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.
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.
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.