Daily Endocrinology Research Analysis
Analyzed 82 papers and selected 3 impactful papers.
Summary
Analyzed 82 papers and selected 3 impactful articles.
Selected Articles
1. Tirzepatide on obstructive sleep apnea-related cardiometabolic risk: secondary outcomes of the SURMOUNT-OSA randomized trial.
Across two 52-week phase 3 RCTs in OSA with obesity, tirzepatide significantly improved cardiometabolic risk factors versus placebo. Mediation analyses showed independent contributions of changes in OSA metrics and weight loss to improvements in hsCRP, HOMA-IR, triglycerides, and systolic blood pressure, suggesting that treating both sleep-disordered breathing and obesity optimizes cardiometabolic benefit.
Impact: This work clarifies mechanistic pathways by which tirzepatide confers cardiometabolic benefits in OSA, informing integrated management beyond weight loss alone.
Clinical Implications: When treating moderate-to-severe OSA with obesity, combining weight-loss pharmacotherapy (e.g., tirzepatide) with targeted OSA therapy may yield additive cardiometabolic benefits. Clinicians should aim to address both obesity and sleep-disordered breathing to optimize risk reduction.
Key Findings
- Tirzepatide improved multiple cardiometabolic risk factors compared with placebo over 52 weeks in two phase 3 RCTs of OSA with obesity.
- Mediation analysis identified independent effects of OSA metric changes and weight loss on hsCRP, HOMA-IR, and triglycerides.
- Systolic blood pressure improvements were mediated by both weight loss and OSA metric changes, whereas diastolic blood pressure showed no significant mediation by either.
Methodological Strengths
- Prespecified analyses within two randomized, double-blind, placebo-controlled, 52-week phase 3 trials
- Robust mediation framework evaluating independent pathways (weight vs OSA metrics)
Limitations
- Secondary outcome analyses; not powered primarily for each cardiometabolic endpoint
- Mediation analyses are observational in nature and assume no unmeasured confounding between mediator and outcome
Future Directions: Test integrated care pathways combining tirzepatide with OSA-targeted therapies (e.g., CPAP, hypoglossal nerve stimulation) to confirm additive cardiometabolic benefits and hard outcomes.
Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. The SURMOUNT-OSA master protocol comprised two, 52-week, randomized, double-blind, placebo-controlled phase 3 studies (study 1 and study 2) and demonstrated a significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Here we report prespecified analysis of cardiometabolic risk measures in SURMOUNT-OSA. Post hoc analyses include chang
2. Diagnostic Yield of Genetic Testing in Children with Short Stature: a Systematic Review.
Across 134 studies, diagnostic yield varied by modality: 4.7% (candidate genes), 16.3% (CMA), 21.6% (gene panels), and 33.3% (exome sequencing), with exome sequencing reaching 50.8% in syndromic short stature versus 15.1% in isolated cases. Facial dysmorphism and skeletal abnormalities markedly increased yield; recurrently implicated genes included PTPN11, NF1, COL2A1, ACAN, and FGFR3.
Impact: Provides quantitative benchmarks for clinicians to select genetic testing strategies in pediatric short stature and identifies phenotypes with the highest diagnostic return.
Clinical Implications: Exome sequencing should be prioritized in syndromic presentations and in children with facial or skeletal dysmorphisms; targeted approaches may suffice in select isolated cases. Counseling should reflect lower yields when excluding VUS.
Key Findings
- Overall diagnostic yields: candidate gene testing 4.7%, chromosomal microarray 16.3%, gene panels 21.6%, exome sequencing 33.3%.
- Exome sequencing achieved 50.8% yield in syndromic short stature vs 15.1% in isolated short stature.
- Facial dysmorphisms (68.2%) and skeletal abnormalities (61.1%) were associated with higher diagnostic yield; recurrent genes included PTPN11, NF1, COL2A1, ACAN, FGFR3.
Methodological Strengths
- Large systematic review encompassing 134 studies with modality-stratified yields
- Re-estimation excluding VUS to assess robust diagnostic rates
Limitations
- Heterogeneity in cohort definitions and testing platforms across included studies
- Potential publication bias and variable reporting of phenotypes
Future Directions: Prospective, phenotype-stratified comparative studies of ES vs genome sequencing and integration with copy-number/structural variant and methylation profiling in short stature.
OBJECTIVE: To synthesize current evidence on genetic testing yield in children with short stature and to identify phenotypic and methodological factors influencing outcomes. The review served as a basis for the development of a consensus guideline on genetic evaluation of short stature. DESIGN: Systematic review. METHODS: Diagnostic yields were calculated by testing modality and clinical characteristics of study cohorts. Results were compared across time periods and recalculated excluding variants of u
3. Distinguishing benign from pathogenic duplications involving GPR101 and VGLL1-adjacent enhancers in the clinical setting with the bioinformatic tool POSTRE.
POSTRE, augmented with pituitary-specific enhancer maps (H3K27ac ChIP-seq, ATAC-seq, RNA-seq), correctly classified all 34 evaluated GPR101 duplications as benign or pathogenic in relation to X-LAG. A case with mild features duplicated only 2/5 VGLL1 enhancers, suggesting partial enhancer hijacking can modulate phenotype. The tool offers clinically actionable predictions without chromatin conformation assays.
Impact: Introduces a validated, tissue-informed regulatory genomics tool that resolves ambiguous SV interpretations in pituitary disease, reducing diagnostic uncertainty and guiding counseling.
Clinical Implications: For suspected X-LAG and related pituitary overgrowth conditions, integrating POSTRE analysis can triage duplications for pathogenicity, potentially informing prenatal counseling and avoiding unnecessary interventions.
Key Findings
- POSTRE correctly classified 27 known X-LAG-associated GPR101 duplications as pathogenic and 7 duplications as benign.
- Pituitary enhancer maps enabled accurate prediction of enhancer hijacking and regulatory impact without 3D conformation assays.
- An atypical mild X-LAG case duplicated only 2/5 VGLL1 enhancers, suggesting partial enhancer hijacking may attenuate phenotype.
Methodological Strengths
- Integration of tissue-specific enhancer maps (H3K27ac ChIP-seq, ATAC-seq, RNA-seq) into SV impact prediction
- Benchmarking against 34 clinically ascertained duplications with complete classification accuracy
Limitations
- Validation focused on GPR101/VGLL1 locus; generalizability to other loci and tissues requires further study
- Functional wet-lab confirmation was not performed for each novel classification
Future Directions: Prospective clinical evaluation of POSTRE-guided decision-making and expansion to genome-wide SV interpretation across endocrine tissues.
Structural variants (SVs) that disrupt topologically associating domains can cause disease by rewiring enhancer-promoter interactions. Duplications involving GPR101 are known to cause X-linked acrogigantism (X-LAG) through ectopic GPR101 expression, but not all of these duplications are pathogenic. This presents a diagnostic challenge, especially in the prenatal setting. We evaluated POSTRE, a tool that predicts the regulatory impact of SVs, to distinguish pathogenic from benign GPR101 duplicat