Safety and effectiveness of the sodium-glucose cotransporter inhibitor bexagliflozin in cats newly diagnosed with diabetes mellitus.

BACKGROUND: Bexagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. A pilot study has shown that bexagliflozin can decrease dependence on exogenous insulin in cats with diabetes mellitus (DM). OBJECTIVE: To evaluate the safety and effectiveness of bexagliflozin as a monotherapy for DM in previously untreated cats. ANIMALS: Eighty-four client-owned cats. METHODS: Historically controlled prospective open-label clinical trial. Cats were dosed PO with 15 mg bexagliflozin once daily for 56 days, with a 124-day extension to evaluate safety and treatment effect durability. The primary endpoint was the proportion of cats experiencing a decrease in hyperglycemia and improvement in clinical signs of hyperglycemia from baseline on day 56. RESULTS: Of 84 enrolled cats, 81 were evaluable on day 56, and 68 (84.0%) were treatment successes. Decreases in mean serum glucose, fructosamine, and ß-hydroxybutyrate (ß-OHB) concentrations were observed, and investigator assessments of cat neurological status, musculature, and hair coat quality improved. Owner evaluations of both cat and owner quality of life were favorable. The fructosamine half-life in diabetic cats was found to be 6.8 days. Commonly observed adverse events included emesis, diarrhea, anorexia, lethargy, and dehydration. Eight cats experienced serious adverse events, 3 of which led to death or euthanasia. The most important adverse event was euglycemic diabetic ketoacidosis, diagnosed in 3 cats and presumed present in a fourth. CONCLUSION AND CLINICAL IMPORTANCE: Bexagliflozin decreased hyperglycemia and observed clinical signs in cats newly diagnosed with DM. As a once-daily PO medication, bexagliflozin may simplify management of DM in cats.

Complete Blood Counts and Blood Smear Analyses in 312 Diabetic Dogs (2007-2017).

Diabetes mellitus is a common endocrinopathy in dogs that has been associated with various biochemical changes and comorbid diseases, but hematologic abnormalities have been rarely reported. The aim of this retrospective study was to evaluate complete blood count and blood smear alterations and to describe their relationship with, and incidence of comorbid diseases in, diabetic dogs. Three-hundred twelve diabetic dogs, 286 dogs diagnosed with systemic, nondiabetic illnesses, and 506 healthy dogs were identified during the study period. Groups were compared using contingency tables and logistic regression. Associations between statistically significant complete blood count and blood smear alterations and comorbidities were evaluated using multivariable analysis. High-grade codocytosis and anisocytosis were identified more frequently in diabetic dogs, whereas high-grade reactive lymphocytosis and keratocytosis were identified less frequently (P < .001). Diabetic dogs with high-grade codocytosis had lower red blood cell, hemoglobin, hematocrit and higher white blood cell counts (P < .001). Diabetic ketoacidosis was diagnosed more frequently in diabetic dogs with high-grade codocytosis when compared with those with low-grade codocytosis (P < .001) or when compared with any other cell morphologic alterations. This study suggests that blood smear analysis should be a routine part of the evaluation of diabetic dogs.

Canine urinary lactate and cortisol metabolites in hypercortisolism, nonadrenal disease, congestive heart failure, and health.

Spontaneous hypercortisolism (HC) is a common endocrine disease of senior dogs, often overlapping in selected clinical signs and hematologic and blood biochemical abnormalities with nonadrenal diseases (NADs). HC and NAD could differentially affect cortisol metabolism, which is a complex 10-enzymatic pathway process. HC might also affect blood and urine lactate levels through its effects on mitochondrial function. We aimed to differentiate between HC and NAD via a urinary cortisol metabolites and lactate panel. We prospectively recruited 7 healthy dogs and 18 dogs with HC, 15 with congestive heart failure (CHF), and 9 with NAD. We analyzed urine by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. We normalized urinary lactate and cortisol metabolites to urine creatinine concentration, and then compared groups using a linear-mixed model and principal component (PC) analysis. A machine-learning classification algorithm generated a decision tree (DT) model for predicting HC. The least-squares means of normalized urinary 6ß-hydroxycortisol and PC1 of the HC and CHF groups were higher than those of the healthy and NAD groups (p = 0.05). Creatinine-normalized urinary 6ß-hydroxycortisol had better sensitivity (Se, 0.78; 95% CI: 0.55-0.91), specificity (Sp, 0.89; 95% CI: 0.57-0.99), and a likelihood ratio (LR; 7), than the Se (0.72; 95% CI: 0.49-0.88), Sp (0.89; 95% CI: 0.57-0.99), and LR (6.5) of PC1 for distinguishing HC from NAD. Lactate and dihydrocortisone had the highest decreasing node-weighted impurity value and were considered the most important features in the DT model; dihydrocortisol had no role in determining whether a dog had HC.

Feline Pituitary Adenomas: Correlation of Histologic and Immunohistochemical Characteristics With Clinical Findings and Case Outcome.

Pituitary glands from 141 feline autopsy cases were reviewed histologically. Adenoma and hyperplasia were the most common lesions at 13 cases each. Pituitary adenoma was more likely than hyperplasia to be associated with clinical evidence of endocrinopathy or an intracranial mass (P < .001). A histochemical and immunohistochemical panel was applied to 44 autopsy- or hypophysectomy-derived pituitary adenomas in 43 cats from 2 diagnostic laboratories. Adenomas were differentiated from hyperplasia by the presence of disrupted reticulin fibers. One cat had a double (somatotroph and melanotroph) adenoma. Twenty somatotroph adenomas consisted of periodic acid-Schiff (PAS)-negative acidophils that expressed growth hormone; 16/20 had hypersomatotropism; 17/20 had diabetes mellitus. Eleven melanotroph adenomas consisted of PAS-positive basophils or chromophobes that expressed melanocyte-stimulating and adrenocorticotrophic hormones; 5/11 had hypercortisolism; 6/11 had diabetes mellitus. Eleven gonadotroph adenomas consisted of PAS-negative chromophobes that expressed follicle-stimulating and/or luteinizing hormones. Two thyrotroph adenomas consisted of PAS-negative basophils or chromophobes that expressed thyroid-stimulating hormone. Pituitary-dependent disease was not recognized in cats with gonadotroph or thyrotroph adenomas. The Ki-67 proliferation index in hypophysectomy specimens was lower in somatotroph than in melanotroph adenomas. Fourteen cats with hypophysectomy-treated somatotroph or melanotroph adenoma had an 899-day median survival time versus 173 days in 17 nonsurgical cases. After adjusting for age, adenoma size and type, hypophysectomized cats had an overall better survival time than nonsurgical cases (P = .029). The study results underscore the value of hypophysectomy and trophic hormone immunohistochemistry in the treatment and classification of feline pituitary adenomas.

Oligomeric collagen as an encapsulation material for islet/ß-cell replacement: effect of islet source, dose, implant site, and administration format.

Replacement of islets/ß-cells that provide long-lasting glucose-sensing and insulin-releasing functions has the potential to restore extended glycemic control in individuals with type 1 diabetes. Unfortunately, persistent challenges preclude such therapies from widespread clinical use, including cumbersome administration via portal vein infusion, significant loss of functional islet mass upon administration, limited functional longevity, and requirement for systemic immunosuppression. Previously, fibril-forming type I collagen (oligomer) was shown to support subcutaneous injection and in situ encapsulation of syngeneic islets within diabetic mice, with rapid (<24 h) reversal of hyperglycemia and maintenance of euglycemia for beyond 90 days. Here, we further evaluated this macroencapsulation strategy, defining effects of islet source (allogeneic and xenogeneic) and dose (500 and 800 islets), injection microenvironment (subcutaneous and intraperitoneal), and macrocapsule format (injectable and preformed implantable) on islet functional longevity and recipient immune response. We found that xenogeneic rat islets functioned similarly to or better than allogeneic mouse islets, with only modest improvements in longevity noted with dosage. Additionally, subcutaneous injection led to more consistent encapsulation outcomes along with improved islet health and longevity, compared with intraperitoneal administration, whereas no significant differences were observed between subcutaneous injectable and preformed implantable formats. Collectively, these results document the benefits of incorporating natural collagen for islet/ß-cell replacement therapies.

Comparison of 2 assays for measuring serum total thyroxine concentration in dogs and cats.

BACKGROUND: No gold standard assay for serum total thyroxine (TT4) concentration in small animals exists. The Microgenics DRI TT4 (MTT4) assay is used by most reference laboratories. HYPOTHESIS/OBJECTIVES: IDEXX Catalyst Total T4 (CTT4) and Immulite 2000 TT4 (ITT4) results will agree with MTT4 results. ANIMALS: Residual small animal sera were randomized before reanalysis (dogs, CTT4 versus MTT4: n = 176, ITT4 versus MTT4: n = 74; cats, CTT4 versus MTT4: n = 319, ITT4 versus MTT4: n = 79). METHODS: Validation and method comparison study. Serum TT4 concentration was measured on all analyzers. Pairwise Pearson correlation, cumulative sum linearity test, regression, and Bland-Altman method were performed. RESULTS: CTT4 versus MTT4 in dogs: constant bias (y-intercept) was 0.10 µg/dL (95% confidence interval [CI], 0.05-0.15), proportional bias (slope) was 0.86 µg/dL (95% CI, 0.83-0.89); in cats, constant bias was 0.13 µg/dL (95% CI, 0.08-0.20) and proportional bias was 1.01 µg/dL (95% CI, 0.98-1.03), but the test for linearity failed. Bland-Altman plots identified increasing disagreement with increasing serum TT4 concentrations. ITT4 versus MTT4 in dogs, constant bias was 0.14 µg/dL (95% CI, 0.04-0.22) and 0.22 µg/dL (95% CI, 0.09-0.33) for cats; proportional bias was 0.76 (95% CI, 0.72-0.80) for dogs and 0.71 (95% CI, 0.69-0.74) for cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Differences in CTT4 and MTT4 results affect interpretation at higher serum TT4 concentrations. The ITT4 proportional bias will underestimate serum TT4 concentrations in dogs and cats, compared to MTT4. Serial TT4 measurements should be done using the same assay.

Radioactive iodine uptake in hyperthyroid cats after administration of recombinant human thyroid stimulating hormone.

BACKGROUND: Radioactive iodine therapy is considered the treatment of choice for hyperthyroidism in cats, but the availability of this modality is limited by costs and hospitalization requirements. Administration of recombinant human thyroid stimulating hormone (rh-TSH) to humans with thyroid neoplasia or nodular goiter can increase thyroidal iodine uptake, thereby allowing the use of lower radioactive iodine doses for treatment. Veterinary studies of this subject are limited, and results are conflicting. OBJECTIVE: To investigate the effects of rh-TSH administration on thyroidal iodine uptake in hyperthyroid cats. ANIMALS: Ten client-owned hyperthyroid cats. METHODS: In this prospective clinical study, cats were administered saline (placebo), 50 µg rh-TSH (low-dose), and 100 µg rh-TSH (high-dose) in randomized crossover design with treatments separated by 7-10 days. After each treatment, thyroid scintigraphy was performed by administering 300 µCi 123 I and assessing radionuclide uptake 8 and 24 hours later. Serum thyroid hormone concentrations were measured at each visit. RESULTS: Thyroidal percent iodine uptakes (mean ± SD at 8 and 24 hours) in cats treated with placebo (25.2 ± 13.4%, 30.0 ± 12.8%), low-dose (24.1 ± 12.5%, 29.4 ± 13.7%), and high-dose rh-TSH (24.2 ± 16.3%, 30.8 ± 15.3%) were not different (P = .76). Independent of rh-TSH administration, percent iodine uptakes were positively correlated with serum thyroid hormone concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: One-time administration of rh-TSH, even at high doses, would not be expected to lower radioactive iodine doses needed for treatment of hyperthyroidism in cats. Investigations of alternate strategies to increase thyroidal uptake of radioactive iodine are warranted.

Immunohistochemical Evaluation of Canine Pituitary Adenomas Obtained by Transsphenoidal Hypophysectomy.

Hypophysectomy specimens from 16 dogs with pituitary adenoma were evaluated with periodic acid-Schiff (PAS), reticulin, and immunohistochemistry for adrenocorticotrophic hormone (ACTH), melanocyte stimulating hormone (MSH), growth hormone (GH), and Ki-67. The reticulin network was obliterated in all adenomas. One adenoma expressed ACTH and GH. Eight corticotroph adenomas were basophilic to chromophobic, and PAS- and ACTH-positive. Seven melanotroph adenomas were distinguished from corticotroph adenomas by expression of MSH. Pituitary-dependent hypercortisolism was diagnosed in 5 of 8 dogs with corticotroph and 4 of 7 with melanotroph adenoma. Pituitary height/brain area (P/B) ratio was elevated in all dogs. Previous canine hypophysectomy studies suggested that melanotroph adenomas were larger and carried a worse prognosis than corticotroph adenomas; however, in this study, corticotroph adenomas in comparison to melanotroph adenomas were larger (median P/B ratio: 1.06 versus 0.76), more proliferative (median Ki-67 index: 9.47% versus 1.99%), and associated with shorter survival (median: 300 versus 793 days). Recommended immunohistochemistry for PAS-positive pituitary adenomas includes ACTH and MSH to distinguish corticotrophs from melanotrophs and Ki-67 for proliferation index.

Histopathologic Findings in Canine Pituitary Glands.

To optimize the histologic evaluation of hypophysectomy specimens, sections of 207 canine pituitary glands (196 postmortem, 11 hypophysectomy specimens) were reviewed. Adenohypophyseal proliferation was the most common (n = 79) lesion. Proliferative lesions were sparsely to densely granulated; the granules were usually basophilic to chromophobic and periodic acid-Schiff-positive. Adenohypophyseal proliferation was classified as hyperplasia (n = 40) if ≤2 mm diameter with intact reticulin network, as microadenoma (n = 22) for 1-5 mm homogeneous nodules with lost reticulin network, or as macroadenoma (n = 17) for larger tumors. Craniopharyngeal duct cysts were common incidental lesions and the only lesion in 15 dogs. Uncommon diagnoses included lymphoma (n = 4), hemorrhagic necrosis (n = 4), metastatic carcinoma (n = 3), hypophysitis (n = 3), ependymoma (n = 2), craniopharyngioma (n = 2), and 1 case each of metastatic melanoma, pituicytoma, gliomatosis, germ cell tumor, meningioma, and atrophy. The pituitary histologic diagnosis was associated with hyperadrenocorticism (HAC; P < .001) and adrenocortical histologic diagnosis ( P = .025). Both HAC and adrenocortical hyperplasia showed a positive trend with the degree of adenohypophyseal proliferation. The association of adrenocortical hyperplasia with HAC was not significant ( P = .077). Dogs with adenohypophyseal proliferations were older than dogs with normal pituitary glands ( P < .05). Brachycephalic breeds were overrepresented among dogs with pituitary macroadenoma or craniopharyngeal duct cysts, but the association was not statistically significant ( P = .076). Adenohypophyseal hyperplasia was more common than adenoma among postmortem specimens, but was unexpected in >80% of cases. Pituitary macroadenoma was the most common diagnosis in hypophysectomy specimens.

Evaluation of circulating eosinophil count and adrenal gland function in California sea lions naturally exposed to domoic acid.

OBJECTIVE: To determine the effect of natural exposure to domoic acid (DA) on eosinophil counts and adrenal gland function in California sea lions (Zalophus californianus). DESIGN: Cross-sectional prospective study. ANIMALS: 39 California sea lions. PROCEDURES: Adult female sea lions admitted to a rehabilitation hospital during 2009 were classified into 1 of 3 groups (acute DA toxicosis, chronic DA toxicosis, or no DA exposure) on the basis of clinical signs, DA concentration in urine or feces, and hippocampal morphology. Endoparasite burden, eosinophil count, and serum cortisol and plasma ACTH concentrations were determined for each sea lion. For a subset of 8 sea lions, fecal glucocorticoid concentration after IM administration of cosyntropin was determined. RESULTS: Sea lions exposed to DA (acute DA toxicosis, n = 11; chronic DA toxicosis, 19) had higher eosinophil counts and lower serum cortisol concentrations, compared with values for sea lions with no DA exposure (9). Eosinophil count was not associated with endoparasite burden. Serum cortisol concentration was associated with plasma ACTH concentrations in sea lions from the no DA exposure group but not in sea lions in the acute or chronic DA toxicosis groups. Following cosyntropin injection, fecal glucocorticoid concentrations increased in all sea lions evaluated except 1. CONCLUSIONS AND CLINICAL RELEVANCE: In adult sea lions, eosinophilia may be a cost-effective biomarker for DA exposure and may reflect alterations in hypothalamic, pituitary gland, or adrenal gland function. Domoic acid exposure may have subtle health effects on marine animals in addition to induction of neurologic signs.

Thyroid disorders in the geriatric veterinary patient.

The effects of age, concurrent illness, and administered medications complicate diagnosis of thyroid dysfunction in geriatric patients. Interpretation of thyroid hormone testing should take these factors into account. The most common thyroid disorder in dogs is acquired hypothyroidism. Therapeutic monitoring should be utilized for monitoring treatment of canine hypothyroidism. The most common thyroid disorder in cats is benign hyperthyroidism. Diagnosis is most often complicated by the presence of concurrent illness. Treatment should be individualized based on individual case characteristics and presence of concurrent illness. Some older cats have a palpable goiter months to years before development of clinical signs of hyperthyroidism.

Characteristics of commercially manufactured and compounded protamine zinc insulin.

OBJECTIVE: To evaluate and compare characteristics of a commercially manufactured protamine zinc insulin (PZI) product and PZI products obtained from various compounding pharmacies. DESIGN: Evaluation study. SAMPLE: 112 vials of PZI (16 vials of the commercially manufactured product and 8 vials from each of 12 compounding pharmacies) purchased over an 8-month period. PROCEDURES: Validated methods were used to analyze 2 vials of each product at 4 time points. Appearance, endotoxin concentration, crystal size, insulin concentration in the supernatant, pH, total insulin and zinc concentrations, and species of insulin origin were evaluated. RESULTS: All 16 vials of commercially manufactured PZI met United States Pharmacopeia (USP) specifications. Of 96 vials of compounded PZI, 1 (1 %) contained a concentration of endotoxin > 32 endotoxin U/mL, 23 (24%) had concentrations of insulin in the supernatant > 1.0 U/mL, and 45 (47%) had pH values < 7.1 or > 7.4; all of these values were outside of specifications. Several vials of compounded PZI (52/96 [54%]) did not meet specifications for zinc concentration (0.06 to 0.1 mg/mL for 40 U of insulin/mL, 0.075 to 0.12 mg/mL for 50 U of insulin/mL, and 0.15 to 0.25 mg/mL for 100 U of insulin/mL), and total insulin concentration in 36 [38%] vials was < 90% of the labeled concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Only 1 of 12 compounded PZI products met all USP specifications in all vials tested. Use of compounded PZI insulin products could potentially lead to serious problems with glycemic control in veterinary patients.

Acquired bilateral laryngeal paralysis associated with systemic lupus erythematosus in a dog.

A 4 yr old spayed female Labrador retriever was referred for acute respiratory distress and was found to have bilateral laryngeal paralysis. Physical examination and biochemical testing were consistent with systemic lupus erythematosus (SLE) and did not reveal a likely alternative cause for the laryngeal paralysis. Following immunosuppressive and supportive treatment, the dog regained normal laryngeal function. At a scheduled follow-up examination 6 wk later, normal laryngeal function was confirmed via sedated laryngeal examination. Laryngeal paralysis associated with SLE has been reported in humans, but this is the first known report of acquired laryngeal paralysis associated with SLE in the dog.

Cyclic estrous-like behavior in a spayed cat associated with excessive sex-hormone production by an adrenocortical carcinoma.

A 15-year-old, spayed female domestic shorthair cat was evaluated for 1-year duration of cyclic intermittent estrous behavior. Diagnostic testing performed before referral, including baseline progesterone concentration, human chorionic gonadotropin (hCG) hormone stimulation test and surgical exploratory laparotomy, had remained inconclusive for a remnant ovary. Evaluation of sex hormones before and after adrenocorticotropic hormone (ACTH) administration revealed increased basal concentrations of androstenedione, estradiol, progesterone, and 17α-hydroxyprogesterone and normal ACTH-stimulated hormone concentrations. Enlargement of the right adrenal gland was identified by abdominal ultrasound. The cat underwent an adrenalectomy and histopathology of the excised adrenal gland was consistent with an adrenocortical carcinoma. Clinical signs resolved immediately following surgery, and most hormone concentrations declined to within or below the reference interval (RI) by 2 months after surgery.

Feline hyperthyroidism: potential relationship with iodine supplement requirements of commercial cat foods.

UNLABELLED: ARTICLE RATIONALE: Since the late 1970s, there has been a significant increase in the prevalence of feline hyperthyroidism (FH). It is now recognized worldwide as the most common endocrinopathy of older cats, resembling toxic nodular goiter of older humans in iodine-deficient areas. The purpose of this article is to identify the potential for iodine concentrations in the diet to contribute to the etiology of FH. HISTORICAL CONTEXT: Iodine concentrations of commercial cat foods vary widely. A review of historical iodine recommendations revealed that the units of iodine supplementation changed in the 1970s. Given this change, foods minimally supplemented since the late 1970s would have been iodine deficient for most cats. PRACTICAL RELEVANCE: Iodine supplementation of commercial cat foods should be evaluated in the light of the iodine recommendations revised in 2006. Foods may remain deficient in iodine if supplemented at the minimum recommended concentration, possibly contributing to the development of FH.

Insulin resistance in cats.

Insulin resistance is defined as decreased sensitivity to insulin. Insulin resistance is an important component of the pathogenesis of type 2 diabetes mellitus (DM), and resolution of peripheral insulin resistance in cats with type 2 DM together with good glycemic control may result in diabetic remission. In insulin-dependent diabetic cats, insulin resistance is manifested clinically as an inadequate response to an appropriate pharmacologic dose of insulin. This article focuses on the clinical problem of insulin resistance in insulin-dependent diabetic cats.

Primary esophageal squamous cell carcinoma in a cat.

Primary esophageal squamous cell carcinoma causing stricture was diagnosed in a cat via endoscopy and computed tomography. Difficulty in making this diagnosis via endoscopic biopsy alone is described. Although balloon dilatation was unsuccessful, supportive care via gastrostomy tube feeding and administration of piroxicam successfully allowed a 16-week survival from the time of presentation and a 4-week survival from the onset of treatment with piroxicam.

A prospective study of unfractionated heparin therapy in dogs with primary immune-mediated hemolytic anemia.

Unfractionated heparin therapy was initiated at a standard dosage of 300 IU/kg subcutaneously q 6 hours to 18 dogs with immune-mediated hemolytic anemia. Heparin's prolongation of activated partial thromboplastin time and change in factor Xa inhibition (anti-Xa activity) were serially monitored during the first 40 hours of therapy. During the initial 40 hours, only eight of 18 dogs had attained anti-Xa activities of > or =0.35 U/mL. No dogs had clinical signs of hemorrhage. Fifteen dogs survived to discharge; 11 dogs were alive at 1 year, and thrombosis was identified in three of six nonsurvivors that were necropsied.

Clinical signs and concurrent diseases of hypothyroidism in dogs and cats.

Canine hypothyroidism may present with a wide range of clinical signs. The most common clinical signs are those of a decreased metabolic rate and dermatologic manifestations; however, many other clinical signs have been associated with hypothyroidism. There is strong evidence for a causal relation between hypothyroidism and a variety of neurologic abnormalities; however, the association between hypothyroidism and other manifestations, such as reproductive dysfunction, clinical heart disease, and behavioral abnormalities, is less compelling. Further studies are necessary to determine the full spectrum of disorders caused by hypothyroidism.