated with SGLT2 inhibitor
Data outside the reference intervals (RIs) are in bold
Presence of platelet clumps at blood smear examination
Considered not clinically significant
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DwVELA = days without velagliflozin; SDMA = symmetric dimethylarginine; T4 = thyroxine; WBC = white blood cell
At the time of presentation (day 0), the cat was not receiving any medication. The physical examination showed generalised muscle atrophy and a body condition score of 2/5 (BW 3.3 kg) (Figure 1). Systolic arterial blood pressure was 150 mmHg. According to the 2018 American College of Veterinary Internal Medicine consensus guidelines on systemic arterial hypertension, this measurement is classified as prehypertension; however, essential hypertension could not be excluded. 1 Urinalysis revealed a USG of 1.034, aciduria (pH 5), proteinuria (1+) and glucosuria (4+). Urine sediment was unremarkable and urine bacterial culture was negative. The urinary protein:creatinine ratio was normal at 0.2. Complete blood count (CBC) was within the RI, while serum biochemical abnormalities included significant hyperglycaemia and an increased plasma fructosamine concentration, mild hypercholesterolaemia and moderate hypokalaemia (Table 1). Thoracic radiographs were also performed and identified a 1.5 cm soft tissue density mass in the left caudal lung lobe. A diagnosis of diabetes mellitus (DM) was made in accordance with the Agreeing Language in Veterinary Endocrinology (ALIVE) consensus definition. 2 Although pulmonary adenocarcinoma was suspected, no additional investigations were performed, as it was considered preferable to first stabilise the DM before undertaking anaesthesia for cytological evaluation.
The cat was prescribed 1 U of glargine (insulin SC q12h, Lantus Solostar 100 U/ml; Sanofi Winthrop Industrie), a high-protein, low-carbohydrate therapeutic diet (Royal Canin Veterinary Feline Diabetic; Royal Canin), both canned and dry, and oral potassium supplementation (K for Cat; MP Labo) (Figure 1). At follow-up 20 days later (day 20), the owner still reported lethargy and PU/PD (Figure 1). The diet change was made but the owner did not administer the insulin because of difficulties with giving the injections. The physical examination revealed weight loss (BW 3.1 kg), and persistent glucosuria was recorded. The cat was prescribed velagliflozin (1 mg/kg PO q24h, Senvelgo; Boehringer Ingelheim Vetmedica) (VELA), along with the high-protein, low-carbohydrate therapeutic diet (Figure 1). During the first 2 weeks of treatment, the client preferred to screen for ketonuria only every other day using urine dipsticks (Multistix 10 SG; Siemens). Plasma glucose concentration was monitored daily using a handheld glucometer (AlphaTRAK 2; Zoetis). No ketonuria was recorded, and the cat achieved euglycaemia.
After 10 days (day 30), weight gain of 200 g was observed (BW 3.3 kg). At recheck with the primary veterinarian 11 days later (day 41), the owner reported diarrhoea for the previous 5 days, associated with persistent PU/PD (Figure 1). Physical examination revealed increased BW of 300 g (BW 3.6 kg). No ketonuria was recorded at urinalysis. Diosmectite (0.5 g PO q8h, Smecta 3 g; Mayoly Pharma) was prescribed, but diarrhoea persisted and justified a gradual diet change over 1 week (Hill’s Prescription Diet i/d Biome Feline dry; Hill’s Pet Nutrition) on day 46 (Figure 1). No improvement in diarrhoea was reported. The dosage of VELA was decreased (0.5 mg/kg PO q24h) but diarrhoea persisted. Velagliflozin was discontinued on day 85.
Thereafter, the owner reported resolution of diarrhoea and PU/PD, while physical examinations revealed progressive weight gain of 500 g (BW 4.1 kg) (Figure 1). Both CBC and serum biochemistries were unremarkable during follow-up, and plasma fructosamine concentrations were within the RI (Table 1). No dietary changes were made. Forty-three days later (days without velagliflozin [DwVELA]+64), remission of DM was confirmed, in accordance with the ALIVE consensus definition. 2 Fifty-seven days after stopping VELA (DwVELA+78), the physical examination showed a BW of 3.9 kg (Figure 1). CBC was unremarkable, while serum biochemistry revealed mild azotaemia (Table 1).
On DwVELA+78, a thoracic and abdominal CT scan confirmed the presence of a cavitated, well-defined, high-vascularised nodule on the left caudal pulmonary lobe, with no evidence of metastasis appreciated. Surgical removal of the nodule was performed on the same day, and histopathological examination of the nodule confirmed an adenocarcinoma. During the 6-day hospitalisation, repeated blood glucose concentration was within the RI (in the range of 100–140 mg/dl, RI 70–160). Based on the owner expectations and absence of evident distant metastasis, chemotherapy was not initiated. Ninety-two days later (DwVELA+113), physical examination revealed stable BW (3.9 kg) (Figure 1). Plasma glucose and fructosamine concentrations were within the RI (Table 1). At the latest follow-up (DwVELA+175), the owner reported no clinical abnormalities, and the physical examination was normal. Plasma glucose concentration was within the RI (Table 1).
Discussion
This case documents DM remission in a cat after treatment with VELA, supporting the hypothesis that DM remission may occur in cats treated with SGLT2 inhibitors.3 –5
Remission of DM is common in cats, but reported remission rates vary significantly between studies, in the range of 17–78%.6 –9 Several factors have been associated with an increased likelihood of remission in diabetic cats, including age at diagnosis,6,10 breed, 10 recent corticosteroid administration,10,11 type of administered insulin,8,9,12 administration of a high-protein, low-carbohydrate diet13 –18 and frequent glucose monitoring with insulin dose adjustments.8,12 No studies have confirmed DM remission in diabetic cats treated with SGLT2 inhibitors. However, given the mechanism of action of this drug class, remission is theoretically possible.3 –5
In this case, corticosteroid-induced type 2 DM was suspected based on the recent administration of long-acting methylprednisolone. Initially, the cat was prescribed a treatment protocol including glargine insulin and a high-protein, low-carbohydrate diet because, in the authors’ opinion, insulin is currently the preferred therapy when diabetic remission is the goal, given that the remission rate with SGLT2 inhibitors is unknown. Indeed, previous studies suggest that diabetic cats with a recent history of corticosteroid administration have a high likelihood of remission.6,10,19 Longer survival times and improved quality of life have been reported in cats that achieve diabetic remission.14,19 Therefore, remission is considered a goal in the treatment of feline DM, while avoiding hypoglycaemia and respecting owner expectations. 15 However, most cats in diabetic remission exhibit impaired glucose tolerance, and some of them also show impaired fasting glucose levels, raising suspicion of a prediabetic state. 20
Approximately 10% of owners of newly diagnosed diabetic cats choose euthanasia, and 1/3 cats is euthanased within the first year after diagnosis of DM because of factors such as cost, advanced age, comorbidities and lack of owner adherence.21,22 In this case, the owner initially accepted insulin therapy; however, after 20 days, they reported difficulties in administering insulin injections. As a result, the cat was prescribed VELA. This case exemplifies how SGLT2 inhibitors have transformed feline DM management. Had this cat been diagnosed 1 year earlier, before VELA was available in France, euthanasia might have been the only option.
Current knowledge suggests that most feline DM cases are characterised by insulin resistance and beta (β)-cell dysfunction, resembling type 2 DM in humans.15,23,24 This leads to sustained hyperglycaemia, peripheral glucotoxicity and increased insulin requirements. 25 However, effective glycaemic control and management of conditions contributing to insulin resistance may reverse glucose toxicity, promote β-cell recovery and facilitate DM remission.6,26 Gliflozins rapidly restore near-euglycaemic states, potentially supporting β-cell recovery and potentially increasing the likelihood of remission. 3 –5 In human medicine, diabetic remission has been reported in newly diagnosed type 2 DM patients treated with canagliflozin for 3 months. 27 In this case report, the cat achieved DM remission within 64 days of VELA treatment. Velagliflozin was discontinued because of chronic diarrhoea that did not respond to symptomatic therapy or dose reduction. Diarrhoea is a known adverse effect of SGLT2 inhibitors in cats, likely caused by SGLT1 inhibition in the small intestine. 28 In this cat, DM remission was an incidental finding. Because SGLT2 inhibitors induce euglycemia and chronic glycosuria, the only way to confirm DM remission while on treatment is to discontinue the drug for several days. 5 However, the optimal timing of discontinuation is unknown, and further studies are needed to establish standardised protocols.
Some evidence suggests that a high-protein, low-carbohydrate diet increases the likelihood of diabetic remission in cats, particularly those with type 2 DM.13,15 –18 However, some clinicians do not choose to change the diet while prescribing SGLT2 inhibitors to avoid changes in appetite and stool consistency. In addition, carbohydrate restriction has been linked to an increased risk of ketosis in humans, but it is unknown whether the same is true for cats.29,30 At this time, it is unclear what effect (if any) low-carbohydrate diets may play in the development of euglycaemic diabetic ketoacidosis in cats treated with SGLT2 inhibitors. Given that their native diet is low in carbohydrates, the risk attributed to carbohydrate restriction in humans on gliflozins may not be relevant.31 –33 Furthermore, carbohydrate restriction may reduce osmotic diarrhoea in patients receiving gliflozins, as reported in human medicine. 34 In this case report, the cat was transitioned to a high-protein, low-carbohydrate diet when insulin was initiated, without developing gastrointestinal (GI) signs. However, GI signs appeared after the initiation of VELA therapy and persisted despite a diet change, resolving only after VELA discontinuation. Therefore, it is unlikely that the diet change contributed to the GI signs, although its role in achieving remission remains unaddressed.
Insulin-treated diabetic cats often experience transient remission. 35 In this case, spot blood glucose levels remained at the upper end of the RI during follow-up, suggesting a possible relapse, although stress-related hyperglycaemia cannot be ruled out. 20
A limitation of this report is the lack of long-term follow-up. Therefore, the duration of the remission or whether the cat relapsed cannot be determined. In addition, VELA was prescribed in a cat with a suspicious pulmonary lesion, and urine ketones were assessed every other day. Moreover, as the dipsticks employed do not detect beta-hydroxybutyrate, the monitoring approach was suboptimal. Finally, the exact role of glucocorticoids remains uncertain, including whether they contributed to the development of DM in this cat, or if the waning effect of the glucocorticoid played a role in facilitating remission. Remission occurred after velagliflozin administration; however, spontaneous remission or resolution after glucocorticoid withdrawal cannot be excluded.
Footnotes
Conflict of interest
The European College of Veterinary Internal Medicine – Companion Animals Internal Medicine Residency programme of Dr Lodarski is sponsored by Zoetis France and Hill’s Pet Nutrition.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS Open Reports. Although not required, where ethical approval was still obtained, it is stated in the manuscript.
Informed consent
Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers, tissues and samples) for all procedure(s) undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required.
