Daily Endocrinology Research Analysis
A prespecified analysis of the SELECT trial shows semaglutide reduces cardiovascular events across adiposity strata, with only partial mediation by waist reduction, implying benefits beyond weight loss. Large multicenter data link acromegaly treatment to improvements and possible remission of hypertension, while rare MECP2 variants in boys expand the genetic architecture of central precocious puberty.
Summary
A prespecified analysis of the SELECT trial shows semaglutide reduces cardiovascular events across adiposity strata, with only partial mediation by waist reduction, implying benefits beyond weight loss. Large multicenter data link acromegaly treatment to improvements and possible remission of hypertension, while rare MECP2 variants in boys expand the genetic architecture of central precocious puberty.
Research Themes
- Cardiometabolic therapeutics beyond weight loss
- Pituitary disease and cardiovascular comorbidity
- Genetic and epigenetic regulation of pubertal timing
Selected Articles
1. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial.
In 17,604 overweight/obese patients with cardiovascular disease but without diabetes, semaglutide reduced MACE consistently across baseline bodyweight and waist categories. Reductions in waist circumference—especially by weeks 20 and 104—partly mediated benefit (about 33%), whereas weight loss per se showed no linear association, implying mechanisms beyond adiposity.
Impact: This analysis clarifies that semaglutide’s cardiovascular protection extends beyond weight loss, refining mechanistic understanding and informing patient counseling and endpoints in obesity cardiometabolic trials.
Clinical Implications: Use semaglutide for secondary cardiovascular prevention in appropriate overweight/obese patients irrespective of baseline adiposity or early weight change; measure waist circumference and communicate that benefits are not solely weight-dependent.
Key Findings
- Semaglutide reduced MACE across all baseline bodyweight and waist circumference categories in 17,604 patients.
- Lower baseline bodyweight and waist circumference were associated with lower MACE risk in the semaglutide arm (HR 0.96 per 5 kg and 0.96 per 5 cm).
- Waist circumference reduction at week 20 and by week 104 correlated with lower subsequent/in-trial MACE; ~33% of benefit was mediated via waist reduction.
- In placebo, weight loss was paradoxically associated with increased MACE risk; baseline waist, but not weight, associated with risk.
Methodological Strengths
- Prespecified analysis within a large randomized, placebo-controlled outcomes trial
- Robust statistical modeling including mediation and time-varying covariates across multiple adiposity measures
Limitations
- Secondary (prespecified) analysis cannot establish causality of mediators
- Industry funding (Novo Nordisk) and limited detail on full follow-up duration in the abstract
Future Directions: Elucidate weight-independent mechanisms (e.g., inflammation, endothelial function), validate waist-mediated effects prospectively, and explore imaging or biomarker endpoints beyond anthropometry.
2. LC-MS/MS techniques for the analysis of steroid panel in human cerebrospinal fluid.
Validated complementary LC-MS/MS workflows—with and without derivatization—enable broad quantification of unconjugated C18/C19/C21 steroids in CSF, with improved sensitivity for pregnenolone-related analytes using derivatization. In CSF from normal pressure hydrocephalus patients, several androgens were below LLOQ, 17-hydroxypregnenolone and 11-deoxycortisol were quantified for the first time, and men showed higher CSF testosterone and 17-hydroxyprogesterone than women.
Impact: Provides a rigorously validated CSF steroidomic platform that expands measurable neurosteroids, enabling mechanistic neuroendocrine studies and potential biomarker development.
Clinical Implications: Standardized CSF steroid panels can support research on neuroendocrine disorders and may inform future diagnostics; sex differences in CSF androgens warrant consideration in study design.
Key Findings
- Developed and validated LC-MS/MS methods with and without derivatization for broad CSF steroid panels (C18, C19, C21).
- Derivatization improved sensitivity for pregnenolone, 17-hydroxypregnenolone, and DHEA compared with non-derivatized assays.
- In NPH CSF, several androgens were below LLOQ; 17-hydroxypregnenolone and 11-deoxycortisol were quantified for the first time.
- Men with NPH had higher CSF testosterone and 17-hydroxyprogesterone than women.
Methodological Strengths
- Comprehensive validation across multiple steroid classes and two complementary workflows
- Application to clinical CSF samples demonstrating feasibility and novel quantitations
Limitations
- Clinical sample analyses limited to NPH patients; generalizability to other populations is uncertain
- Absolute sample sizes for clinical CSF analyses not detailed in the abstract
Future Directions: Extend panels to conjugated steroids, validate across neurological/endocrine conditions, and define reference ranges with larger, sex-stratified cohorts.
3. Prevalence and evolution of hypertension in a large Iberian cohort of patients with acromegaly.
In a 434-patient multicenter cohort, nearly half of acromegaly patients had hypertension at diagnosis. Blood pressure improved 3 months after pituitary surgery, and over 8.4 years, 14.1% of hypertensive patients achieved remission—more likely with fewer antihypertensives, higher baseline IGF-1, and greater postoperative GH/IGF-1 reduction.
Impact: Quantifies the trajectory of hypertension in acromegaly and identifies endocrine and therapeutic predictors of remission, informing integrated cardiometabolic care.
Clinical Implications: Screen for hypertension at diagnosis, anticipate BP reductions after surgery, and recognize that tighter biochemical control (GH/IGF-1 reduction) and minimizing antihypertensive burden may favor remission.
Key Findings
- Hypertension prevalence at acromegaly diagnosis was 48.2% (209/434).
- BP improved 3 months post-pituitary surgery (ΔSBP −5.0 mmHg; ΔDBP −2.2 mmHg).
- Over median 8.4 years, 16% of initially normotensive patients developed hypertension; 14.1% of hypertensive patients achieved remission.
- Hypertension remission associated with fewer antihypertensives, higher baseline IGF-1, and larger postoperative GH/IGF-1 reductions.
Methodological Strengths
- Large multicenter cohort across 25 tertiary hospitals with long follow-up
- Clinically meaningful endpoints (BP change, hypertension remission/incidence) and endocrine predictors
Limitations
- Retrospective design with potential confounding and treatment changes over time
- CI reporting in abstract suggests ordering issues; detailed BP measurement protocols not described
Future Directions: Prospective studies to confirm remission predictors, evaluate antihypertensive de-escalation strategies post-surgery, and define BP targets aligned with biochemical control.