In today’s VETgirl online veterinary continuing education blog, we review two different protocols for trilostane administration in dogs with pituitary-dependent hyperadrenocorticism (PDH). Hyperadrenocorticism, or Cushing’s disease, is one of the most common endocrinopathies of dogs. As you all may remember, naturally occurring Cushing’s disease comes in two flavors: pituitary-dependent or adrenal-dependent. Approximately 85% of dogs with Cushing’s disease have the pituitary-dependent form (Feldman). While a number of treatment strategies are available, trilostane has become an increasingly popular and effective first-line therapy (Alenza). Trilostane is a competitive inhibitor of 3B-hydroxysteroid dehydrogenase (Potts). Personally, I need a translation for what on earth that means! Basically trilostane inhibits an enzyme essential to the synthesis of both glucocorticoids and mineralocorticoids in the adrenal cortex. The manufacturer recommends a trilostane starting dose of 2.2-6.7 mg/kg/day. So, Cho et al wanted to evaluate this in a study entitled Efficacy of Low- and High-Dose Trilostane Treatment in Dogs (<5 kg) with Pituitary-Dependent Hyperadrenocorticism. In this study, the safety and efficacy of two alternative protocols of trilostane administration were evaluated in dogs with PDH. The first was a twice-daily low-dose protocol, and the second was a once-daily high-dose protocol.

Sixteen dogs with newly diagnosed PDH and that weighed less than 5 kg were included. For all dogs, a history, physical examination, complete blood count, biochemical profile, and urinalysis were performed. Additionally, each dog had an adrenocorticotropic hormone (ACTH) stimulation test, a low-dose dexamethasone suppression test (LDDST), and an abdominal ultrasound performed. The LDDST and abdominal imaging were used to differentiate PDH from adrenal tumors. The dogs were then randomly assigned into 2 groups. Group A included 9 dogs, and these were treated with low-dose trilostane, 0.5-1 mg/kg, given twice daily. The 7 dogs in Group B were treated with high-dose trilostane, 30 mg/dog, administered once daily. After starting treatment, each dog was reassessed at 2 weeks, and again at 4, 8, 12, 16, and 24 weeks. Interviews to assess for adverse effects of treatment or clinical signs of PDH were performed, with particular attention paid to polydipsia, polyuria, and polyphagia. A physical examination, biochemical profile, urinalysis, and ACTH stimulation test were also performed at each visit. The ACTH stimulation test was started 3-4 hours after trilostane administration with a target range of stimulated cortisol of 2-5.5 mcg/dL. Despite findings at follow-up visits, all dogs were maintained on the initial starting dose for at least 4 weeks, but thereafter the dose could be adjusted as needed using an algorithm created by the authors, which incorporated ACTH stimulation test results and clinical signs.

Trilostane treatment for hyperadrenocorticism in dogs

So, what did the authors find in this study? There were no differences between the two groups regarding age or weight, and the clinical signs and laboratory abnormalities reported for the two groups were fairly similar. Not surprisingly, the most common clinical sign in each group was polyuria/polydipsia, and polyphagia, abdominal distention, and dermatologic changes were also reported in many dogs in each group. All dogs in both groups had elevated ALP levels, and both groups had numerous dogs with leukocytosis, elevated ALT, hypercholesterolemia, hyperglycemia, and hypertriglyceridemia. Urine specific gravities were similar between groups. All dogs had abnormal ACTH stimulation test results, and all dogs had adrenal widths at least at the upper limits of normal. More than half of dogs in each group had bilaterally symmetric adrenomegaly, and all dogs had an enlarged hyperechogenic liver.

You’re probably anxious to hear how the two groups responded to therapy right? Well, here’s the important part – let’s dive in! First of all, it’s important to note that all dogs in both groups had resolution of their clinical signs by 24 weeks. Therefore by the end of the study, there was no difference in outcome of clinical resolution between groups. However, if you break down resolution of clinical signs by time point, symptoms such as polyuria, polydipsia, and polyphagia improved more quickly in the Group B (i.e., higher, once-daily dose) dogs. Unfortunately at 20 weeks, there were 2 dogs in Group B that did develop vomiting, collapse, and ACTH stimulation results consistent with hypoadrenocorticism. In these dogs, trilostane was temporarily discontinued, and the patients improved. Trilostane was restarted at 24 weeks with a 50% dose reduction. No dogs in Group A developed hypoadrenocorticism. Dogs in both groups had significant decreases in ACTH-stimulated cortisol levels during treatment. According to the study protocol, if dogs post-ACTH cortisol levels were >5.5 mcg/dL, despite whether clinical signs were present, the dose of trilostane was increased by 25%. If that level was > 9.0 mcg/dL, they increased the dose by 50%. All dogs in Group A had levels > 5.5 mcg/dL at 4 weeks of treatment, but the target levels were achieved in all Group A dogs by 24 weeks of treatment. In group B, however, 5 out of the 7 dogs had target levels achieved within 4 weeks of treatment, and all dogs had appropriate levels by 8 weeks. There were no statistically significant differences in cortisol levels between groups prior to treatment or at 24 weeks after treatment. However, there were significant differences at 2, 4, 8, 12, and 16 weeks! In other words, both ACTH-stimulation results and clinical signs normalized more quickly in the dogs in Group B. Many of the biochemical changes improved in dogs from both groups during treatment. Some noteworthy limitations of this study include only evaluating dogs weighing less than 5kg, and the overall small sample size.

So what can we take away from this VETgirl podcast? The twice-daily low-dose protocol effectively controlled PDH, and no dogs in the lower-dose group developed signs consistent with hypoadrenocorticism unlike the higher-dose group. Important considerations to using this protocol, however, are that the lower dose can take longer to see clinical and laboratory control of PDH, and this protocol could prove logistically more challenging given the need for small pill sizes and the requirement for more frequent medication administration for owners. That all said, it appears that low-dose twice-daily protocol for trilostane is a good choice, despite being quite a bit lower than previous recommendations!

Abbreviations:
ACTH: adrenocorticotropic hormone
LDDST: low-dose dexamethasone suppression test
PDH: Pituitary-dependent hyperadrenocorticism

References:
1. Cho KD, Kang JH, Chang D, et al. Efficacy of Low- and High-Dose Trilostane Treatment in Dogs (<5 kg) with Pituitary-Dependent Hyperadrenocorticism. J Vet Intern Med 2013;27:91-98.
2. Feldman EC. Distinguishing dogs with functioning adrenocortical tumors from dogs with pituitary-dependent hyperadrenocorticism. J Am Vet Med Assoc 1983;183:195–200.
3. Alenza DP, Arenas C, Lopez ML, et al. Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism. J Am Anim Hosp Assoc 2006;42: 269–276.
4. Potts GO, Creange JE, Hardomg HR, et al. Trilostane, an orally active inhibitor of steroid biosynthesis. Steroids 1978;32:257–267.

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