Evaluation of the effectiveness of combination therapy with somatostatin analogues and D2-dopamine receptor agonists in the treatment of persistent or recurrent course of Cushing’s disease

Background. Cushing’s disease (CD) is a severe neuroendocrine pathology caused by adrenocorticotropic hormone (ACTH) hypersecretion by a pituitary tumor. Modern methods of treating CD include neurosurgical intervention, radiation and drug therapy. Drug therapy is an alternative treatment option for persistent or relapsing disease. With CD, the most pathogenetically justified drugs that act on corticotropinoma are somatostatin analogues (pasireotide) and D2-dopamine receptor agonists (cabergoline). Combination therapy is a valuable and understudied treatment option for CD. Objective. Improvement and optimization of the tactics of choosing drug therapy for patients with persistent or recurrent CD. Methods. The work was performed according to the design of an interventional study. The study involved 51 patients with confirmed CD in the active stage of persistent and relapsing course, with indications for the appointment of drug therapy with drugs of the central type of action. By random number method, all patients were divided into 3 comparable groups of 18, 18 and 15 persons, respectively. The first group was prescribed pasireotide (1.2 mg/day), the second - cabergoline (2.0 mg per week), the third - their combination (0.6 mg/day and 1.0 mg per week). The patients were followed-up for 6 months. Assessment of laboratory and instrumental indicators of the activity of endogenous hypercortisolism, as well as the presence of adverse events, was carried out at the beginning of the study and 6 months after the start of therapy. Results. Statistically significant results of therapy efficacy were obtained in the pasireotide monotherapy group in terms of the dynamics of a decrease in the salivary cortisol at 23:00 (P=0.004), blood cortisol (P=0.03) and ACTH (P=0.03) levels. When assessing the decrease in the urinary free cortisol (UFC) level, there was no significant difference in this group (P=0.07). There was a statistically significant decrease in the levels of UFC (P=0.03) and salivary cortisol at 23:00 (p=0.05) in the combination therapy group without a significant decrease in ACTH (p=0.325) and blood cortisol (p=0.135) levels. In the cabergoline group, there was no significant decrease in the ACTH (p=0.468), blood cortisol (p=0.367) and urine cortisol (p=0.226) levels. Normalization of the UFC level in the pasireotide group reached 30%, in the cabergoline group - 22%, in combination therapy - 67% of patients. When assessing adverse events, statistically significant differences were noted in the occurrence of newly diagnosed diabetes mellitus (P=0.0007), hyperglycemia (P=0.0000001), cholelithiasis (P=0.004), bradycardia (P=0.001) in the pasireotide group. Orthostatic hypotension (P=0.003) was more common in the cabergoline group. In the combination therapy group, diabetes mellitus (P=0.003) and hyperglycemia (P=0.000002) occurred statistically significantly more frequently. Gallstone disease (GSD) occurred more frequently in the pasireotide group (44.44%; 8) compared with cabergoline group (0.00% 0; P=0.009); in the combination therapy group, GSD occurred in 26.67% (4) of patients and did not reach statistical significance compared to cabergoline group (p=0.07). Conclusion. When analyzing the effectiveness of various options for drug therapy in patients with CD, the advantage of using somatostatin analogues both in the form of monotherapy and combination therapy was demonstrated. The rationality of prescribing combination therapy was confirmed due to comparable efficacy with greater safety in the treatment of CD with an extension of the terms of use.

Cushing's disease, endogenous hypercortisolism, drug therapy, somatostatin analogs, D2-dopamine receptor agonists