Daily Endocrinology Research Analysis
A phase 3 RCT in NEJM showed that once-weekly mazdutide (a GLP-1/glucagon dual agonist) produced 11–14% mean weight loss at 48 weeks with broad cardiometabolic benefits and acceptable tolerability. In type 1 diabetes, simple clinic-based β-cell metrics (QRS, fasting C-peptide, CPest) and a 12-week Beta2 score predicted immunotherapy response across multiple trials. In Cushing disease, combining USP8 tumor mutation status with early postsurgical cortisol/DST robustly stratified 5-year recurrence
Summary
A phase 3 RCT in NEJM showed that once-weekly mazdutide (a GLP-1/glucagon dual agonist) produced 11–14% mean weight loss at 48 weeks with broad cardiometabolic benefits and acceptable tolerability. In type 1 diabetes, simple clinic-based β-cell metrics (QRS, fasting C-peptide, CPest) and a 12-week Beta2 score predicted immunotherapy response across multiple trials. In Cushing disease, combining USP8 tumor mutation status with early postsurgical cortisol/DST robustly stratified 5-year recurrence risk.
Research Themes
- Incretin-based dual agonists for obesity
- Pragmatic biomarkers and trial endpoints in recent-onset type 1 diabetes
- Genomic and biochemical predictors of recurrence in Cushing disease
Selected Articles
1. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight.
In a 48-week, phase 3, double-blind RCT (n=610), mazdutide 4 mg and 6 mg produced −11.0% and −14.0% mean weight loss at week 48 versus 0.3% with placebo and improved multiple cardiometabolic measures. Rates of ≥15% weight loss were 35.7% and 49.5% (vs 2.0% placebo); gastrointestinal events were the most common and were mostly mild–moderate.
Impact: First phase 3 evidence for a GLP-1/glucagon dual agonist demonstrating double-digit weight loss with favorable tolerability, expanding anti-obesity pharmacotherapy options.
Clinical Implications: Mazdutide could become an additional weekly pharmacologic option for adults with overweight/obesity requiring substantial weight loss and cardiometabolic risk reduction; head-to-head and long-term outcome data will guide positioning versus existing incretin therapies.
Key Findings
- At week 32, mean weight change: −10.09% (4 mg), −12.55% (6 mg), vs +0.45% (placebo); ≥5% weight loss in 73.9% and 82.0% vs 10.5% (P<0.001).
- At week 48, mean weight change: −11.00% (4 mg), −14.01% (6 mg), vs 0.30% (placebo); ≥15% weight loss in 35.7% and 49.5% vs 2.0% (P<0.001).
- Mazdutide improved prespecified cardiometabolic measures; GI adverse events were most common and mostly mild–moderate; discontinuation rates were low (1.5%, 0.5%, 1.0%).
Methodological Strengths
- Phase 3, double-blind, placebo-controlled RCT with treatment-policy estimand.
- Large sample size with two active doses and comprehensive cardiometabolic endpoints.
Limitations
- Single-country (China) population limits generalizability across ethnicities.
- No head-to-head comparison with established incretin agents; long-term safety and outcomes beyond 48 weeks unknown.
Future Directions: Head-to-head trials versus semaglutide/tirzepatide, longer-term cardiovascular and renal outcomes, NASH/NAFLD endpoints, and real-world effectiveness across diverse populations.
2. β-Cell Function Derived From Routine Clinical Measures Reports and Predicts Treatment Response to Immunotherapy in Recent-Onset Type 1 Diabetes.
Clinic-derived β-cell measures (QRS, fasting C-peptide, CPest) distinguished baricitinib from placebo at 24/48 weeks in the BANDIT RCT. A 12-week Beta2 score predicted 1-year treatment response to baricitinib and to rituximab, abatacept, and ATG, and a 6.2% Beta2 decrease predicted meaningful HbA1c and insulin-use improvements.
Impact: Provides validated, low-burden outcome and predictive markers for immunotherapy trials in recent-onset type 1 diabetes, enabling more efficient trials and personalized decisions.
Clinical Implications: QRS, fasting C-peptide, and CPest can serve as pragmatic primary outcomes; the 12-week Beta2 score can guide adaptive trial designs and early clinical decisions about continuing or switching immunotherapies.
Key Findings
- QRS, fasting C-peptide, and CPest reliably differentiated baricitinib vs placebo at 24 and 48 weeks.
- The 12-week Beta2 score predicted QRS>0 at 1 year for baricitinib (AUC 0.864) and other immunotherapies (AUC 0.765).
- A 6.2% decrease in Beta2 at week 12 predicted improvements in HbA1c (−0.6%) and insulin dose (−0.26 U/kg/day) across combined trials.
Methodological Strengths
- Use of randomized trial data with cross-trial validation across multiple immunotherapies.
- Objective, reproducible metrics with ROC-based performance assessment.
Limitations
- Secondary analyses; not prospectively implemented as decision rules in clinical practice.
- Heterogeneity among trials and populations may influence generalizability.
Future Directions: Prospective validation of Beta2-guided decision-making, integration into adaptive trial protocols, and assessment of cost-effectiveness and patient-reported outcomes.
3. The USP8 Mutational Status in Combination With Postsurgical Cortisol Levels for Predicting Recurrence of Cushing Disease.
In 107 corticotroph adenomas with mean 65-month follow-up, recurrence was higher with USP8 mutation (26.5% vs 5.8%). Combining USP8 mutation with elevated postsurgical morning cortisol (>2.5 μg/dL) or 1-mg DST (>0.78 μg/dL) markedly improved recurrence risk stratification (PPV up to 86%; NPV up to 100%).
Impact: Introduces a practical genomic–biochemical composite predictor that robustly stratifies long-term recurrence in Cushing disease, informing surveillance and adjuvant strategies.
Clinical Implications: USP8 genotyping with early postoperative MSC/DST can identify patients at high recurrence risk for intensified monitoring, earlier imaging, and consideration of adjuvant therapy; low-risk patients may avoid over-surveillance.
Key Findings
- Recurrence occurred in 12.6% overall; higher in USP8-mutated vs wildtype tumors (26.5% vs 5.8%; P=0.009).
- USP8 mutation, high postsurgical morning cortisol, and elevated 1-mg DST independently increased 5-year recurrence risk.
- Combining USP8 mutation with MSC>2.5 μg/dL or DST>0.78 μg/dL improved PPV to 55% and 86%, while NPV reached 98% and 100%.
Methodological Strengths
- Pathology-confirmed cohort with targeted genotyping and multivariate Cox modeling.
- Kaplan–Meier and ROC analyses quantified prognostic performance and predictive values.
Limitations
- Single-center retrospective cohort with moderate sample size.
- Sanger sequencing may miss non-hotspot variants; external validation needed.
Future Directions: Prospective, multi-center validation; integration into postoperative algorithms; evaluation of adjuvant therapy triggers based on composite risk.