The treatment with pasireotide in Cushing’s disease: effect of long-term treatment on clinical picture and metabolic profile and management of adverse events in the experience of a single center

Abstract

Purposes Pasireotide is the first medical therapy officially approved for adult patients with Cushing's disease (CD) experiencing failure of pituitary surgery or not candidates for surgery. The current study aimed at investigating pasireotide effects on clinical picture and metabolic profile in patients enrolled in the phase III CSOM230B2305 trial at Naples center. In addition, the current study focused on safety issues encountered during the study, detailing the management of the different adverse events associated with the treatment with pasireotide in Naples center. Methods Fourteen patients entered the study; eight patients, receiving pasireotide for at least 6 months, were considered for the efficacy analysis, whereas the entire cohort of 14 patients was considered for the safety analysis. Results Full or partial disease control was obtained in 85.7% of patients, according to a "per-protocol" methodology analysis, and in 42.9% of patients, according to an "intention-to-treat" methodology analysis, after 12 months of treatment. A relevant improvement in clinical signs and symptoms, mainly in facial rubor, supraclavicular fat pad, bruising, hirsutism, and muscle strength was observed; body weight, body mass index, and waist circumference significantly reduced, and a slight non-significant reduction was observed in the prevalence of visceral obesity, hypercholesterolemia, and hypertriglyceridemia. Deterioration of glucose metabolism represented the most common adverse event, occurring in 71.4% of patients, and requiring a dietary regimen as first step, metformin therapy and/or long-acting insulin as second step, and short-acting insulin, as third step; no patients discontinued treatment for hyperglycaemia. Additional adverse events of interest were nausea (21.4%), and vomiting (14.3%), spontaneously resolved in few weeks or some months, except in one patient unsuccessfully treated with metoclopramide and ondansetron, and diarrhoea (14.3%), improved with loperamide treatment. Millimetric gallstones and biliary sludge (7.1%) were managed with ursodeoxycholic acid, inducing lithiasis and biliary sludge resolution, whereas hypocortisolism-related adverse events (7.1%) were resolved with a reduction in the pasireotide dose. Conclusions The current study on a limited series of patients contributes to confirm that pasireotide may be considered a valid option for treatment of patients with CD, although it requires an appropriate management of adverse events, especially hyperglycaemia.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Novel ι-Carrageenan Tetrasaccharide Alleviates Liver Lipid Accumulation via the Bile Acid–FXR–SHP/PXR Pathway to Regulate Cholesterol Conversion and Fatty Acid Metabolism in Insulin-Resistant Mice

“…Today, drug-based therapies represent the gold standard to address abnormal lipid. However, the therapeutic approach has a major limitation, side effects, which in most cases could lead to nausea and vomiting for patients . This has encouraged scientists to search for novel routes to deal with it, and dietary intervention comes up to be a better choice.…”

“…However, the therapeutic approach has a major limitation, side effects, which in most cases could lead to nausea and vomiting for patients. 36 This has encouraged scientists to search for novel routes to deal with it, and dietary intervention comes up to be a better choice. Related to the present data, the research of galacto-oligosaccharides in treating lipid metabolic disorders has been reported widely.…”

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

“…Pasireotide, as subcutaneous injection, is formulated as three different immediate-release ampoules, containing 300, 600, and 900 µg doses, with suggestion of a maximum total daily dose of 1,800 µg. Pasireotide has been extensively evaluated in human clinical studies, leading to a large amount of evidence about its efficacy and safety in CD treatment (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). The first classical formulation of pasireotide was subcutaneously administered in a twice-daily schedule, with two doses, 600 and 900 µg.…”

“…Treatment discontinuation occurred in 84 (51.8%) patients, because of AEs in 26 (16%) and lack of efficacy in 37 (22.8%) patients (18). Following the first two main clinical trials, additional clinical studies focused on long-term response to pasireotide treatment (21)(22)(23)(24)(25)(28)(29)(30). In an extension study to 24 months of the phase II trial (clinicaltrials.gov code: NCT00171951) on 19 CD patients, considering the 18 patients included in the primary efficacy analysis, pasireotide treatment at doses ranging from 300 to 1,800 µg/day demonstrated mUC normalization in four (22.2%) patients and a reduction in mUC, defined as lower than that at core study baseline, but not within normal range, in additional six (33.3%) patients after 6 months of treatment, with a total success rate of 55.5%.…”

“…In a report on eight patients, followed-up in one of the main centers participating at the clinical trial, a tumor shrinkage >25% was observed in five (62.5%) patients after 6 months and in the totality (100%) of patients after 12 months, with a mean tumor shrinkage of 42.4 and 61.6%, respectively, and tumor mass disappearance in one (14.3%) case after 12 months of treatment ( 23 ). Regarding safety profile, the most frequently reported AEs were diarrhea (58%), nausea (51.8%), and hyperglycemia (40%), whereas serious AEs were reported in 40 (24.7%) patients, mainly represented by diabetes mellitus (3.1%), hyperglycemia (2.5%), cholelithiasis (2.5%), and adrenal insufficiency (AI) (1.2%) ( 18 , 28 ). AEs were also grouped in categories of special interest, including hyperglycemia-related AEs (73%), gallbladder-related AEs (30%), liver safety-related AEs (29%), hypocortisolism-related AEs (8%), and QT prolongation (1.8%).…”