How to manage Cushing's syndrome

Dechra Veterinary Products

Cushing's syndrome is a common differential diagnosis for older dogs presenting with increased thirst and urination. It can be a frustrating disease due to the number of available diagnostic tests, multiple treatment options, and variety of monitoring strategies. Ultimately, accurate diagnosis of the disease and carefully monitored treatment with FDA-approved Vetoryl® Capsules (trilostane) results in healthier patients who can maintain a good quality of life despite the disease.

Clinical Presentation

Dogs with Cushing's syndrome tend to be older, with a mean age of 11 years.² Some breeds appear to be predisposed to the disease, including the beagle, Boston terrier, boxer, dachshund, miniature schnauzer, and poodle.² The disease is more common in small-to medium-sized dogs, with 75% of patients weighing less than 20 kg.²

Cushing's syndrome results from overproduction of glucocorticoids by the adrenal glands (spontaneous disease) or chronic, excessive exposure to steroids (iatrogenic disease). In 80% to 85% of cases of spontaneous Cushing's syndrome, the disease results from excess secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland and is termed pituitary-dependent hyperadrenocorticism (PDH).^1,2 The remaining 15% to 20% of spontaneous Cushing's syndrome cases arise from an adrenal tumor producing excess glucocorticoids.

High levels of glucocorticoids, particularly cortisol, are responsible for causing clinical signs of the condition. These signs are nonspecific but can greatly affect quality of life for both pet and owner. They most commonly include polyuria and polydipsia (PU/PD), polyphagia, excessive panting, abdominal distention, endocrine alopecia, hepatomegaly, muscle weakness, and systemic hypertension.^1,3

There are no pathognomonic laboratory changes with Cushing's syndrome, and all abnormalities should be interpreted in the context of clinical signs.³ Possible changes include:

• stress leukogram (leukocytosis with neutrophilia, lymphopenia, and eosinopenia) and thrombocytosis in the complete blood cell count;
• increased alkaline phosphatase, hypercholesterolemia, hypertriglyceridemia, and hyperglycemia in the serum biochemistry profiles; and
• urine specific gravity less than 1.020, proteinuria.

Patients presenting with consistent clinical signs, physical examination findings, and laboratory abnormalities should be further evaluated with endocrine testing. When discussing diagnostic testing, veterinarians should educate their clients on the costs of testing and treatment as well as potential life-threatening sequelae of untreated disease.

Endocrine Testing

The 2012 American College of Veterinary Internal Medicine Consensus Statement on the diagnosis of Cushing's syndrome recommends testing for hyperadrenocorticism only in patients with clinical signs supportive of the disease.³

There are numerous tests available for Cushing's syndrome, but no test is 100% accurate.^1,3 To improve testing accuracy, patients should be appropriately screened, and testing should be postponed until concurrent diseases are controlled. If there is a strong clinical suspicion of Cushing's syndrome in a patient but negative test results are obtained, clinicians should consider an additional test or retesting in 3 to 6 months.³

The low-dose dexamethasone suppression (LDDS) test is the screening test of choice for spontaneous Cushing's syndrome in patients without concurrent illness.³ In patients with nonadrenal illness, such as diabetes mellitus or a suspicion of iatrogenic Cushing's syndrome, the ACTH stimulation test is preferred.³

Once Cushing's syndrome is diagnosed, differentiation between pituitary-dependent and adrenal-dependent disease is necessary to determine prognosis and treatment strategy. The LDDS test can differentiate between the 2 forms in some patients. In other patients, a high-dose dexamethasone suppression test, ACTH assay, abdominal ultrasound, or other advanced imaging may be needed.³

Vetoryl® Provides a Safe Treatment Option for Cushing's Syndrome

The primary goal of treatment is to reduce cortisol secretion, resulting in improved clinical signs.^1,2 “Dogs with Cushing's syndrome rarely die from Cushing's syndrome. Instead, they are often euthanized due to clinical signs and comorbid conditions that develop,” Heather Kvitko-White, DVM, DACVIM (SAIM), says.

Surgical, radiation, and medical therapies exist for Cushing's syndrome,^1,2 but medical therapy is the most practical approach for most owners and can be managed in general practice.

Historically, mitotane was used off-label for the medical treatment of Cushing's syndrome. Mitotane decreases cortisol production by causing necrosis of portions of the adrenal gland. Due to its mode of action, its use comes with potential for significant adverse effects and mortality, with 25% to 30% of dogs experiencing adverse effects and up to 5% of dogs experiencing adrenal necrosis.²

Since the early 2000s, trilostane has been used for the management of Cushing's syndrome.⁴ It reduces cortisol production by competitively inhibiting the 3β-hydroxysteroid dehydrogenase enzyme. Because of the specific enzyme inhibition, production of glucocorticoids is reduced with minimal impact on mineralocorticoid production.⁴ The inhibition of the enzyme is dose dependent and reversible.⁴

Trilostane has been commercially available as Vetoryl® Capsules since 2009. Vetoryl® Capsules are the only FDA-approved medication for treatment of both pituitary-dependent and adrenal-dependent Cushing's syndrome in dogs. The “literature shows that Vetoryl® is safe,” Kvitko-White says. She notes a roughly 15% overall complication rate and only about a 2% adrenal necrosis rate with trilostane, with more adverse effects seen at higher doses.

Improvement in clinical signs after starting therapy with Vetoryl® can be rapid. Activity levels are usually the first clinical sign to improve, followed by improvement in PU/PD, polyphagia, and panting.^1,4 Changes in the skin, hair coat, and musculature also will improve with time, although this can take several months.¹ In a manufacturer clinical trial of Vetoryl®, less than 15% of dogs remained symptomatic for Cushing's syndrome.

The most common reported adverse effects are those of cortisol deficiency and include anorexia, lethargy, vomiting, and diarrhea.^1,4 More severe adverse effects, such as severe depression, hemorrhagic diarrhea, collapse, hypoadrenocortical crisis, and adrenal necrosis have been reported. Death occurred in rare cases, most often due to adrenal necrosis. The drug should not be used in patients with renal or hepatic insufficiency, and it may interact with some cardiac medications.

Multiple studies have evaluated the safety of trilostane at both once- and twice-daily dosing. Across 11 studies, adverse effects were noted in 13%of dogs treated once daily and 19% of dogs treated twice daily.⁴ Results of a study of dogs treated with trilostane found that only 15% of dogs experienced an episode of Cushing's syndrome during the first 2 years of treatment, and 25% experienced an episode over a 4-year treatment period.5 Because of the reversible action of the drug, many dogs that experience a hypoadrenocortical crisis will respond to supportive treatment and temporary discontinuation of trilostane.^4,5 Some dogs will have permanent hypoadrenocorticism and require glucocorticoid and mineralocorticoid supplementation long term.

Dogs with PDH that are treated with trilostane may live longer than those left untreated.⁶ Ultimately, treatment is recommended for patients with hyperadrenocorticism to improve quality of life and prevent comorbidities. Vetoryl® provides veterinarians with a safe and effective way to provide this treatment.

Maximizing Treatment Success with Vetoryl® Vetoryl® Capsules are available in 5 sizes: 5 mg,10 mg,30 mg,60 mg, and 120 mg. Capsule sizes can be combined to achieve the desired dose. Absorption is improved when administered with food.¹ The manufacturer recommends a starting dose of 2.2 to 6.7 mg/kg once daily,1 noting that the lowest possible dose based on body weight and available capsule sizes should be used.

Because the drug suppresses cortisol levels for less than 12 hours, some literature has found that twice- daily dosing may be necessary to control clinical signs over the course of the day.⁴ The manufacturer notes that approximately 25% of dogs will require this alternative dosing schedule.¹

“Twice-daily administration really does appear to be slightly better than once-daily administration with lower doses, faster responses, and fewer—or in some cases less severe—[adverse] effects,” Kvitko-White says. However, she notes, “once daily administration may still be acceptable in some cases.”

One consideration in choosing to dose once or twice daily is owner finances. It may be more cost-effective to dose once daily, depending on the total daily dose and available capsule sizes. For patients requiring twice-daily dosing, it is the total daily dose that matters, and the patient does not have to receive the same dose in morning and evening.¹ For instance, if a pet requires a 40-mg total daily dose, a 30-mg capsule could be administered in the morning and a 10-mg capsule in the evening, as opposed to the need for 20 mg (2 of the 10-mg capsules) at each dose.

Treatment Monitoring

Clear owner communication is essential for the safe and effective use of Vetoryl®. Owners should be advised of potential adverse effects and monitor for signs of hypocortisolemia—changes in appetite, gastrointestinal signs, and decreases in energy level. If these clinical signs are noted, the owner should stop Vetoryl® and contact their veterinarian.

The manufacturer recommends rechecking patients 10 to 14 days after starting therapy and any dose change. The recheck should include evaluation of clinical signs with a thorough history, physical examination, serum biochemistry profile with electrolytes, and an ACTH stimulation test.

The ACTH stimulation test is the current gold standard for monitoring Cushing disease.⁴ It should be performed 4 to 6 hours after Vetoryl® administration; the timing of the test can affect results.^1,4 The first recheck is used to ensure that the patient is not becoming overly suppressed, and dosage increases are not recommended until after 30 days of treatment, when another recheck is performed.¹

Over time, dosage adjustments are made based on control of clinical signs and the results of ACTH stimulation testing. Once the pet is regulated based on lab work and control of clinical signs, they should be monitored every 3 months, as dosing adjustments may be needed over time to prevent episodes of Cushing's syndrome.

Alternative monitoring strategies have been investigated.4 Repeated ACTH stimulation tests on top of the cost of medication can add up quickly for owners, especially in the early stages of treatment. Additionally, Cortrosyn®, the synthetic ACTH product, has had periodic back orders in recent years.

“Methods for monitoring using single cortisol measurements were developed in Europe and are also a really great option to save cost,” Kvitko-White says. “[Treating] a dog with Cushing's syndrome does not need to be extensive or expensive. It may be that monitoring based solely on the control of clinical signs, return to a normal physical examination, and outcomes of owner satisfaction are better than current laboratory methods.”

In 1 study, pre-trilostane cortisol measurements correlated better with owner assessment of clinical control than the results of the ACTH stimulation test.⁷ Further research is needed to determine the best monitoring strategies to balance safety and efficacy of Vetoryl^®.^4,7 Further studies are needed to determine the most accurate monitoring strategy, but careful surveillance for signs of Cushing's syndrome must be included to ensure the safe use of trilostane. "Vetoryl should never be given to a hospitalized or otherwise ill pet," Kvitko-White states.

Treatment Considerations for Patients With Diabetes

In rare cases, dogs with diabetes also may have Cushing's syndrome, which can make gaining control of the diabetes challenging. Kvitko-White notes that only approximately 1 in 8 dogs with Cushing's syndrome is also diabetic and that other causes for insulin resistance should be thoroughly investigated before pursuing testing for Cushing's syndrome.

“Indicators that Cushing's syndrome might be the cause of diabetes include that the insulin dose is exceeding 1 to 1.5 units/kg, clinical signs such as PU/PD and polyphagia have persisted despite decent control of blood sugar, and physical examination findings are more specific to Cushing's syndrome such as comedones, thinning hair, and secondary infections [eg, urinary tract infection and pyoderma],” Kvitko-White states.

In cases where Cushing's syndrome is suspected in a dog with diabetes, an ACTH stimulation test is the diagnostic test of choice as it will have fewer false negative results. In cases where Cushing's syndrome is found to be the reason for insulin resistance, clinicians can expect diabetic control to improve quickly after starting Vetoryl®. Kvitko-White reminds veterinarians to “monitor the glucose and be prepared to decrease the insulin dose.”

Take-Home Points

Although Cushing's syndrome can be a frustrating disease to diagnose, it can be managed in general practice. Patients can be safely and effectively treated with Vetoryl®. Elimination of clinical signs of Cushing's syndrome is the primary goal of treatment and may be the most reliable monitoring strategy available to determine appropriate dosing. However, laboratory testing should be routinely performed to monitor for changes consistent with hypoadrenocorticism that may necessitate dosage reductions or discontinuation to maximize patient safety and prevent severe adverse effects.

References

1. Treat their hyperadrenocorticism. Dechra Veterinary Products. Accessed October 27, 2021. https://dechra-us.com/Files/Files/ SupportMaterialDownloads/us/01TB-VET50030-0720TechBro- chureFinal.pdf?_ga=2.239296966.474528713.1635341013- 1063997861.1635341013.
2. Hyperadrenocorticism. VINcyclopedia. Accessed October 26, 2021. www.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&Di seaseId=1324&pid=607.
3. Behrend EN, Kooistra HS, Nelson R, Reusch CE, Scott-Moncrieff JC. Diagnosis of spontaneous hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med. 2013;27(6):1292-1304. doi:10.1111/jvim.12192
4. Lemetayer J, Blois S. Update on the use of trilostane in dogs. Can Vet J. 2018;59(4):397-407.
5. King JB, Morton JM. Incidence and risk factors for hypoadreno- corticism in dogs treated with trilostane. Vet J. 2017;230:24-29. doi:10.1016/j.tvjl.2017.10.018
6. Nagata N, Kojima K, Yuki M. Comparison of survival times for dogs with pituitary-dependent hyperadrenocorticism in a primary-care hospital: treated with trilostane versus untreated. J Vet Intern Med. 2017;31(1):22-28. doi:10.1111/jvim.14617
7. Macfarlane L, Parkin T, and Ramsey I. Pre-trilostane and three-hour post-trilostane cortisol to monitor trilostane therapy in dogs. Vet Rec 2016;179(23):597. https://bvajournals.onlinelibrary.wiley.com/doi/ pdf/10.1136/vr.103744