Daily Endocrinology Research Analysis

BACKGROUND: A phase 2 trial of setmelanotide, a melanocortin-4 receptor agonist, showed substantial weight loss in patients with acquired hypothalamic obesity, but additional data are needed. METHODS: We conducted a phase 3 trial in which participants were randomly assigned in a 2:1 ratio to receive setmelanotide (at a dose of 1.5 to 3.0 mg) or placebo administered subcutaneously once daily for 52 weeks after a dose-escalation period. Persons at least 4 years of age were potentially eligible for the trial if they had acquired hypothalamic obesity, which was defined by a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) that was at or above the 95th percentile for age and sex (for participants <18 years of age) or at least 30 (for participants ≥18 years of age) and a history of a hypothalamic tumor, lesion, or injury. The primary end point was the mean percent change in BMI from baseline to 52 weeks after the end of the dose-escalation period. Secondary end points included the mean change in the weekly average of the maximal daily hunger score (range, 0 to 10, with higher scores indicating more severe hunger), assessed in participants at least 12 years of age. RESULTS: From April 26, 2023, to March 18, 2025, a total of 120 participants were assigned to receive setmelanotide (81 participants) or placebo (39 participants). The mean (±SD) age was 19.9±13.8 years (range, 4 to 66). Among participants 18 years of age or older, the mean BMI was 41.2±9.7; the mean BMI z score among those younger than 18 years of age was 3.61±1.66. The least-squares mean (LSM) change in BMI at 52 weeks was -16.5% (95% confidence interval [CI], -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001), and the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P = 0.009). Adverse events were reported in 100% of the participants in the setmelanotide group and in 90% of those in the placebo group, and serious adverse events were reported in 28% and 8%, respectively. The most common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache. CONCLUSIONS: Setmelanotide led to significantly greater reductions in BMI and hunger than placebo at 52 weeks among participants 4 to 66 years of age with acquired hypothalamic obesity. (Funded by Rhythm Pharmaceuticals; TRANSCEND ClincialTrials.gov number, NCT05774756.).

BACKGROUND: Mild autonomous cortisol secretion (MACS), the most common hormonal abnormality in adrenal incidentalomas, is associated with increased cardiometabolic risk. MACS is defined by cortisol concentrations higher than 50 nmol/L after a 1-mg overnight dexamethasone suppression test (1-mg DST). The prognostic value of a single test remains uncertain. We examined longitudinal changes in 1-mg DST results, cumulative cortisol exposure, and their associations with cardiometabolic outcomes and mortality. METHODS: In this retrospective cohort study conducted in 25 adrenal centres that are part of the European Network for the Study of Adrenal Tumours consortium across 14 countries with adults (aged ≥18 years) with benign adrenal incidentalomas diagnosed from Jan 1, 2000, to Dec 1, 2020, two or more 1-mg DSTs, and follow-up of at least 36 months, we used multivariable Cox models to assess associations between longitudinal 1-mg DST results and all-cause mortality and cardiovascular and thrombotic events. Patients with Cushing's syndrome, primary aldosteronism, phaeochromocytoma, or androgen-secreting tumour at baseline; active malignancy within 36 months of incidentaloma diagnosis; or suspicion of unreliable 1-mg DST results were excluded, along with patients taking oral glucocorticoids, strong CYP3A4 modulators, adrenal enzyme inhibitors, oral oestrogen, or selective oestrogen receptor modulators. Cumulative cortisol exposure was estimated from serial 1-mg DSTs. Restricted mean survival time (RMST) quantified differences in event-free time. Data were collected from the electronic health records of all eligible patients at each participating centre. FINDINGS: Among 2525 patients (median follow-up 80 months [IQR 49-122]), 563 (22·3%) had changes in 1-mg DST results leading to a change in diagnosis, most within 3 years of their baseline 1-mg DST. Patients with persistently abnormal 1-mg DST results (ie, MACS-to-MACS patients; n=839) were older and had a greater cardiometabolic burden than those with persistently normal results (ie, non-functioning adrenal tumours [NFAT]-to-NFAT patients; n=1103). MACS-to-MACS patients had a higher rate of worsening hypertension (adjusted hazard ratio 1·34 [95% CI 1·03-1·73]) and a shorter event-free time for worsening hypertension (10-year RMST 60·4 months [56·8-75·5] vs 86·1 months [79·1-93·4]) than NFAT-to-NFAT patients. In crude analyses, patients with higher baseline post-1-mg DST cortisol, patients with greater cumulative cortisol exposure, and MACS-to-MACS patients had shorter survival and event-free time; however, these associations were not independent of age and baseline cardiometabolic risk factors after multivariable adjustment. INTERPRETATION: Longitudinal 1-mg DST changes are common. MACS-to-MACS patients had worsening hypertension, but rates of mortality and cardiovascular or thrombotic events were not significantly associated with 1-mg DST trajectories after adjustment for age and cardiovascular risk factors. These findings identify patients with persistently abnormal 1-mg DST results as a group with high cardiometabolic risk that warrants closer attention to modifiable risk factors. Prospective studies are needed to establish the clinical significance of repeated 1-mg DSTs for risk stratification.

CONTEXT: Arginine vasopressin deficiency (AVP-D) is a well-known complication of transsphenoidal pituitary surgery (TPS) that is difficult to predict due to the lack of specific biomarkers. While oxytocin (OXT) and copeptin were previously suggested as possible biomarkers, there is, to date, no study that compared those two markers in the prediction of post-TPS AVP-D. OBJECTIVES: To compare plasma OXT and copeptin levels among patients operated by TPS presenting with AVP-D and those remaining normonatremic. To establish OXT and copeptin cutoff values for the prediction of post-TPS AVP-D. DESIGN AND PATIENTS: Both OXT and copeptin levels in the blood of 74 consecutive patients subjected to TPS were measured. OXT and copeptin values were then compared between patients developing AVP-D and patients remaining normonatremic. SETTING: Neurosurgical department of a University Hospital. MAIN OUTCOME MEASURES: Blood levels of copeptin and OXT were measured before, one day after and 3 months after TPS. RESULTS: Patients developing AVP-D showed significantly lower levels of OXT in blood, both before and immediately after TPS, and significantly lower levels of copeptin only after TPS. We identified a preoperative cutoff value for OXT of 69 pg/ml (sensitivity: 90% ; specificity: 66% ; AUC: 0.76+/-0.06 (p = 0.0089)) for the prediction of AVP-D. No such significant cutoff values were identified for preoperative copeptin. Of note, OXT, but not copeptin, levels were still significantly lower at 3 months after TPS in AVP-D patients. CONCLUSIONS: These results show for the first time that OXT is superior to copeptin for the preoperative prediction of postoperative AVP-D, acting as a preoperative marker of posterior "pituitary reserve".