The Double Challenge of the Diabetic Cushingoid
World Small Animal Veterinary Association Congress Proceedings, 2018
Cynthia R. Ward, VMD, PhD, DACVIM (SAIM)
Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA

Hyperadrenocorticism and diabetes mellitus often occur concurrently and these patients can be a challenge to diagnose and manage.1 They have similar clinical signs and the diagnostic tests are affected by the clinical diseases. Additionally, treatment of one disease will affect the treatment of the other. So, how to proceed with such challenging cases. Diabetes mellitus is usually diagnosed first as it is the easiest to recognize. Clinical signs include polyuria/polydipsia, weight loss, persistent or recurrent urinary tract infections, weakness and muscle wasting, cataracts (usually dogs), and peripheral neuropathies (usually cats). Diagnosis can be made by recognition of appropriate clinical signs, and demonstration of persistent hyperglycemia and glucosuria. One confounding factor to this diagnosis is stress. Stress, alone, can cause hyperglycemia, which can be high enough to be cause spill over into the urine and glucosuria. Should the clinician have any doubt of whether hyperglycemia and glucosuria are due to diabetes mellitus, s/he should check a serum fructosamine level. This value gives the average of the blood glucose over the preceding 2–3 weeks. If elevated, then diabetes mellitus can be diagnosed. After diagnosis, stable diabetics may be sent home with insulin to begin therapy. Optimal insulins for dogs include NPH, Lente (Vetsulin®), Detemir (Levemir®). Of these, Vetsulin® is the only one approved for veterinary use by the FDA. NPH insulin is an inexpensive option for owners, although the duration of action may not be optimal in some dogs. Vetsulin® and Detemir are more appropriate choices if insulin can only be given once per day. The optimal diet for diabetic dogs is one high in insoluble fiber. This diet slows glucose absorption from the gut and postprandial hyperglycemia. The patient should be re-examined in 7–10 days to determine insulin effect. Optimal monitoring includes evaluation of a glucose curve.2-4

Concurrent HAC in the diabetic patient is usually suspected if the diabetes mellitus is not controlled with insulin doses climbing over 1.5 U/kg (insulin resistance) or if clinical signs consistent with HAC persist with insulin therapy.5 Other reasons for insulin resistance should be considered to include improper insulin injection technique, outdated insulin, or incorrect syringes. The practitioner should also check for other concurrent diseases such as urinary tract infections. If HAC is still suspected, adrenal function testing should be initiated. Do not test for HAC if the dog is clinically unstable. There should be loose control of diabetes mellitus with the blood sugar ideally ranging from 100–350 mg/dl for most of the day. Do not test for HAC if the dog is ketotic, hypoglycemic, or hyperosmolar. Three screening tests FOR HAC are available.6 The urine cortisol:creatinine ratio is very sensitive (100%) although not specific. A second screening test for HAC is the low dose dexamethasone suppression test. This should be to go to test unless there is significant concurrent disease such as diabetes mellitus. A third screening test for HAC is the ACTH Stimulation Test. It is more specific in animals with concurrent disease and recommended for use in dogs with concurrent diabetes mellitus to decrease the possibility of a false positive response. The practitioner measures cortisol before and 60 min after injection of 5 μg/kg synthetic ACTH (Cortrosyn). In diabetic patients, the owner should feed and administer insulin as usual. A simultaneous glucose curve should be performed in conjunction with the ACTH-stimulation test to ensure that the animal has blood glucose within the optimal range during testing. If ACTH-stimulation testing supports HAC, then treatment should be initiated. If HAC is still suspected but is not supported by the ACTH-stimulation test, then the test can be repeated 2–4 weeks later.

Medical treatment of HAC includes trilostane (Vetoryl®) and mitotane (Lysodren®). Ketoconazole and deprenyl (Anipril®) have also been advocated, but are substantially less effective than trilostane or Lysodren. Surgical options include adrenalectomy and hypophysectomy. Trilostane is a competitive 3B-OH steroid dehydrogenase inhibitor that inhibits the conversion of pregnenolone to progesterone in the adrenal gland. This blocks the formation of the end products of progesterone including cortisol and aldosterone. Trilostane can be compounded but a manufactured product is available (Vetoryl®, Dechra Pharmaceuticals). Vetoryl® is FDA approved for veterinary use so that the veterinarian is legally protected. Vetroryl® is much more consistent in active ingredients than compounded trilostane and should be used when possible. The drug must be given daily. The recommended dose is 1.5–3 mg/kg, with the lower dose given bid considered safer and more efficacious.7Trilostane therapy should be monitored 10–14 days after initiation. An ACTH-stimulation test measuring cortisol is performed 4–6 hours after the morning dose of trilostane is given. A sodium/potassium level should be measured as well. This often decreases with trilostane treatment because of increasing K+ due to loss of aldosterone function.8

Mitotane is a DDT derivative. It kills adrenocortical cells with a preference for the cortisol producing ones (zonae fasciculata and reticularis). The induction phase consists of administering 35 (big dog) to 50 (little dog) mg/kg PO q.d. x 5–7 d. The maintenance phase is 35–50 mg/kg PO divided twice per week. Which therapy should the practitioner choose to treat HAC. In comparing trilostane and mitotane, both are as efficacious in controlling clinical signs and in the longevity of the treated animals.9,10 We recommend starting with trilostane therapy as it is easier for owners to manage while simultaneously giving insulin injections. If the response to trilostane is not optimal, then Lysodren therapy can be initiated.

Treatment for HAC in the patient with concurrent diabetes mellitus should be approached cautiously. 11 Removal of excess glucocorticoids will lessen the concurrent insulin resistance and result in more profound glucose-lowering activity by the usual insulin dose. The current insulin dose should be decreased by 25% upon initiation of treatment of HAC. Owners should be sent home with Keto-Diastix and instructed to measure urine at least once per day approximately 6 hours after insulin is given (if given twice per day). If ketones are detected or the absence of urine glucose is detected more than twice in a row, the owner should be instructed to inform the veterinarian. Lack of urine glucose may indicate hypoglycemia that may necessitate therapy. Alternately, if owners are able to collect blood glucoses at home, they should perform spot checks 4–8 hours after the insulin is given. Severe hyperglycemia or hypoglycemia should be reported to the veterinarian.

A glucose curve should be performed at every recheck to monitor HAC treatment. After the HAC is controlled, tight control of glucose with insulin can be attempted.


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6.  Behrend EN, Kooistra HS, Nelson R, et al. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med. 2013;27:1292–1304.

7.  Vaughan MA, Feldman EC, Hoar BR, et al. Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc. 2008;232:1321–1328.

8.  Reid LE, Behrend EN, Martin LG, et al. Effect of trilostane and mitotane on aldosterone secretory reserve in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med. 2014;28:443–450.

9.  Helm JR, McLauchlan G, Boden LA, et al. A comparison of factors that influence survival in dogs with adrenal-dependent hyperadrenocorticism treated with mitotane or trilostane. J Vet Intern Med. 2011;25:251–260.

10.  Clemente M, De Andres PJ, Arenas C, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Vet Rec. 2007;161:805–809.

11.  McLauchlan G, Knottenbelt C, Augusto M, et al. Retrospective evaluation of the effect of trilostane on insulin requirement and fructosamine concentration in eight diabetic dogs with hyperadrenocorticism. J Small Anim Pract. 2010;51:642–648.


Speaker Information
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Cynthia R. Ward, VMD, PhD, DACVIM (SAIM)
Department of Small Animal Medicine and Surgery
College of Veterinary Medicine
University of Georgia
Athens, GA, USA

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