ObjectiveThe first-line treatment for Cushing’s disease is transsphenoidal surgery, after which the rates of remission are 60 to 80%, with long-term recurrence of 20 to 30%, even in those with real initial remission. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. The objective of this study was to evaluate the safety profile of and the treatment response to ketoconazole in Cushing’s disease patients followed up at the endocrinology outpatient clinic of a Brazilian university hospital.Patients and methodsThis was a retrospective cohort of Cushing’s disease patients with active hypercortisolism who used ketoconazole at any stage of follow-up. Patients who were followed up for less than 7 days, who did not adhere to treatment, or who were lost to follow-up were excluded.ResultsOf the 172 Cushing’s disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. However, complete data was only available for 33 of these patients. Of these, 26 (78%) underwent transsphenoidal surgery prior to using ketoconazole, five of whom (15%) had also undergone radiotherapy; seven used ketoconazole as a primary treatment. Ketoconazole use ranged from 14 days to 14.5 years. A total of 22 patients had a complete response (66%), three patients had a partial response (9%), and eight patients had no response to treatment (24%), including those who underwent radiotherapy while using ketoconazole. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-h urinary free cortisol levels than the uncontrolled group [times above the upper limit of normal: 0.62 (SD, 0.41) vs. 5.3 (SD, 8.21); p < 0.005, respectively] in addition to more frequent previous transsphenoidal surgery (p < 0.04). The prevalence of uncontrolled patients remained stable over time (approximately 30%) despite ketoconazole dose adjustments or association with other drugs, which had no significant effect. One patient received adjuvant cabergoline from the beginning of the follow-up, and it was prescribed to nine others due to clinical non-response to ketoconazole alone. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness, and loss of appetite. Only four patients had serious adverse effects that warranted discontinuation. There were 20 confirmed episodes of hypokalemia among 10/33 patients (30%).ConclusionKetoconazole effectively controlled hypercortisolism in 66% of Cushing’s disease patients, being a relatively safe drug for those without remission after transsphenoidal surgery or whose symptoms must be controlled until a new definitive therapy is carried out. Hypokalemia is a frequent metabolic effect not yet described in other series, which should be monitored during treatment.

IntroductionThe first-line treatment for Cushing’s disease is transsphenoidal surgery for pituitary tumor resection. Ketoconazole has been used as a second-line drug despite limited data on its safety and efficacy for this purpose. The objective of this meta-analysis was to analyze hypercortisolism control in patients who used ketoconazole as a second-line treatment after transsphenoidal surgery, in addition to other clinical and laboratory criteria that could be related to therapeutic response.MethodsWe searched for articles that evaluated ketoconazole use in Cushing’s disease after transsphenoidal surgery. The search strategies were applied to MEDLINE, EMBASE, and SciELO. Independent reviewers assessed study eligibility and quality and extracted data on hypercortisolism control and related variables such as therapeutic dose, time, and urinary cortisol levels.ResultsAfter applying the exclusion criteria, 10 articles (one prospective and nine retrospective studies, totaling 270 patients) were included for complete data analysis. We found no publication bias regarding reported biochemical control or no biochemical control (p = 0.06 and p = 0.42 respectively). Of 270 patients, biochemical control of hypercortisolism occurred in 151 (63%, 95% CI 50-74%) and no biochemical control occurred in 61 (20%, 95% CI 10-35%). According to the meta-regression, neither the final dose, treatment duration, nor initial serum cortisol levels were associated with biochemical control of hypercortisolism.ConclusionKetoconazole can be considered a safe and efficacious option for Cushing’s disease treatment after pituitary surgery.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#searchadvanced, (CRD42022308041).