Daily Endocrinology Research Analysis
Three studies stand out today in endocrinology: a pre-registered systematic review/meta-analysis links post-treatment renin normalization with fewer cardiovascular events and lower mortality in medically treated primary aldosteronism; an international cohort characterizes cyclic Cushing’s syndrome and highlights diagnostic pitfalls and management strategies; and a multi-ancestry polygenic score substantially improves type 1 diabetes risk prediction in non-European populations without sacrificing
Summary
Three studies stand out today in endocrinology: a pre-registered systematic review/meta-analysis links post-treatment renin normalization with fewer cardiovascular events and lower mortality in medically treated primary aldosteronism; an international cohort characterizes cyclic Cushing’s syndrome and highlights diagnostic pitfalls and management strategies; and a multi-ancestry polygenic score substantially improves type 1 diabetes risk prediction in non-European populations without sacrificing performance in Europeans.
Research Themes
- Therapeutic targets and outcome surrogates in endocrine hypertension
- Improving genetic risk prediction across ancestries in autoimmune diabetes
- Diagnostic optimization and care pathways in cyclic hypercortisolism
Selected Articles
1. Post-treatment renin status and cardiovascular, renal, and mortality outcomes in medically treated primary aldosteronism: a systematic review and meta-analysis.
Across 24 studies (n=6621), patients with primary aldosteronism whose renin was unsuppressed after medical therapy experienced substantially fewer cardiovascular events and lower all-cause mortality than those with suppressed renin. Most studies used a post-treatment plasma renin activity cutoff of 1.0 ng/mL/h. Findings support using renin normalization as a therapeutic target, warranting prospective trials of renin-guided mineralocorticoid receptor antagonist titration.
Impact: Identifies a modifiable, measurable biomarker (renin) linked to hard outcomes in primary aldosteronism under medical therapy, with potential to guide treatment intensity.
Clinical Implications: Consider titrating mineralocorticoid receptor antagonists to achieve unsuppressed renin as a therapeutic goal, while monitoring for hyperkalemia and renal function. Clinicians may incorporate post-treatment renin status into risk stratification and follow-up planning.
Key Findings
- Across five studies in meta-analysis, unsuppressed post-treatment renin was associated with lower cardiovascular events (pooled HR 0.43, 95% CI 0.23–0.80).
- Unsuppressed renin also correlated with lower all-cause mortality compared with suppressed renin after medical therapy.
- Most studies classified renin status using plasma renin activity with a 1.0 ng/mL/h cutoff, supporting a pragmatic target threshold.
Methodological Strengths
- Pre-registered protocol (PROSPERO) with systematic multi-database search and QUIPS risk-of-bias appraisal.
- Random-effects meta-analysis of prognostic associations with pooled hazard ratios and 95% CIs.
Limitations
- Only five studies contributed to primary quantitative meta-analyses, limiting precision.
- Heterogeneity in renin assays and definitions; potential residual confounding in non-randomized data.
Future Directions: Prospective, renin-guided titration trials of mineralocorticoid receptor antagonists to test causality and define optimal renin targets and safety thresholds.
BACKGROUND: Renin suppression persists in many patients with primary aldosteronism despite targeted medical treatment, which might indicate suboptimal mineralocorticoid receptor blockade. This study systematically reviewed the evidence for an association between post-treatment renin status and cardiovascular, renal, and mortality outcomes in medically treated primary aldosteronism. METHODS: For this systematic review and meta-analysis, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched from database inception up to May 5, 2025, for studies that investigated the association between post-treatment renin status and clinical outcomes among medically treated patients with primary aldosteronism. The primary outcomes were the incidence of cardiovascular events, renal events, and all-cause mortality. Risk-of-bias was assessed using the Quality in Prognostic Studies (QUIPS) tool. Random-effects models were employed to estimate pooled hazard ratios (HRs) with 95% CIs. The protocol was pre-registered on PROSPERO (CRD42024598737). FINDINGS: 3814 records were identified and 24 studies involving 6621 patients with primary aldosteronism on mineralocorticoid receptor antagonists were eligible and included, of which five studies contributed data to the meta-analyses of the primary outcomes. Most studies used plasma renin activity with a cut-off of 1·0 ng/mL per h to classify post-treatment renin as suppressed or unsuppressed. For the primary meta-analysis, individuals with unsuppressed post-treatment renin had a significantly lower risk of cardiovascular events compared with those with suppressed renin (pooled HR 0·43 [95% CI 0·23-0·80], I INTERPRETATION: The association between unsuppressed renin following medical therapy for primary aldosteronism and reduced risk of cardiovascular events and all-cause mortality suggests that renin normalisation might serve as a therapeutic target. Prospective studies are required to formally confirm that medication titration to normalise renin improves clinical outcomes. FUNDING: None.
2. Development and Validation of a Type 1 Diabetes Multi-Ancestry Polygenic Score.
Using multi-ancestry GWAS, the authors built T1D MAPS and validated it across biobanks: in non-European ancestries, AUC reached 0.90, outperforming ancestry-specific scores; in Europeans, MAPS was comparable, and the combined MAPS2 matched the best European score (AUC 0.91) while retaining superior performance in non-Europeans. This advances equitable genetic risk prediction for T1D.
Impact: Addresses a major equity gap by improving T1D genetic risk prediction across ancestries without sacrificing performance in Europeans.
Clinical Implications: Enables more accurate pre-clinical risk stratification in diverse populations, informing screening, trial enrichment, and potential preventive strategies when combined with autoantibodies and clinical features.
Key Findings
- In non-European ancestries, T1D MAPS achieved AUC 0.90 versus 0.82 for both GRS2EUR and GRSAFR.
- In European ancestry, T1D MAPS AUC 0.89 was slightly below GRS2EUR 0.91, but MAPS2 matched GRS2EUR at 0.91.
- Training set: 372 T1D cases (MGB Biobank); external testing: 86 T1D cases (All of Us).
Methodological Strengths
- External validation across biobanks with ancestry-stratified performance reporting.
- Incorporation of multi-ancestry GWAS signals and a combined score (MAPS2) to optimize cross-ancestry performance.
Limitations
- Relatively small absolute numbers in training (n=372) and external testing (n=86) limit precision.
- Clinical utility not yet tested in prospective screening or prevention trials.
Future Directions: Prospective evaluation of polygenic risk-integrated screening across ancestries, combined with islet autoantibodies and clinical markers, to guide prevention trials and early diagnosis.
UNLABELLED: Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to create a Type 1 Diabetes Multi-Ancestry Polygenic Score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores for European (EUR) and African (AFR) populations: T1D Genetic Risk Score 2 (GRS2EUR) and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82) and T1D GRSAFR (0.82). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91) and performed better in non-European ancestry (0.90 vs. 0.82). Overall, these findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations. ARTICLE HIGHLIGHTS: Type 1 diabetes polygenic scores are highly predictive of disease risk, but their performance varies based on genetic ancestry. Can we develop a polygenic score that accurately predicts type 1 diabetes risk across diverse populations? Our novel polygenic score performs similar to existing scores in European populations, and it demonstrates superior performance in non-European populations. This polygenic score will improve prediction of type 1 diabetes risk in genetically diverse populations.
3. Cycle characterisation and clinical complications in patients with cyclic Cushing's syndrome: insights from an international retrospective cohort study.
In 110 cCS cases from 43 centers, cycles were commonly irregular with median 24-h UFC peaks 7.4× ULN and troughs 0.31× ULN; ectopic disease had the most frequent and severe peaks. Imaging missed tumors in 32% and 8% underwent inappropriate surgeries; 28% developed spontaneous adrenal insufficiency. Findings emphasize confirming hypercortisolism at time of localization testing (e.g., BIPSS) and equipping patients to capture peaks.
Impact: Provides granular, international data on cCS cyclicity and diagnostic pitfalls, directly informing timing of biochemical confirmation and invasive localization.
Clinical Implications: Confirm hypercortisolism biochemically at time of BIPSS to avoid misclassification; provide patients with salivary cortisol kits and emergency glucocorticoids; anticipate adrenal insufficiency; be cautious with imaging-negative cases to prevent inappropriate surgery.
Key Findings
- Median 24-h UFC peaks were 7.40× ULN and troughs 0.31× ULN; cycles were irregular in 86% of evaluable patients.
- Imaging missed tumors in 32% and 8% had inappropriate surgeries; 28% experienced spontaneous adrenal insufficiency.
- Ectopic cCS showed the most frequent and pronounced peaks; after median 5.8 years, 50% achieved surgical remission, 6% spontaneous remission.
Methodological Strengths
- Large international multicenter cohort with standardized inclusion based on cyclic biochemical criteria.
- Comprehensive capture of biochemical, imaging, interventional, and outcome data over a median 5.8-year follow-up.
Limitations
- Retrospective design with potential selection and information biases.
- Heterogeneity in testing intervals and local practices may influence cycle detection and management.
Future Directions: Prospective protocols standardizing biochemical sampling to capture peaks, and decision algorithms for timing of BIPSS and imaging in ACTH-dependent cCS.
BACKGROUND: Cyclic Cushing's syndrome (cCS) features fluctuating cortisol secretion, often causing diagnostic errors or delays, and possibly poorer outcomes. We aimed to identify unpublished cCS cases to characterise clinical challenges and guide strategies for improving outcomes by characterising cycle patterns, peak frequency, and evaluating complications. METHODS: This was a retrospective observational study at 43 endocrine centres in 21 countries, including patients with confirmed Cushing's syndrome showing two or more hypercortisolaemic peaks and one or more spontaneous eucortisolaemic or hypocortisolaemic trough. Data included both clinical (eg, comorbidities and physical signs of cortisol excess) and biochemical (eg, screening and confirmatory tests) parameters, imaging, treatment, complications, and outcomes. FINDINGS: Between Dec 1, 2023 and Feb 2, 2025, 116 potentially eligible patients were identified and 110 were included. Most patients were female (84 [76%] of 110 patients), with a median age at diagnosis of 44·0 years (IQR 31·8-58·3). cCS origin was pituitary in 70 (64%), ectopic in 25 (23%), adrenal in three (3%), and occult in 12 (11%). Cyclicity was primarily determined by 24 h urinary free cortisol, with median peaks of 7·40 × ULN (range 0·44-299) and troughs of 0·31 × ULN (0·02-0·98). The median peak count was 3·0 (IQR 2·0-4·0), mostly (55 [86%] of 64 patients) occurring at irregular intervals, and was most frequent and pronounced in ectopic cCS. Symptoms worsened in 87 (81%) of 108 patients during peaks and improved in 79 (74%) of 107 patients during troughs; 31 (28%) of 110 patients had spontaneous adrenal insufficiency. Bilateral inferior petrosal sinus sampling (BIPSS) was performed during troughs in 14 patients (18% of the 78 procedures done). Imaging missed tumours in 35 (32%) of the 110 patients, and nine (8%) underwent unwarranted surgeries at the wrong anatomical site due to misclassification. After 5·8 years (IQR 2·6-10·5) median follow-up, 55 (50%) of 110 patients had complete biochemical surgical remission, seven (6%) had spontaneous remission, 22 (20%) were medically controlled, six (5%) had partial remission, 11 (10%) remained uncontrolled, nine (8%) were lost to follow-up. During the entire observation period, 3% (3/110) died. Delayed diagnosis (45 [41%] of 110 patients) and therapy (47 [43%]) were also observed. INTERPRETATION: Even in specialised centres, cCS diagnosis and management remain challenging with high rates of spontaneous adrenal insufficiency, inappropriate surgeries, and poor outcomes. Ectopic cCS showed the most frequent and severe peaks. These findings might help to guide imaging localisations or the timing of BIPSS in patients with active occult ACTH-dependent cCS. Hypercortisolism needs to be biochemically confirmed before BIPSS to enable correct tumour localisation. Patients with suspected or proven cCS should be equipped with salivary cortisol collection kits to capture dynamic changes as well as being prescribed glucocorticoids to be used as a precaution. FUNDING: None.