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.
BACKGROUND: The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk. METHODS: Patients aged at least 45 years, with a BMI of at least 27 kg/m FINDINGS: Semaglutide significantly reduced MACE incidence compared with placebo among 17 604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE-an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94-0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93-0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94-0·99]; p=0·007), but not bodyweight (0·99 [0·97-1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77-0·97] after adjustment for time-varying changes in waist circumference). INTERPRETATION: The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction. FUNDING: Novo Nordisk.
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.
The metabolic processes within the brain are reflected in the cerebrospinal fluid (CSF). It is in close contact with the nervous system, which is both target and source of multiple steroids. The aim of our study was to develop and validate robust, sensitive LC-MS/MS methods with and without derivatization step for the analysis of unconjugated steroids from all major steroid classes in CSF. The validation of the method without derivatization was performed for ten C19- steroids (dehydroepiandrosterone (DHEA), 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, testosterone, epitestosterone, dihydrotestosterone, 11-hydroxytestosterone, 11-ketotestosterone and androstenedione), ten C21- steroids (cortisol, 11-deoxycortisol, 21-deoxycortisol, cortisone, corticosterone, 11-deoxycorticosterone, pregnenolone, progesterone, 17-hydroxyprogesterone, aldosterone) and three C18- steroids (estrone, estradiol, estriol). The method with derivatization is validated for determination of eleven C19- steroids (testosterone, 11-ketodihydrotestosterone, 11-hydroxytestosterone, DHEA, 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, androstenedione, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone) and six C21- steroids (cortisol, cortisone, corticosterone, pregnenolone, 17-hydroxypregnenolone, progesterone) in CSF. The method without derivatization is applicable for the determination of the majority of steroids in CSF, except for pregnenolone, 17-hydroxypregnenolone and DHEA, for which the derivatization method provides better sensitivity. When analyzing CSF samples of normal pressure hydrocephalus (NPH) patients, 11-ketodihydrotestosterone, epitestosterone, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone, 7-ketoDHEA and 21-deoxycortisol were found to be below the LLOQ, suggesting that their presence is very limited. 17-hydroxypregnenolone, and 11-deoxycortisol were quantified for the first time, their CSF levels in NPH subjects are presented. We also observed significantly increased CSF levels of testosterone and 17-hydroxyprogesterone in men compared to women, both with NPH.
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.
PURPOSE: To analyze the prevalence of hypertension in patients with acromegaly and assess the impact of acromegaly treatment on blood pressure (BP) outcomes. METHODS: Retrospective multicenter study of 434 patients with acromegaly surveilled at 25 tertiary hospitals in Spain and Portugal. The cohort was divided into two subgroups: patients with (n = 209) and without (n = 225) hypertension at the time of acromegaly diagnosis. RESULTS: Of the 434 patients, 209 (48.2%) had hypertension at the time of acromegaly diagnosis. Patients with acromegaly and hypertension were older and had a higher prevalence of cardiovascular disease and risk factors. A significant BP improvement was observed 3 months after pituitary surgery, with a marked reduction of the SBP (ΔSBP - 5.0mmHg, 95%CI -2.37 to -7.61) and DBP (ΔDBP - 2.2mmHg, 95% CI -0.66 to -3.75). Over a median follow-up of 8.4 years [IQR 4.8-12.8], 16% (n = 35/218) of initially normotensive patients developed hypertension, while 14.1% (n = 27/192) of hypertensive patients achieved hypertension remission. Hypertension remission was more likely in patients taking fewer antihypertensive drugs and with higher IGF1 levels at diagnosis, and in those who had a greater decrease in GH and IGF-1 after surgery. CONCLUSION: At the time of acromegaly diagnosis up to 50% of patients have hypertension, and around 15% of them experience hypertension remission after pituitary surgery. The probability of remission is higher in patients with milder baseline hypertension and higher IGF-1 levels and in those achieving a greater postoperative decrease of GH and IGF-1.