Daily Endocrinology Research Analysis

BACKGROUND: Evidence suggests that incretin-based dual agonist pharmacotherapy is helpful in persons with obesity. Mazdutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, may have efficacy in persons with overweight or obesity. METHODS: In a phase 3, double-blind, placebo-controlled trial in China, we randomly assigned, in a 1:1:1 ratio, adults 18 to 75 years of age who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 28 or had a BMI of 24 to less than 28 plus at least one weight-related coexisting condition to receive 4 mg of mazdutide, 6 mg of mazdutide, or placebo for 48 weeks. The two primary end points were the percentage change in body weight from baseline and a weight reduction of at least 5% at week 32, as assessed in a treatment-policy estimand analysis (which assessed effects regardless of early discontinuation of mazdutide or placebo and the initiation of new antiobesity therapies).

OBJECTIVE: Baricitinib preserves β-cell function in people with recently diagnosed type 1 diabetes. We aimed to determine whether simple routine clinical measures could be used to assess β-cell preservation and predict treatment response. RESEARCH DESIGNS AND METHOD: Measures of β-cell function derived from clinical and biochemical measures were calculated using data from the BAricitinib in Newly DIagnosed Type 1 diabetes (BANDIT) randomized trial of baricitinib in recent-onset type 1 diabetes. Measures that reported and predicted treatment efficacy were determined using linear regression and receiver operator characteristic analysis, respectively. Therapeutic predictors were validated using data from trials of rituximab, abatacept, and antithymocyte globulin. RESULTS: Quantitative response score (QRS), fasting C-peptide, and model-estimated C-peptide (CPest) most reliably differentiated placebo-treated from baricitinib-treated participants at 24 and 48 weeks. The Beta2 score, derived from fasting glucose, C-peptide, HbA1c, and insulin dose at 12 weeks, was optimal for predicting QRS >0 following 1 year of treatment with baricitinib and the other immunotherapies (areas under receiver operator curve 0.864 and 0.765, respectively). A 6.2% decrease in the Beta2 score at week 12 predicted significant improvement in HbA1c (-0.6% or -6 mmol/mol) and insulin use (-0.26 units/kg/day) in combined data from the rituximab, abatacept, and antithymocyte globulin trials. CONCLUSIONS: QRS, fasting C-peptide, and CPest could be used as more efficient, less burdensome primary outcome measures for future immunotherapy trials. The ability of the Beta2 score to predict treatment responses could facilitate adaptive trial designs and help guide treatment decisions in the clinic.

CONTEXT: The ubiquitin-specific protease 8 (USP8) gene mutations are the most common driver changes in Cushing disease (CD). However, few studies have investigated the association between USP8 mutation and recurrence, and the results have been inconclusive. OBJECTIVE: To identify the predictors of recurrence and evaluate the prognostic role of USP8 mutation. METHODS: One hundred and seven patients with pathologically confirmed corticotroph adenomas were included. Somatic USP8 mutations were identified using Sanger sequencing. Recurrence predictors were estimated using multivariate Cox models, followed by receiver operating characteristic curves and Kaplan-Meier analysis. RESULTS: Thirteen patients (12.6%) experienced recurrence, with a mean follow-up period of 65 months after surgery. The recurrence rate was significantly higher in USP8-mutated tumors than in USP8 wildtype tumors (26.5% vs 5.8%; P = .009). Multivariate Cox models revealed that USP8 mutation, high postsurgical morning serum cortisol (MSC), and high 1-mg dexamethasone suppression test (DST) were associated with an increased 5-year recurrence risk. Furthermore, Kaplan-Meier survival analysis showed that patients with USP8 mutation, combined with either high postsurgical MSC (>2.5 μg/dL) or high 1-mg DST (>0.78 μg/dL), were more prone to recurrence (log-rank P < .001). The negative predictive values were 98% and 100%, while the positive predictive values improved from 33% to 55% and from 47% to 86%, respectively. CONCLUSION: Our study corroborates USP8 mutational status in combination with postsurgical MSC or 1-mg DST as independent predictors of long-term remission, highlighting their potential role in stratifying patients at risk for suboptimal outcomes.