Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial in Cushing's disease.

PURPOSE: Cushing's disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specific manifestations of hypercortisolism during osilodrostat (potent oral 11ß-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC). METHODS: LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2 mg bid; maximum: 30 mg bid) that enrolled 137 adults with Cushing's disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138 nmol/24 h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughout the study. RESULTS: At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control. CONCLUSIONS: Improvements in clinical signs and additional specific manifestations of hypercortisolism associated with Cushing's disease occurred alongside decreases in mUFC. Trial registration NCT02180217 (first posted July 2014).

A systematic literature review to evaluate extended dosing intervals in the pharmacological management of acromegaly.

PURPOSE: This systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness. METHODS: MEDLINE/Embase/the Cochrane Library (2001-June 2021) and key congresses (2018-2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required. RESULTS: In total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens. CONCLUSIONS: Clinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results.

PURPOSE: Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. METHODS: CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. RESULTS: Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. CONCLUSIONS: OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

Echocardiographic findings in acromegaly: prevalence of concentric left ventricular remodeling in a large single-center cohort.

PURPOSE: Acromegaly is a rare disease and is associated with increased cardiovascular (CV) morbidity and mortality, especially in patients with uncontrolled disease. We aimed to analyze the prevalence and severity of cardiomyopathy and valvular heart disease in a large cohort of patients with a confirmed acromegaly diagnosis, at baseline and after treatment. METHODS: We retrospectively reviewed an institutional approved database; 190 patients with confirmed acromegaly and follow-up data available (years 2006-2018). Patients with at least one baseline echocardiogram, were included. Demographic, disease control and echocardiogram variables were collected for analysis. RESULTS: Of the 190 patients 110 (58%) had a baseline echocardiogram and 43 (39.1%) had at least one follow-up echocardiogram after surgical, medical or multimodal treatment. Baseline left ventricular hypertrophy (LVH) prevalence was 17.8% (64.7% concentric; 35.3% eccentric), diastolic and systolic dysfunction, and overt cardiomyopathy with heart failure were 15.8, 7.9, and 3.0%, respectively. Concentric remodeling of the left ventricle (LV) was noted in 31.4% of patients without LVH. Valve defects were found in 87.3% of patients (14.6% with significant valvular heart disease). CONCLUSION: Early diagnosis of acromegaly and disease control should be attempted to prevent LVH/LV dysfunction and development of valvular heart disease. Concentric LV remodeling develops prior to obvious LV hypertrophy in almost a third of patients with acromegaly, which is a novel finding. Similar to other epidemiological studies, we found a high prevalence of LVH/LV dysfunction. Although possible, reversal of systolic and diastolic dysfunction is sporadic after treatment of acromegaly.

STEREOTACTIC RADIATION THERAPY IN PITUITARY ADENOMAS, IS IT BETTER THAN CONVENTIONAL RADIATION THERAPY?

Pituitary radiotherapy (RT) has undergone important progress in the last decades due to the development of new stereotactic techniques which provide more precise tumour targeting with less overall radiation received by the adjacent brain structures. Pituitary surgery is usually first-line therapy in most patients with nonfunctioning (NFPA) and functioning adenomas (except for prolactinomas and large growth hormone (GH) secreting adenomas), while RT is used as second or third-line therapy. The benefits of RT (tumour volume control and, in functional tumours, decreased hormonal secretion) are hampered by the long latency of the effect and the potential side effects. This review presents the updates in the efficacy and safety of the new stereotactic radiation techniques in patients with NFPA, GH-, ACTH- or PRL-secreting pituitary adenomas. METHODS: A systematic review was performed using PubMed and articles/abstracts and reviews detailing RT in pituitary adenomas from 2000 to 2017 were included. RESULTS: Stereotactic radiosurgery (SRS) and fractionated stereotactic RT (FSRT) provide high rates of tumour control i.e. stable or decrease in tumour size, in all types of pituitary adenomas (median 92 - 98%) at 5 years. Endocrinological remission is however significantly lower: 44-52% in acromegaly, 54-64% in Cushing's disease and around 30% in prolactinomas at 5 years. The rate of new hypopituitarism varies from 10% to 50% at 5 years in all tumour types and as expected increases with the duration of follow-up (FU). The risk for other radiation-induced complications is usually low (0-5% for new visual deficits, cranial nerves damage or brain radionecrosis and extremely low for secondary brain tumours), however longer FU is needed to determine rates of secondary tumours. Notably, in acromegaly, there may be a higher risk for stroke with FSRT. CONCLUSION: Stereotactic radiotherapy can be an effective treatment option for patients with persistent or recurrent pituitary adenomas after unsuccessful surgery (especially if residual tumour is enlarging) and/or resistance or unavailability of medical therapy. Comparison with conventional radiation therapy (CRT) is rather difficult, due to the substantial heterogeneity of the studies. In order to evaluate the potential brain-sparing effect of the new stereotactic techniques, suggested by the current data, long-term studies evaluating secondary morbidity and mortality are needed.

Extended treatment of Cushing's disease with pasireotide: results from a 2-year, Phase II study.

In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 µg sc bid reduced urinary free cortisol (UFC) levels in 76% of patients and normalized UFC in 17%. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56% of the 18 patients had lower UFC than at core baseline and 22% had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease.

Pasireotide versus octreotide in acromegaly: a head-to-head superiority study.

CONTEXT: Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control. OBJECTIVE: Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly. DESIGN AND SETTING: We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries. PATIENTS: A total of 358 patients with medically naive acromegaly (GH >5 µg/L or GH nadir ≥1 µg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging. INTERVENTIONS: Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5µg/L and/or IGF-1 was above the upper limit of normal. MAIN OUTCOME MEASURE: The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 µg/L and normal IGF-1) at month 12. RESULTS: Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 µg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%). CONCLUSIONS: Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.

Failure of successful renal transplant to produce appropriate levels of 1,25-dihydroxyvitamin D.

INTRODUCTION: Bone metabolism disturbances following renal transplantation (RT) are complex and multifactorial in origin. Abnormalities in 1,25-dihydroxyvitamin D levels in RT patients under treatment at our Bone Center prompted this retrospective study. METHODS: Parameters of vitamin D metabolism were compared in RT patients and a cohort of patients with primary hyperparathyroidism (PHTP) who mimicked the hyperparathyroid state of the RT patients. Thirty-one RT recipients (from 300 reviewed) matched our inclusion criteria with a stable graft function for more than 1 year and a glomerular filtration rate (GFR) >50 mL/min per 1.73 m(2) (Group A); these were compared with 42 consecutive patients with PHTP who had been referred to the same Bone Center for treatment for over 1 month (Group B). Statistical analysis included the chi-square or Fisher's exact tests for categorical data and the Wilcoxon rank sum test for quantitative measures. RESULTS: The mean (+/-SD) 1,25-dihydroxyvitamin D level was significantly lower (p < 0.001) in Group A patients (29.8 +/- 16.2) than in Group B patients (70.2 +/- 25.9) despite non-significant differences in the levels of parathyroid hormone (PTH) (mean: 184.0 vs.101.1;p < 0.29), phosphorus (mean: 3.2 vs. 3.1; p < 0.3) and 1,25-vitamin D (mean: 19.5 vs. 25.2; p < 0.06). Group A patients had lower levels (p < 0.05) of mean serum calcium and calculated GFR (9.3 mg/dL, 65.7 mL/min) than Group B patients (10.6 mg/dL, 97.6 mL/min). 1,25-Dihydroxyvitamin D significantly correlated with calcium (p < 0.001), 25-vitamin D (p < 0.005) and GFR (p < 0.001) in both groups, but there was a notable lack of association between 1,25-dihydroxyvitamin D and PTH (p < 0.64) or phosphorus (p < 0.26) in Group A patients. In this group, 1,25-dihydroxyvitamin D was not influenced by the type of immunosuppresion regimen (p < 0.06), use of biphosphonates (p < 0.73), presence of diabetes (p < 0.59), menopause in women (p < 0.08), season (p < 0.43) or race (p < 0.31). Our data indicate that 1,25-dihydroxyvitamin D metabolism remains disturbed for a considerable time after successful RT, with the result that the level of 1,25-dihydroxyvitamin D in RT patients is lower despite physiological signals that should stimulate its production. Our analysis of many clinical variables was unable to elucidate the underlying mechanism(s) for this disturbance. CONCLUSION: Successful RT may not produce appropriate levels of 1,25-dihydroxyvitamin D commensurate to the elevated levels of PTH. This abnormality along with sustained hyperparathyroidism may contribute to bone loss following transplantation.