Daily Endocrinology Research Analysis
A multicentre randomized trial shows that adrenalectomy for mild autonomous cortisol secretion (MACS) significantly improves hypertension control and reduces antihypertensive medications. A UK Biobank proteomics study identifies plasma protein signatures that stratify heterogeneous risks in MASLD independent of steatosis severity, highlighting ADM, ASGR1, FABP4, and CDHR2 as mediators. A large adaptive RCT finds crisugabalin provides rapid pain relief in diabetic peripheral neuropathic pain, wit
Summary
A multicentre randomized trial shows that adrenalectomy for mild autonomous cortisol secretion (MACS) significantly improves hypertension control and reduces antihypertensive medications. A UK Biobank proteomics study identifies plasma protein signatures that stratify heterogeneous risks in MASLD independent of steatosis severity, highlighting ADM, ASGR1, FABP4, and CDHR2 as mediators. A large adaptive RCT finds crisugabalin provides rapid pain relief in diabetic peripheral neuropathic pain, with effects evident by day 2 and earlier than pregabalin.
Research Themes
- Adrenal disorders and hypertension management
- Proteomics-driven risk stratification in metabolic liver disease
- Rapid-acting analgesic therapy for diabetic neuropathic pain
Selected Articles
1. Surgery for the treatment of arterial hypertension in patients with unilateral adrenal incidentalomas and mild autonomous cortisol secretion (CHIRACIC): a multicentre, open-label, superiority randomised controlled trial.
In this multicentre RCT of hypertensive patients with MACS and unilateral adrenal incidentalomas, adrenalectomy led to a higher proportion achieving normal home blood pressure with reduced antihypertensive therapy versus conservative care (46% vs 15%; adjusted RD 0.34; p=0.0038). The surgery group required fewer and lower-intensity medications, with supportive ABPM changes and similar rates of serious adverse events.
Impact: Provides the first randomized evidence that adrenalectomy improves hypertension management in MACS, addressing a long-standing clinical controversy.
Clinical Implications: For hypertensive patients with unilateral incidentalomas and MACS, minimally invasive adrenalectomy should be actively considered to reduce medication burden and normalize BP, with structured pre/postoperative BP assessment.
Key Findings
- Primary endpoint achieved more often with adrenalectomy: 46% vs 15% with conservative care (adjusted RD 0.34; p=0.0038).
- Fewer patients required antihypertensive therapy after surgery (43% vs 96% still on treatment at study end); mean treatment step was markedly lower (−2.05).
- 24-hour ABPM improvements paralleled HBPM findings; serious adverse events were similar between groups, with three surgery-related events.
Methodological Strengths
- Randomised, multicentre design with standardized stepped-care antihypertensive protocol and rigorous HBPM/ABPM endpoints.
- Intention-to-treat analysis with stratified blocked randomisation and 13-month follow-up.
Limitations
- Open-label design may introduce performance bias.
- Modest sample size after run-in and limited to 13 months; generalizability beyond trial criteria requires caution.
Future Directions: Assess long-term cardiovascular outcomes, metabolic effects (e.g., diabetes risk), and cost-effectiveness of surgical versus medical management in MACS.
BACKGROUND: Adrenal incidentalomas are found in 3-10% of adults undergoing abdominal imaging. Of these, 30-50% are responsible for mild autonomous cortisol secretion (MACS), which is frequently associated with hypertension. The impact of adrenalectomy on hypertension in patients with unilateral incidentalomas and MACS remains uncertain. The aim of the CHIRACIC study was to prospectively assess the impact of surgical excision of the incidentaloma on blood pressure with a randomised trial combining accurate blood pressure measurement and standardisation of antihypertensive treatment. METHODS: CHIRACIC was a multicentre, superiority, open-label, parallel, randomised controlled trial performed at 17 university hospitals in France, Italy, and Germany. Adults with hypertension with MACS entered a run-in phase to confirm hypertension with multiple home blood pressure measurements (HBPM) before blood pressure was normalised with standardised stepped-care antihypertensive treatment. Eligible participants were then randomly assigned (1:1) to adrenalectomy or conservative management. Randomisation was blocked (random block size of 4 and 6) and stratified by intensity of antihypertensive treatment. Participants were followed up for 13 months and systematic attempts were made to gradually reduce antihypertensive treatment. The primary endpoint was the proportion of normotensive participants using HBPM who reduced their antihypertensive treatment in the intention-to-treat population at study completion. Key secondary endpoints included 24 h ambulatory blood pressure measurement (ABPM), mean change in antihypertensive treatment, and the proportion of participants with antihypertensive treatment at study completion.
2. Proteomic variation underlies the heterogeneous risk of metabolic dysfunction-associated steatotic liver disease for subsequent chronic diseases.
In 42,508 UK Biobank participants with MASLD, a plasma proteomic signature derived from 2,911 proteins predicted higher risks of liver fibrosis, CVD, CKD, CRD, and depression (adjusted HRs 1.30–4.94). Risk stratification by the signature remained largely independent of steatosis severity and cardiometabolic factors, and mediation analyses highlighted ADM, ASGR1, FABP4 (common mediators) and CDHR2 (fibrosis-specific).
Impact: Introduces a proteome-based risk signature that explains MASLD heterogeneity across multiple organ systems and pinpoints candidate mediators and therapeutic targets.
Clinical Implications: Proteomic profiling may enhance risk stratification beyond steatosis severity, identifying MASLD patients who need intensified surveillance for fibrosis, CVD, CKD, and CRD, and informing biomarker-driven interventions targeting ADM/ASGR1/FABP4 or CDHR2 pathways.
Key Findings
- Proteomic signature associated with higher risks of liver fibrosis, CVD, CKD, CRD, and depression in MASLD (adjusted HRs 1.30–4.94).
- Risk gradients by signature persisted after adjusting for steatosis degree and cardiometabolic risk factors (except depression).
- Mediation implicated ADM, ASGR1, FABP4 as common mediators; CDHR2 was fibrosis-specific.
Methodological Strengths
- Large prospective cohort (N=42,508) with broad plasma proteomics (2,911 proteins) and multiorgan outcomes.
- Robust statistical approach including Cox models, adjusted survival curves, and mediation analyses with adjustment for steatosis and cardiometabolic factors.
Limitations
- Steatosis defined by fatty liver index, not imaging/biopsy; potential misclassification.
- Observational design limits causal inference; residual confounding possible; depression association attenuated after adjustments.
Future Directions: Validate proteomic signatures across cohorts and modalities (imaging/biopsy), test biomarker-guided surveillance strategies, and experimentally interrogate ADM/ASGR1/FABP4 and CDHR2 pathways for therapeutic targeting.
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition. Whether and how the plasma proteome underlies the heterogeneous associations between MASLD and subsequent health outcomes remain unclear. METHODS: This study included 42 508 participants from the UK Biobank. Steatosis was defined by the fatty liver index. Individuals' MASLD-related proteomic signature was derived from 2911 plasma proteins. Cox models were used to assess the associations of the proteomic signature with 8 chronic diseases: liver fibrosis, cardiovascular disease (CVD), chronic kidney disease (CKD), chronic respiratory disease (CRD), dementia, depression, anxiety, and cancers. Adjusted survival curves were fitted to compare the cumulative incidence rate of diseases across quantiles of the proteomic signature; we further adjusted for the steatosis degree and cardiometabolic factors to test whether the association was independent of them. Mediation analyses were performed to identify mediating proteins. RESULTS: The proteomic signature was significantly associated with liver fibrosis, CVD, CKD, CRD, and depression in the MASLD population, with adjusted hazard ratios ranging from 1.30 to 4.94. Survival curves showed that individuals with the highest proteomic signature had the highest risk for these 5 diseases. These risk differences by signature persisted after adjustment for steatosis degree and cardiometabolic factors, except for depression. Proteins including ADM, ASGR1, and FABP4 were identified as common mediators of the association between MASLD and multiple diseases. Mediators of liver fibrosis showed specificity, with CDHR2 being the key protein. CONCLUSIONS: Metabolic dysfunction-associated steatotic liver disease patients with the same steatosis severity but different proteomic responses may have different risks for future outcomes. Several key proteins may contribute to the progression of MASLD-related diseases.
3. Rapid Onset of Pain Relief with Crisugabalin in Patients with Diabetic Peripheral Neuropathic Pain: Findings from a Multicenter, Randomized, Double-Blind, Controlled Study.
In a phase 2/3 adaptive, multicentre, double-blind RCT (n=596), crisugabalin 40 or 80 mg/day significantly reduced average daily pain versus placebo from week 1 through week 13, while pregabalin separated from placebo from week 6. NRS and sleep interference improved as early as day 2 with crisugabalin, and safety was acceptable with low serious adverse event rates.
Impact: Demonstrates rapid-onset analgesia in diabetic neuropathic pain with earlier separation from placebo than pregabalin, addressing an unmet need for faster symptom control.
Clinical Implications: Crisugabalin may be considered when rapid pain relief is prioritized in DPNP, potentially reducing early disability and sleep disruption; head-to-head effectiveness and long-term safety studies are warranted.
Key Findings
- Crisugabalin 40 and 80 mg/day reduced ADPS versus placebo from week 1 through week 13 (P<0.05), while pregabalin differences emerged from week 6.
- Secondary outcomes (NRS and daily sleep interference) improved as early as day 2 with crisugabalin.
- Safety profile was acceptable with low serious adverse event rates and no increase in dropouts.
Methodological Strengths
- Multicentre, randomized, double-blind, placebo- and active-controlled design with large sample (n=596).
- Pre-specified early time-point assessments enabling detection of onset of action; adaptive phase 2/3 framework.
Limitations
- 13-week duration limits long-term efficacy/safety inference and functional outcomes.
- Details on rescue analgesics and subgroup efficacy (e.g., by HbA1c control) were not reported in the abstract.
Future Directions: Head-to-head trials versus pregabalin/gabapentin on onset and magnitude of analgesia, evaluation of quality-of-life and function, and long-term safety in diverse DPNP populations.
INTRODUCTION: This study aims to evaluate the efficacy and safety of Crisugabalin in patients with diabetic peripheral neuropathic pain (DPNP), with a focus on its rapid onset of action. METHODS: All the analyses in this study were based on data from a phase 2/3 adaptive randomized clinical trial that enrolled 596 patients. Participants were categorized into four treatment groups according to the intervention received: Crisugabalin 40 mg/day, Crisugabalin 80 mg/day, placebo, and Pregabalin 300 mg/day. The primary endpoint was the change in the average daily pain score (ADPS) over a 13-week treatment period. Secondary endpoints included changes in the Numeric Rating Scale (NRS) and the daily sleep interference score (DSIS) during the first two weeks of treatment. RESULTS: Both Crisugabalin treatment groups (40 mg/day and 80 mg/day) demonstrated statistically significant reductions in ADPS compared to the placebo group starting from week 1 and continuing through week 13 (P < 0.05). Significant differences in pain relief for the Pregabalin group were observed only from week 6. Improvements in NRS and DSIS scores were also noted in both Crisugabalin groups, with statistically significant enhancements evident as early as day 2 of administration. Safety assessments indicated that Crisugabalin was well-tolerated, with a low incidence of serious adverse events and no significant increase in dropout rates among participants. CONCLUSION: The findings suggest that Crisugabalin offers effective pain relief with an acceptable safety profile, highlighting its rapid onset in patients with DPNP. CLINICAL TRIAL REGISTRATION: Clinical trial registration number derived from our parent project, we have retained the original registration identifier: NCT04647773.