Efficacy and safety of once daily oral administration of sodium-glucose cotransporter-2 inhibitor velagliflozin compared with twice daily insulin injection in diabetic cats.

BACKGROUND: Options for treatment of diabetes mellitus in cats are limited to insulin injections and monitoring for hypoglycemia. HYPOTHESIS: Once daily sodium-glucose cotransporter-2 inhibitor velagliflozin PO is noninferior to insulin injections. ANIMALS: Client-owned diabetic cats (127 safety; 116 efficacy assessment). METHODS: Prospective, randomized (1 mg/kg velagliflozin), positive controlled (titrated Caninsulin), open label, noninferiority field trial, comparing number of cats with treatment success in ≥1 clinical variable and ≥1 glycemic variable (margin Δ: 15%) on Day 45; secondary endpoints included glycemic and clinical assessments during 91 days. RESULTS: On Day 45, 29/54 (54%) velagliflozin-treated cats and 26/62 (42%) Caninsulin-treated cats showed treatment success, demonstrating noninferiority (difference -11.8%; upper 1-sided 97.5% confidence interval, -∞ to 6.3%). By Day 91, quality of life (QoL), polyuria, and polydipsia had improved in 81%, 54% and 61% (velagliflozin); on blood glucose (BG) curves, mean BG was <252 mg/dL in 42/54 (78%; velagliflozin) and 37/62 (60%; Caninsulin); minimum BG was <162 mg/dL in 41/54 (76%; velagliflozin) and 41/62 (66%; Caninsulin); serum fructosamine was <450 µmol/L in 41/54 (76%; velagliflozin) and 38/62 (61%; Caninsulin). Velagliflozin's most frequent adverse events were loose feces/diarrhea (n = 23/61, 38%), positive urine culture (n = 19/61, 31%), and nonclinical hypoglycemia (BG <63 mg/dL; n = 8/61, 13%); Caninsulin's: clinical and nonclinical hypoglycemia (n = 35/66, 53%), positive urine culture (n = 18/66, 27%), and loose feces/diarrhea (n = 10/66, 15%). Diabetic ketoacidosis occurred in 4/61 (7%; velagliflozin) and 0/66 (Caninsulin). CONCLUSIONS AND CLINICAL IMPORTANCE: Once daily oral administration of velagliflozin was noninferior to insulin injections, showed good QoL and glycemia without clinical hypoglycemia.

Pegylated-l-asparaginase therapy for feline large cell lymphoma: 82 cases (2017-2020).

OBJECTIVES: The present study aimed to investigate pegylated-l-asparaginase monotherapy for feline large cell lymphoma as a potential alternative to palliative corticosteroids treatment in animals whose owners declined cytotoxic chemotherapy. METHODS: A retrospective, descriptive case series of cats treated initially with pegylated-l-asparaginase as a sole therapy for feline large cell lymphoma is reported. The treatment protocol consisted of 12 intramuscular injections of pegylated-l-asparaginase with increasing intervals. If cats were unresponsive to pegylated-l-asparaginase monotherapy, a second-line treatment was initiated. Signalment, origin of lymphoma, staging, treatment, possible adverse events and follow-up data were extracted from the medical records. Responses and survival data were analysed. RESULTS: Eighty-two cats with lymphoma of five different anatomic types were included: alimentary, abdominal extra-alimentary, peripheral nodal, nasal/nasopharyngeal and other (mediastinal, renal [solitary] and miscellaneous combined in one group for analytical purposes). The response rate was 74.1% (95% confidence interval = 63.4-83.5) with 38.3% (95% confidence interval = 27.8-48.8) in complete remission. The median disease-free period and calculated overall survival time were 70 days (12-1702+) and 79 days (1-1715+), respectively. The response rate was significantly correlated with the origin of the lymphoma and the combined group had a significantly lower response rate (P = 0.035). Twenty-four cats were also treated with corticosteroids. There was no significant difference in outcomes between the group treated with or without corticosteroids. Adverse events were present in a small number of cats (14/82). The majority of these adverse events were mild to moderate in 5/14 cats; however, the adverse events were severe enough to cause discontinuation of therapy. CONCLUSIONS AND RELEVANCE: Based on the response rate and median disease-free period, treatment with pegylated-l-asparaginase is inferior when compared with historical chemotherapy protocols. However, some cats demonstrated an exceptional long disease-free period. Therefore, pegylated-l-asparaginase could be offered as an alternative to corticosteroid therapy alone. Further studies are needed to evaluate the additional benefit over palliative corticosteroid monotherapy.

A genome-wide association study identifies novel candidate genes for susceptibility to diabetes mellitus in non-obese cats.

Diabetes mellitus (DM) is a common feline endocrinopathy, which is similar to human type 2 diabetes (T2DM) in terms of its pathophysiology. T2DM occurs due to peripheral insulin resistance and/or ß-cell dysfunction. Several studies have identified genetic and environmental factors that contribute to susceptibility to human T2DM. In cats, environmental factors such as obesity and physical inactivity have been linked with DM, although to date, the only genetic association that has been demonstrated is with a polymorphism in the feline MC4R gene. The aim of this study was to perform a genome-wide association study (GWAS) to identify polymorphisms associated with feline DM. Illumina Infinium 63k iSelect DNA arrays were used to analyse genomic DNA samples from 200 diabetic domestic shorthair cats and 399 non-diabetic control cats. Data was analysed using PLINK whole genome data analysis toolset. A linear model analysis, EMMAX, was done to test for population structure and HAPLOVIEW was used to identify haplotype blocks surrounding the significant SNPs to assist with candidate gene nomination. A total of 47,497 SNPs were available for analysis. Four SNPs were identified with genome-wide significance: chrA2.4150731 (praw = 9.94 x10-8); chrUn17.115508 (praw = 6.51 x10-8); chrUn17.394136 (praw = 2.53 x10-8); chrUn17.314128 (praw = 2.53 x10-8) as being associated with DM. The first SNP is located within chromosome A2, less than 4kb upstream of the dipeptidyl-peptidase-9 (DPP9) gene, a peptidase involved in incretin inactivation. The remaining three SNPs are located within a haplotype block towards the end of chromosome A3; within this region, genes of interest include TMEM18 and ACP1, both previously associated with T2DM. This study indicates a polygenic component to susceptibility to DM in cats and has highlighted several loci and candidate genes worthy of further investigation.

Pilot study assessing the use of cabergoline for the treatment of cats with hypersomatotropism and diabetes mellitus.

OBJECTIVES: An affordable and effective treatment is needed to manage feline hypersomatotropism. The aim of this study was to assess whether treatment with oral cabergoline for 90 days in cats with hypersomatotropism and diabetes mellitus improved diabetic and insulin-like growth factor 1 (IGF-1) control. METHODS: This was a prospective cohort non-blinded pilot study enrolling client-owned cats with spontaneously occurring diabetes mellitus and hypersomatotropism. Cats received oral cabergoline (5-10 µg/kg q24h) for 90 consecutive days. Serum IGF-1 and fructosamine concentrations were measured on days 1, 30 and 90. Quality of life was determined using the DIAQoL-pet questionnaire on days 1 and 90. RESULTS: Nine cats were enrolled and eight completed the study. There was no significant change in the following: IGF-1 (day 1 median 2001 ng/ml [range 890-2001 ng/ml]; day 30 median 2001 ng/ml [range 929-2001 ng/ml]; day 90 median 1828 ng/ml [range 1035-2001 ng/ml]; χ2(2) = 0.667, P = 0.805); fructosamine (day 1 median 499 µmol/l [range 330-887 µmol/l], day 30 median 551 µmol/l [range 288-722 µmol/l], day 90 median 503 [range 315-851 µmol/l]; χ2(2) = 0.581, P = 0.764); or DIAQoL-pet score (median on day 1 -2.79 [range -4.62 to -0.28], median on day 90 -3.24 [range -4.41 to -0.28]; P = 0.715). There was a significant change of insulin dose (χ2(2) = 8.667, P = 0.008) with cats receiving higher insulin doses at day 90 compared with day 1 (median on day 1 was 0.98 [range 0.63-1.49] and median on day 90 was 1.56 [range 0.49-2.55] units/kg q12h; P = 0.026). CONCLUSIONS AND RELEVANCE: Cabergoline did not improve diabetic control or normalise insulin-like growth factor concentration, or improve patient quality of life.

Efficacy of hypophysectomy for the treatment of hypersomatotropism-induced diabetes mellitus in 68 cats.

BACKGROUND: Hypersomatotropism (HST) is an increasingly recognized endocrinopathy in cats and is mostly described associated with diabetes mellitus (DM). OBJECTIVES: To evaluate the efficacy and safety of transsphenoidal hypophysectomy in treating HST and DM in cats. ANIMALS: Sixty-eight client-owned cats with HST and DM treated by transsphenoidal hypophysectomy. METHODS: Retrospective cohort study. Medical records were reviewed for glycemic control and serum insulin-like growth factor-1 (IGF-1) concentrations. Postoperative complications, death within 4 weeks, and proportion achieving diabetic remission were recorded. Survival times and DM-free intervals were calculated. RESULTS: Fifty-eight cats (85.3%) were alive 4 weeks postoperatively with 10 (15%) postoperative deaths. Complications included hypoglycemia (n = 9), electrolyte imbalance (n = 9), and transient congestive heart failure (n = 5). Fifty-five cats (95% of 58 surviving cats [81% of all cats undergoing surgery]) had improved control of diabetes. Diabetic remission occurred in 41 cats (71% of 58 surviving cats [60% of all cats]) with insulin administration discontinued after a median of 9 days (range, 2-120). Postoperative 4-week serum IGF-1 concentration nadir was significantly lower in cats achieving diabetic remission (median 20 ng/mL [15-708] than those that did not (324 ng/mL [15-1955]; P = .03). All cats received long-term levothyroxine and hydrocortisone PO, alongside desmopressin (conjunctival) in 38 of 53 cats (72%). Recurrence of DM occurred in 5 of 41 cats (12%) after a median of 248 days (range, 84-1232). Median survival time of all cats was 853 days (range, 1-1740). CONCLUSIONS AND CLINICAL IMPORTANCE: Transsphenoidal hypophysectomy is an effective treatment for cats with HST and DM, with a long-term outcome that compares favorably to existing options.

Pituitary Pathology and Gene Expression in Acromegalic Cats.

The prevalence of GH-secreting pituitary tumors in domestic cats (Felis catus) is 10-fold greater than in humans. The predominant inhibitory receptors of GH-secreting pituitary tumors are somatostatin receptors (SSTRs) and D2 dopamine receptor (DRD2). The expression of these receptors is associated with the response to somatostatin analog and dopamine agonist treatment in human patients with acromegaly. The aim of this study was to describe pathological features of pituitaries from domestic cats with acromegaly, pituitary receptor expression, and investigate correlates with clinical data, including pituitary volume, time since diagnosis of diabetes, insulin requirement, and serum IGF1 concentration. Loss of reticulin structure was identified in 15 of 21 pituitaries, of which 10 of 15 exhibited acinar hyperplasia. SSTR1, SSTR2, SSTR5, and DRD2 mRNA were identified in the feline pituitary whereas SSTR3 and SSTR4 were not. Expression of SSTR1, SSTR2, and SSTR5 was greater in acromegalic cats compared with controls. A negative correlation was identified between DRD2 mRNA expression and pituitary volume. The loss of DRD2 expression should be investigated as a mechanism allowing the development of larger pituitary tumors.

Determination of serum fPLI concentrations in cats with diabetes mellitus.

Diabetes mellitus (DM) is one of the most common feline endocrinopathies. Pancreatitis is a reported cause for poor control of DM in cats; however, its prevalence in diabetic cats is unknown. Measurement of serum feline pancreatic lipase immunoreactivity (fPLI) has been proposed as a sensitive and specific test for the detection of pancreatitis in cats. The aim of this study was to assess fPLI concentrations in diabetic cats and compare these with non-diabetic cats of similar age. Samples from 29 cats with DM and 23 non-diabetic cats were analysed. Serum fPLI concentrations were significantly higher in samples from diabetic cats (P<0.01). A weak association was found between serum fructosamine and fPLI concentrations (R(2)=0.355, P=0.015), but there was no association between fPLI concentrations and the degree of diabetic control. There were no significant differences in reported clinical signs between cats with or without DM regardless of serum fPLI concentration. This is the first study to demonstrate elevated serum fPLI concentrations in cats with DM, suggesting that pancreatitis could be a significant comorbidity in these cats.

Prospective evaluation of a protocol for transitioning porcine lente insulin-treated diabetic cats to human recombinant protamine zinc insulin.

Objectives The objective was to evaluate a nadir-led protocol for transitioning porcine lente insulin suspension (PLIS)-treated diabetic cats onto human recombinant protamine zinc insulin (PZIR). Methods Recently diagnosed (<5 months) diabetic cats, treated with PLIS q12h for ⩾6 weeks, were recruited. Fructosamine, 24 h blood glucose curve (BGC), quality of life assessment (DIAQoL-pet score) and Diabetic Clinical Score (DCS) were assessed at enrolment (PLIS-treated) and 2, 4 and 12 weeks after transitioning to PZIR (starting dose 0.2-0.7 U/kg q12h). Short duration of insulin action was defined as <9 h. Linear mixed effects modelling assessed for change in fructosamine, mean blood glucose (MBG) during BGCs, DIAQoL-pet score, DCS and q12h insulin dose. McNemar's tests compared the proportion of cats with hypoglycaemia at week 0 (PLIS-treated) and week 4 (PZIR-treated). Results Twenty-two cats were recruited. Median PLIS dose at enrolment was 0.5 U/kg (interquartile range 0.3-0.7 U/kg) q12h, equalling median PZIR starting dose (0.5 U/kg; interquartile range 0.3-0.7 U/kg q12h). Transitioning was followed by significant decreases in fructosamine ( P = 0.00007), insulin dose ( P = 0.02), DCS ( P = 8.1 × 10-8) and DIAQoL-pet score ( P = 0.003), indicating improved quality of life. MBG did not alter significantly ( P = 0.1). Five cats (22.7%) achieved remission. Hypoglycaemia was recorded in 30/190 12 h BGCs (15.8%) and five cats experienced clinical hypoglycaemia. The proportion of cats with hypoglycaemia did not differ between PLIS (week 0) and PZIR (week 4) ( P = 1.0). Duration of action was analysed in 19 cats. Six cats (31.6%) showed short duration of action on PLIS, compared with two cats (10.5%) after 4 weeks on PZIR. All six cats with short PLIS duration showed duration of ⩾9 h on PZIR. Conclusions and relevance Used alongside a low-carbohydrate diet, transitioning to PZIR was associated with significantly improved clinical signs and quality of life, with some cats achieving remission. Transition to PZIR should be considered for cats with short duration of action on PLIS.

Acceptance of home blood glucose monitoring by owners of recently diagnosed diabetic cats and impact on quality of life changes in cat and owner.

Objectives This study aimed to evaluate the acceptance of home blood glucose monitoring (HBGM) by owners of recently diagnosed diabetic cats, and the impact of choosing HBGM on the quality of life (QoL) changes of cat and owner, in addition to glycaemic changes during 6 months of follow-up. Methods Owners of cats diagnosed with diabetes mellitus (DM) and treated with insulin for 6-20 weeks were divided into an HBGM group and a non-HBGM group, based on their ability and willingness to perform HBGM after a standardised instruction session. The HBGM acceptance level and reasons for acceptance failure were documented; a questionnaire evaluated owners' experiences. For the following 6 months, changes in QoL, measured using the validated DIAQoL-pet quantification tool, and changes in glycaemic control parameters (clinical signs, serum fructosamine, blood glucose curve average/minimal/maximal/pre-insulin blood glucose) were compared between HBGM and non-HBGM groups at months 1, 3 and 6, as well as within the groups between baseline and months 1, 3 and 6. Results Thirty-eight cats were enrolled; 28 (74%) entered the HBGM group. There was no significant difference between groups in overall DIAQoL-pet score or glycaemic control parameters at any time point apart from the maximal blood glucose at month 6 (lower in the HBGM group). However, the DIAQoL-pet score, including indicators of owner worry about DM, worry about hypoglycaemia and costs, as well as glycaemic parameters, improved at all time points within the HBGM group but not within the non-HBGM group. Remission occurred in 9/28 (32%) HBGM group cats and 1/10 (10%) non-HBGM group cats ( P = 0.236). Conclusions and relevance HBGM was adopted successfully by most diabetic cat owners. Despite the extra task, positive changes in QoL parameters occurred in the HBGM group and not in the non-HBGM group. Although no difference was found in glycaemic control between the HBGM and non-HBGM groups during the 6 months of follow-up, significant glycaemic improvements were documented in the HBGM group.

Studying Cat (Felis catus) Diabetes: Beware of the Acromegalic Imposter.

Naturally occurring diabetes mellitus (DM) is common in domestic cats (Felis catus). It has been proposed as a model for human Type 2 DM given many shared features. Small case studies demonstrate feline DM also occurs as a result of insulin resistance due to a somatotrophinoma. The current study estimates the prevalence of hypersomatotropism or acromegaly in the largest cohort of diabetic cats to date, evaluates clinical presentation and ease of recognition. Diabetic cats were screened for hypersomatotropism using serum total insulin-like growth factor-1 (IGF-1; radioimmunoassay), followed by further evaluation of a subset of cases with suggestive IGF-1 (>1000 ng/ml) through pituitary imaging and/ or histopathology. Clinicians indicated pre-test suspicion for hypersomatotropism. In total 1221 diabetic cats were screened; 319 (26.1%) demonstrated a serum IGF-1>1000 ng/ml (95% confidence interval: 23.6-28.6%). Of these cats a subset of 63 (20%) underwent pituitary imaging and 56/63 (89%) had a pituitary tumour on computed tomography; an additional three on magnetic resonance imaging and one on necropsy. These data suggest a positive predictive value of serum IGF-1 for hypersomatotropism of 95% (95% confidence interval: 90-100%), thus suggesting the overall hypersomatotropism prevalence among UK diabetic cats to be 24.8% (95% confidence interval: 21.2-28.6%). Only 24% of clinicians indicated a strong pre-test suspicion; most hypersomatotropism cats did not display typical phenotypical acromegaly signs. The current data suggest hypersomatotropism screening should be considered when studying diabetic cats and opportunities exist for comparative acromegaly research, especially in light of the many detected communalities with the human disease.

Systematic review of feline diabetic remission: separating fact from opinion.

It is increasingly recognised that diabetic remission is possible in the cat. This systematic review, following Cochrane Collaboration (CC) guidelines, critically appraises the level of evidence on factors influencing remission rate and factors predicting remission. A systematic online, bibliographic search and reference list examination was conducted. A level of evidence was assigned to each identified article by five internists using the Newcastle-Ottawa Scale for follow-up, cohort, case-series and case-control studies, the CC's risk of bias tool for trials and the Cochrane Effective Practice and Organisation of Care Group risk of bias criteria for before and after trials. Twenty-two studies were included in the review, assessing influence of pharmaceutical intervention (n = 14) and diet (n = 4), as well as diagnostic tests (n = 9) and feline patient characteristics (n = 5) as predictors of remission. The current level of evidence was found to be moderate to poor. Common sources of bias included lack of randomisation and blinding among trials, and many studies were affected by small sample size. Failure to provide criteria for the diagnosis of diabetes, or diabetic remission, and poor control of confounding factors were frequent causes of poor study design. Addressing these factors would significantly strengthen future research and ultimately allow meta-analyses to provide an excellent level of evidence. No single factor predicts remission and successful remission has been documented with a variety of insulin types and protocols. Dietary carbohydrate reduction might be beneficial, but requires further study. A lack of well-designed trials prevents reliable remission rate comparison. Factors associated with remission resemble those in human medicine and support the hypothesis that reversal of glucotoxicity is a major underlying mechanism for feline diabetic remission.

Screening diabetic cats for hypersomatotropism: performance of an enzyme-linked immunosorbent assay for insulin-like growth factor 1.

Screening diabetic cats for feline hypersomatotropism (HS) is currently dependent on using a radioimmunoassay (RIA) for measurement of growth hormone or insulin-like growth factor 1 (IGF-1), both of which require radioactivity, are costly and have limited availability. Performance of an enzyme-linked immunosorbent assay (ELISA) using anti-human IGF-1 antibodies was assessed. Total IGF-1 was determined in diabetic cat samples across a wide range of IGF-concentrations using a previously validated RIA (serum: 92 cats; plasma: 31 cats). Repeat IGF-1 measurement was then performed using the ELISA-system. Mean IGF-1 recovery after serial dilution proved satisfactory with a correlation coefficient of 0.96 (serum) and 0.97 (plasma). Appropriate precision was established [intra-assay coefficient of variation (CV) 9.5 ± 2% (serum) and 13.6 ± 7% (plasma); inter-assay CV 11.4 ± 4% (serum) and 7.6 ± 6% (plasma)] and significant effect of hyperlipidaemia, haemoglobinaemia, bilirubinaemia and storage was excluded, with the exception of an increase in serum IGF-1 when left at room temperature for more than 24 h. ELISA concentrations correlated significantly with RIA concentrations (serum Pearson r(2): 0.75; plasma: 0.83, P <0.001). Receiver operating characteristics analysis showed an area under the curve of 0.99 (serum) and 0.96 (plasma), and indicated high diagnostic accuracy for categorising a diabetic cat correctly as suspicious for HS at a serum IGF-1 cut-off of 997 ng/ml (sensitivity, 100%; specificity, 88.1%). The current study is the first to validate an easy-to-use and economical IGF-1 ELISA for the screening for HS among diabetic cats, which is important given the suspected significant prevalence of HS-induced diabetes mellitus.

Computed tomographic signs of acromegaly in 68 diabetic cats with hypersomatotropism.

In order to describe the signs of acromegaly in cats, a case-control study was done based on computed tomography (CT) scans of the heads of 68 cats with hypersomatotropism and 36 control cats. All cats with a diagnosis of hypersomatotropism had diabetes mellitus, serum insulin-like growth factor-1 >1000 ng/ml and a pituitary mass. Measurements of bones and soft tissues were done by two independent observers without knowledge of the diagnosis. Pituitary masses were identified in CT images of 64 (94%) cats with hypersomatotropism. Analysis of variance found a moderate effect of gender on the size of bones and a large effect of hypersomatotropism on the size of bones and thickness of soft tissues. In cats with hypersomatotropism the frontal and parietal bones were, on average, 0.8 mm thicker (P <0.001); the distance between the zygomatic arches was, on average, 5.4 mm greater (P <0.001); and the mandibular rami were, on average, 1.1 mm thicker (P <0.001) than in control cats. The skin and subcutis dorsal to the frontal bone were, on average, 0.4 mm thicker (P = 0.001); lateral to the zygomatic arch were, on average, 0.7 mm thicker (P <0.001); and ventral to the mandibular rami were, on average, 1.1 mm thicker (P = 0.002) in cats with hypersomatotropism than in control cats. The cross-sectional area of the nasopharynx was, on average, 11.1 mm(2) smaller in cats with hypersomatotropism than in control cats (P = 0.02). Prognathia inferior and signs of temporomandibular joint malformation were both observed more frequently in cats with hypersomatotropism than in control cats (P = 0.03). Overall, differences between affected and unaffected cats were small. Recognising feline acromegaly on the basis of facial features is difficult.

Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus.

When confronted with a diabetic cat in clinical practice, it is tempting to assume it has a form of diabetes mellitus akin to human type 2 diabetes mellitus (diabetes). For most diabetic cats examined, this will indeed be justified. Nevertheless, a significant proportion have other specific types of diabetes with distinctly different etiologies. This article discusses the concept of other specific types of feline diabetes caused by endocrinopathies, and more specifically feline hypersomatotropism, acromegaly, and hyperadrenocorticism, including relevance, presentation, diagnosis, and therapy.