Daily Endocrinology Research Analysis
A phase 4 randomized trial showed that an inclisiran-based strategy markedly improved LDL-C goal attainment with fewer muscle-related adverse events versus optimized conventional lipid-lowering therapy. Dual-modal photoacoustic plus ultrasound imaging improved biopsy decision-making for thyroid nodules, reducing unnecessary FNAs while maintaining high sensitivity. Mechanistic work identified genetic drivers (low renal Lrp2 and Vdr expression) of discordance between calcidiol and calcitriol, chal
Summary
A phase 4 randomized trial showed that an inclisiran-based strategy markedly improved LDL-C goal attainment with fewer muscle-related adverse events versus optimized conventional lipid-lowering therapy. Dual-modal photoacoustic plus ultrasound imaging improved biopsy decision-making for thyroid nodules, reducing unnecessary FNAs while maintaining high sensitivity. Mechanistic work identified genetic drivers (low renal Lrp2 and Vdr expression) of discordance between calcidiol and calcitriol, challenging reliance on 25(OH)D alone.
Research Themes
- Cardiometabolic therapeutics and LDL-C goal attainment
- Imaging innovation for thyroid nodule triage
- Genetic and mechanistic determinants of vitamin D metabolism
Selected Articles
1. Inclisiran-based treatment strategy in hypercholesterolaemia: the VICTORION-Difference trial.
In this phase 4 double-blind randomized trial (n=1770), an inclisiran-based strategy led to markedly higher LDL-C goal attainment at Day 90 versus individually optimized lipid-lowering therapy (84.9% vs 31.0%; OR 12.09, p<0.001). Mean LDL-C reduction through Day 360 was substantially greater with inclisiran (−59.5% vs −24.3%; LSMTD −35.14%, p<0.001), and fewer muscle-related adverse events occurred (11.9% vs 19.2%; OR 0.57, p<0.001).
Impact: This large, well-designed RCT provides high-level evidence that an inclisiran-based regimen improves LDL-C goal attainment and tolerability in high/very-high risk patients, supporting real-world adoption of siRNA-based PCSK9 inhibition.
Clinical Implications: In high or very-high ASCVD risk patients not meeting LDL-C goals with maximally tolerated statins±ezetimibe, inclisiran offers early and sustained LDL-C lowering with fewer muscle-related adverse events, enabling greater target attainment. Integration into combination regimens could simplify adherence (twice-yearly dosing) and improve patient-reported outcomes.
Key Findings
- LDL-C goal attainment at Day 90: 84.9% with inclisiran vs 31.0% with optimized therapy (OR 12.09, p<0.001).
- Mean LDL-C change through Day 360: −59.5% (inclisiran) vs −24.3% (optimized therapy), LSMTD −35.14% (p<0.001).
- Fewer muscle-related adverse events with inclisiran (11.9% vs 19.2%; OR 0.57, p<0.001); no new safety signals.
Methodological Strengths
- Phase 4 double-blind, placebo-controlled randomized design with large sample size (n=1770).
- Patient-centered outcome (LDL-C goal attainment) and sustained efficacy assessed to Day 360 with safety profiling.
Limitations
- Primary outcomes focused on lipid targets and safety, not hard cardiovascular outcomes.
- Open-label statin up-titration may introduce performance bias despite blinded inclisiran/placebo allocation.
Future Directions: Evaluate effects on cardiovascular outcomes, cost-effectiveness, and implementation strategies in diverse health systems; assess synergy in combination regimens and adherence benefits of twice-yearly dosing.
2. Smarter biopsy decisions in thyroid nodules via dual-modal photoacoustic and ultrasound imaging.
Combining photoacoustic imaging parameters (spectral gradient, oxygen saturation, and saturation skewness) with ultrasound under an SVM classifier yielded the ATA-Photoacoustic (ATAP) score. In 106 patients, the ATAP approach achieved 97% sensitivity and 38% specificity for nodules requiring FNAB and reduced unnecessary biopsies in 11/29 benign nodules.
Impact: Introduces a clinically pragmatic, dual-modal imaging workflow that improves triage of thyroid nodules, addressing a key limitation of ultrasound and reducing unnecessary FNABs.
Clinical Implications: Integrating PAI with ultrasound could refine ATA-guided biopsy decisions, particularly for indeterminate and follicular-pattern nodules, reducing patient burden, complications, and costs while maintaining high sensitivity.
Key Findings
- Three PAI-derived parameters combined with US under SVM formed the ATAP score.
- ATAP achieved 97% sensitivity and 38% specificity for identifying nodules requiring FNAB.
- Unnecessary FNABs were avoided in 11 of 29 benign nodules while maintaining diagnostic sensitivity.
Methodological Strengths
- Prospective clinical cohort with multiparametric imaging and machine learning integration.
- Inclusion of follicular neoplasms, a key diagnostic challenge for US-based triage.
Limitations
- Single-center study with modest specificity; external validation is needed.
- Cost-effectiveness, workflow integration, and inter-operator variability not assessed.
Future Directions: Multicenter prospective validation, standardized acquisition protocols, and cost-effectiveness analyses; explore integration with molecular testing and risk calculators.
3. Interindividual Genetic Differences Drive Discordance Between Serum Calcidiol and Calcitriol Concentrations in Females.
Across seven inbred mouse strains, substantial calcidiol–calcitriol discordance was observed under vitamin D sufficiency and deficiency. Under sufficiency, low-calcitriol strains lacked the expected positive calcidiol-to-calcitriol relationship and exhibited reduced renal Lrp2 (megalin) and Vdr expression with impaired vitamin D signaling, implicating genetic determinants of calcitriol production beyond 25(OH)D levels.
Impact: Reveals a mechanistic basis for calcidiol–calcitriol discordance through Lrp2/Vdr expression differences, challenging current reliance on 25(OH)D alone and informing future precision approaches to vitamin D assessment.
Clinical Implications: Findings suggest that 25(OH)D may misclassify functional vitamin D status in genetically diverse populations; future clinical studies should assess when calcitriol or proxy measures (e.g., markers of vitamin D signaling) add value, especially in individuals with suspected renal handling defects.
Key Findings
- Calcidiol–calcitriol discordance varied by mouse strain under both vitamin D sufficiency (VDS) and deficiency (VDD).
- Low-calcitriol strains under VDS lacked the expected positive calcidiol-to-calcitriol association and showed reduced renal Lrp2 and Vdr expression.
- Discordance was not explained by increased calcitriol degradation or transcriptional dysregulation of canonical vitamin D metabolism enzymes.
Methodological Strengths
- Use of genetically diverse inbred strains to dissect interindividual effects.
- Parallel evaluation under vitamin D sufficiency and deficiency with mechanistic readouts (Lrp2, Vdr, target genes).
Limitations
- Preclinical mouse study without human validation; cross-species conservation not established.
- Sample-level numbers per strain not reported; external generalizability to clinical populations is unknown.
Future Directions: Human studies to test calcidiol–calcitriol discordance predictors, including LRP2/VDR expression or function, and to define when calcitriol testing improves risk stratification or treatment decisions.