Trilostane (marketed as Vetoryl) is the primary medical treatment for canine hyperadrenocorticism (Cushing's disease), both pituitary-dependent and adrenal-dependent. By competitively inhibiting the 3β-hydroxysteroid dehydrogenase (3β-HSD) enzyme system, trilostane blocks the synthesis of cortisol and other adrenal steroids. While this mechanism is highly effective at reducing the clinical signs of cortisol excess, it carries an inherent risk: excessive suppression can lead to iatrogenic hypoadrenocorticism (Addison's disease), which represents a life-threatening endocrine emergency.

To evaluate this risk at scale, VetMedGuide analyzed a June 2026 public extract of the FDA Center for Veterinary Medicine (CVM) animal adverse-event database, containing 1.34 million reports. We identified 11,533 adverse event reports in dogs where the active ingredient was trilostane.

The FDA's standard caveat applies throughout: these are spontaneous reports, so they do not establish true event rates or prove that trilostane caused any given event. A "report involving trilostane" means the drug was being given when the problem was recognized, not that the drug caused it — and trilostane is, by definition, given to dogs already sick from cortisol excess. Read with that framing, the dataset provides a quantitative picture of trilostane's clinical safety margins, showing that iatrogenic adrenal insufficiency and secondary electrolyte disturbances represent a significant portion of reported adverse events.

The Top Clinical Signs: Lethargy and Gastrointestinal Distress

Among the 11,533 reports involving trilostane in dogs, the most common clinical presentations span systemic signs of over-suppression and gastrointestinal upset:

Note: Individual reports can contain multiple signs, so percentages do not sum to 100%.

While lethargy and vomiting are non-specific, their occurrence in 17% of trilostane cases is a critical signal. In a dog receiving trilostane, sudden onset of lethargy, vomiting, or anorexia should never be dismissed as simple GI upset; it requires immediate clinical evaluation to rule out hypoadrenocorticism.

The Biochemical Signature of Adrenal Over-Suppression

Because 3β-hydroxysteroid dehydrogenase is also involved in the synthesis of aldosterone (the primary mineralocorticoid), trilostane can suppress both glucocorticoid and mineralocorticoid pathways. When aldosterone is depleted, the kidneys lose the ability to retain sodium and excrete potassium, leading to a classic electrolyte shift:

1. Hyperkalemia (1,718 reports): Elevated serum potassium is the most common electrolyte abnormality in this dataset, appearing in 14.9% of all reports.
2. Low Sodium-Potassium Ratio (824 reports): A Na:K ratio below 27 (often dropping below 23 in crisis) is highly suggestive of primary adrenal insufficiency.
3. Hyponatremia (454 reports): Depleted serum sodium due to renal wasting.

Clinically, 689 reports explicitly document a diagnosis of "Hypoadrenocorticism" (iatrogenic Addison's disease). In these cases, the suppression was severe enough to cause clinical collapse or warrant emergency steroid replacement therapy.

Fatal Outcomes in Trilostane Therapy

Adrenal crisis (Addisonian crisis) is rapidly progressive and, if unrecognized, fatal. Within the 11,533 reports:

• Euthanized: 894 dogs (7.8%)
• Died: 425 dogs (3.7%)
• Ongoing/Unresolved: 1,347 dogs (11.7%)
• Recovered/Normal: 1,963 dogs (17.0%)
• Outcome Unknown: 6,580 dogs (57.1%)

A total of 1,319 reports ended in a fatal outcome (death or euthanasia), representing 11.4% of all reported canine trilostane cases. This reinforces the importance of structured dosing strategies and rigorous laboratory monitoring to catch over-suppression before it becomes irreversible; the full diagnostic-to-monitoring pathway is laid out in our Cushing's disease testing and trilostane monitoring guide.

Clinical Management and Monitoring Protocols

Under FDA NADA 141-291, Vetoryl is approved for treatment of pituitary-dependent and adrenal-tumor hyperadrenocorticism in dogs at a labeled starting dose of 2.2–6.7 mg/kg once daily with food. To minimize the risk of iatrogenic Addison's, clinicians should adhere to the following best practices:

1. Start Low and Dose Twice-Daily

The labeled dose range is 2.2–6.7 mg/kg once daily, but many endocrinologists now start lower — approximately 1–2 mg/kg once daily, or divided into 0.5–1 mg/kg twice daily for pituitary-dependent Cushing's, because trilostane's duration of action is often shorter than 24 hours. Twice-daily dosing at lower levels provides smoother cortisol control and reduces the risk of large transient adrenal blocks.

2. Rigorous ACTH Stimulation and Electrolyte Checks

ACTH stimulation testing remains the gold standard for monitoring trilostane:

• Perform the first ACTH stim test at 10–14 days after starting therapy or changing a dose.
• Subsequent tests should occur at 30 days, 90 days, and then every 3–6 months.
• Timing is critical: The ACTH stim test must be initiated 4 to 6 hours after pill administration, which represents the peak serum concentration and enzyme block.
• Always check electrolytes: Run a baseline biochemistry panel alongside the ACTH stim to monitor sodium, potassium, and the Na:K ratio.

3. Patient Criteria and Contraindications

• Do not start trilostane in dogs with pre-existing renal insufficiency (creatinine > 2.0 mg/dL) or hepatic disease, as drug clearance is compromised.
• Do not administer trilostane to pregnant dogs, as it will disrupt gestational progesterone synthesis.
• Instruct owners to stop the medication immediately and contact the clinic if the dog shows any signs of vomiting, diarrhea, extreme lethargy, or collapse.

Sources

• FDA Center for Veterinary Medicine (CVM), animal adverse-event database (public extract dated June 9, 2026; 1.34 million reports); analysis by VetMedGuide of 11,533 reports naming trilostane in dogs. The FDA cautions that spontaneous reports do not establish causation or true event rates. https://www.fda.gov/animal-veterinary/safety-health/reporting-animal-drug-and-device-side-effects-and-product-problems
• FDA, Freedom of Information Summary, Original NADA 141-291, Vetoryl (trilostane) Capsules, approved December 5, 2008 (labeled starting dose 2.2–6.7 mg/kg once daily with food). https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/855
• VETORYL (trilostane) Capsules prescribing information, DailyMed (post-approval experience, iatrogenic hypoadrenocorticism, monitoring). https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=22a5e838-c9a3-40d2-84cd-15df6ada913b
• Behrend EN, Kooistra HS, Nelson R, et al. Diagnosis and Monitoring of Hyperadrenocorticism in Dogs: AAHA Consensus Guidelines. Journal of the American Animal Hospital Association. 2012;48(6):375-394. doi:10.5326/JAAHA-MS-5821