Daily Endocrinology Research Analysis
Analyzed 72 papers and selected 3 impactful papers.
Summary
Analyzed 72 papers and selected 3 impactful articles.
Selected Articles
1. Head-to-head comparison between vibration-controlled transient elastography and histology in predicting liver-related events due to metabolic dysfunction-associated steatotic liver disease.
In 3,532 MASLD patients undergoing both LSM and biopsy, transient elastography achieved prognostic performance for liver-related events equivalent to histology over a median 56.6 months. Comparable AUROCs, Brier scores, and precision-recall metrics support LSM as a non-invasive surrogate endpoint in trials and longitudinal care.
Impact: Demonstrating equivalence of a non-invasive test to histology for outcome prediction can reduce biopsy reliance and accelerate therapeutic trials. This large, event-adjudicated, multicenter analysis sets a benchmark for MASLD prognostication.
Clinical Implications: LSM by VCTE can be used to stratify MASLD patients for decompensation risk and may serve as a surrogate endpoint, streamlining monitoring and trial enrollment without biopsy. Threshold optimization and integration with other non-invasive markers can refine risk models.
Key Findings
- LSM and histology showed nearly identical 5-year AUROC for liver-related events (0.870 vs 0.869).
- Integrated Brier scores (1.389% vs 1.391%) and precision-recall metrics were similar between LSM and histology.
- Findings were consistent across outcomes (decompensation, HCC), time-points, and sensitivity analyses in a 56.6-month median follow-up.
- One-third of the cohort had advanced fibrosis (F3–F4), yet LSM maintained prognostic accuracy.
Methodological Strengths
- Large multicenter cohort (n=3,532) with paired LSM and biopsy at baseline.
- Robust prognostic benchmarking using AUROC, integrated AUROC, precision-recall, and Brier scores with sensitivity analyses.
Limitations
- Observational design with potential residual confounding and biopsy sampling variability.
- Relatively low event rate (3.6%) may limit precision of subgroup analyses.
Future Directions: Define clinically actionable LSM thresholds across MASLD stages; validate LSM as a surrogate endpoint in interventional trials; evaluate cost-effectiveness and integration with serum fibrosis panels and imaging.
2. CADD-engineered peptide protacs efficiently target PCSK9 for hypercholesterolemia in vivo.
A CADD-designed peptide degrader (Cadd4) achieved intracellular PCSK9 degradation, increased LDLR, and reduced LDL-C by 29% in hypercholesterolemic mice, with liver-selective biodistribution and supportive ex vivo effects in human liver tissue. Compared with a clinical-stage PCSK9 inhibitor, Cadd4 showed greater lipid-lowering and durability, illustrating the therapeutic potential of peptide-based targeted protein degradation.
Impact: Introduces a first-in-class peptide degrader strategy against intracellular PCSK9, addressing limitations of antibodies and gene editing while demonstrating robust in vivo efficacy and tissue selectivity.
Clinical Implications: If translated, Cadd4-like agents could offer durable LDL-C lowering with liver-selective action, potentially improving access and safety versus biologics. IND-enabling studies should assess pharmacokinetics, immunogenicity, and long‑term safety.
Key Findings
- Cadd4 degraded intracellular PCSK9, increased LDLR expression, and reduced hepatic PCSK9 by 38%.
- In HFD-fed mice, total cholesterol decreased by 25% and LDL-C by 29% with liver-specific biodistribution and no systemic toxicity.
- Ex vivo human liver tissue studies confirmed PCSK9 degradation and LDLR restoration.
- Cadd4 demonstrated superior lipid-lowering efficacy and longer duration versus AZD0780.
Methodological Strengths
- Rational design with CADD and molecular docking, followed by multi-system validation (cells, mice, human liver tissue).
- Biodistribution and toxicity profiling demonstrated liver selectivity and safety; active comparator used.
Limitations
- Preclinical study; human pharmacokinetics, immunogenicity, and long-term safety remain unknown.
- Efficacy demonstrated in diet-induced models; performance in genetic dyslipidemias and comorbid states needs evaluation.
Future Directions: Advance to GLP toxicology and IND-enabling studies; optimize peptide stability and delivery; assess combination with statins/ezetimibe; evaluate efficacy in diverse dyslipidemia phenotypes.
3. Comprehensive risk factor control and its biomarker-mediated association with diabetic microvascular complications.
In 11,083 UK Biobank participants with early-stage T2D, optimal control of ≥6 modifiable risk factors halved the risk of microvascular complications and extended complication-free survival by 5.5 years. Mediation by inflammatory, hepatic, and metabolic biomarkers suggests biological pathways linking comprehensive control to outcomes.
Impact: Quantifies the benefit of comprehensive risk management in early T2D with clinically meaningful effect sizes and elucidates biomarker pathways, supporting integrated care models and measurable targets.
Clinical Implications: Prioritize multi-factor risk control (blood pressure, adiposity, lipids, HbA1c, lifestyle, etc.) early in T2D to reduce microvascular events and prolong complication-free years; track inflammatory and metabolic biomarkers to monitor pathway engagement.
Key Findings
- Optimal control of ≥6 modifiable risk factors was associated with HR 0.55 (95% CI 0.41–0.76) for diabetic microvascular complications.
- Complication-free survival from age 45 was extended by 5.51 years (95% CI 3.10–7.91) with optimal control.
- Inflammatory, hepatic, and metabolic biomarkers mediated 1.79%–30.31% of the association between control and outcomes.
- Findings arise from a large prospective cohort (n=11,083) with median 11.26 years of follow-up.
Methodological Strengths
- Large prospective cohort with long follow-up and adjudicated outcomes.
- Mediation analysis identifying biological pathways through multiple biomarker classes.
Limitations
- Observational design susceptible to residual confounding and healthy volunteer bias of UK Biobank.
- Operationalization of ‘optimal control’ and single-timepoint measurements may not capture longitudinal variability.
Future Directions: Randomized trials of integrated, biomarker-guided multifactorial interventions; evaluation of scalable care pathways and digital tools to achieve ≥6-factor control; external validation in diverse populations.