Daily Endocrinology Research Analysis
Three impactful endocrinology studies stood out today: immunogenetic interactions between HLA class I and KIR receptors predict type 1 diabetes progression; a validated noninvasive KASAI score can accurately triage primary aldosteronism subtypes and reduce the need for adrenal venous sampling; and real-world comparative effectiveness shows GLP-1 RAs and DPP-4 inhibitors are associated with lower cardiovascular risk than several alternatives in type 2 diabetes with hypertension.
Summary
Three impactful endocrinology studies stood out today: immunogenetic interactions between HLA class I and KIR receptors predict type 1 diabetes progression; a validated noninvasive KASAI score can accurately triage primary aldosteronism subtypes and reduce the need for adrenal venous sampling; and real-world comparative effectiveness shows GLP-1 RAs and DPP-4 inhibitors are associated with lower cardiovascular risk than several alternatives in type 2 diabetes with hypertension.
Research Themes
- Immunogenetic determinants of autoimmune diabetes progression
- Noninvasive diagnostic pathways in endocrine hypertension
- Real-world comparative effectiveness of antidiabetic therapies on cardiovascular outcomes
Selected Articles
1. Profiling associations of interactive ligand-receptors (HLA class I and KIR gene products) with the progression to type 1 diabetes among seroconverted participants.
In 1,215 seroconverted participants from DPT-1 and TN07, specific HLA class I–KIR ligand–receptor interactions, rather than individual HLA or KIR genes, were associated with progression to clinical type 1 diabetes. An example is HLA-A*03:01–KIR2DS4, which was linked to slower progression, and structural analyses suggest stabilization by electrostatic and van der Waals forces near the HLA-I groove.
Impact: This study reframes T1D progression risk around specific HLA–KIR interactions, offering a mechanistic and potentially actionable immunogenetic framework beyond single-locus associations.
Clinical Implications: HLA–KIR interaction profiling could refine risk stratification and monitoring of autoantibody-positive individuals and inform immunoprevention trial design targeting NK cell pathways.
Key Findings
- Nine HLA-A and 14 HLA-B ligand–receptor interactions showed modest associations (p<0.05) with progression from stage 1/2 to stage 3 type 1 diabetes.
- The HLA-A*03:01–KIR2DS4 interaction was associated with slower progression (HR 0.36).
- Individual HLA or KIR genes alone showed minimal or sporadic associations, highlighting the importance of ligand–receptor complexes.
- Structural analyses suggest stabilization of KIR–HLA-I complexes via electrostatic and van der Waals forces at the C-terminal region of the HLA-I groove, potentially peptide dependent.
Methodological Strengths
- Large, well-characterized seroconverted cohort (n=1215) from DPT-1 and TN07.
- High-resolution NGS genotyping of HLA-I and KIR with Cox regression modeling and structural analyses.
Limitations
- Effect sizes are modest and multiple testing may increase type I error risk.
- Lack of an independent external replication cohort; generalizability across ancestries requires validation.
Future Directions: Replicate findings in independent cohorts with diverse ancestries, integrate peptide-binding data, and test whether KIR–HLA-informed risk models improve prediction and guide immunopreventive interventions.
AIMS/HYPOTHESIS: The aim of this work was to explore associations between type 1 diabetes progression from stages 1 or 2 to stage 3 and interacting ligand-receptor complexes of HLA class I (HLA-I) and KIR gene products. METHODS: Applying next-generation sequencing technology to genotype HLA-I genes (HLA-A, -B, -C) and KIR genes (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL3, KIR3DS1, KIR2DP1, KIR3DP1) from 1215 participants in the Diabetes Prevention Trial-Type 1 (DPT-1) and the Diabetes Prevention Trial (TN07), we systematically explored associations of HLA-I-KIR ligand-receptor interactions (LRIs) with disease progression via a Cox regression model. We investigated the structural properties of identified LRI complexes. RESULTS: KIR and HLA-I genes had no or sporadic associations with disease progression. Out of all possible LRIs, nine HLA-A Ligands and 14 HLA-B ligands with corresponding receptors had modest associations with progression (p<0.05). As an example, carriers of A*03:01-KIR2DS4 had slower progression (HR 0.36, p=3.06 × 10
2. Validation of a new non-invasive predictive score (KASAI) for primary aldosteronism subtyping.
The KASAI score integrates four clinical and biochemical parameters to noninvasively predict unilateral versus bilateral primary aldosteronism. At extreme cut-offs (>9 or <4), it achieved 100% specificity in both development and external validation cohorts and could have avoided AVS in ~40% of patients.
Impact: Provides a validated, simple tool to triage PA patients for AVS, potentially reducing invasive procedures and accelerating definitive management.
Clinical Implications: Use KASAI to identify clear unilateral or bilateral cases without AVS at extreme scores, while reserving AVS for intermediate scores (4–9). This may expedite surgical referral and reduce delays and risks associated with AVS.
Key Findings
- Four predictors (minimum serum K+, supine aldosterone, post–saline infusion aldosterone, adrenal imaging) formed the KASAI score with item weights of 0, 1, or 3 points.
- Score >9/12 identified unilateral PA and <4/12 identified bilateral PA with 100% specificity in both cohorts.
- The score could have avoided AVS in 40–42% of patients, with AUROC 0.81 (development) and 0.86 (validation).
Methodological Strengths
- External multicenter validation with reproducible thresholds and performance.
- Combines routine biochemical testing with imaging in a simple point-based model.
Limitations
- Retrospective design with modest sample size in the development cohort.
- Generalizability may depend on standardized saline infusion testing and imaging quality; prospective impact on outcomes not tested.
Future Directions: Prospective, multi-ethnic validation with clinical impact assessment (e.g., randomized AVS vs KASAI-guided pathways) and potential integration with machine-learning–assisted imaging.
INTRODUCTION: Adrenal venous sampling (AVS) is considered the gold standard test for primary aldosteronism (PA) subtyping. Considering the limited availability of this challenging procedure, we propose a noninvasive score predicting unilateral (UPA) or bilateral (BPA) form of PA in order to reduce the need for AVS. MATERIAL AND METHODS: The score was retrospectively developed from a cohort of 72 patients who underwent AVS (21 patients with BPA and 51 with UPA) at Cliniques Universitaires Saint Luc between 1993 and 2021. Another multicenter cohort of 130 patients who underwent AVS (67 patients with BPA and 63 with UPA) served as external validation. RESULTS: Four predictive parameters of UPA highlighted by logistic regression analysis were integrated into the KASAI score: minimal serum potassium value, supine resting aldosteronemia, aldosteronemia at the end of the saline infusion test, and results of adrenal imaging. Depending on the results, 0, 1, or 3 points were assigned to each parameter. In both cohorts, a score greater than 9/12 identified UPA and a score less than 4/12 identified BPA with 100% specificity, while performing AVS remained indicated for scores between 4 and 9. The score may have avoided AVS in 40% of patients in the primary cohort and in 42% of patients in the validation cohort. The area under the ROC curve for discrimination of UPA from BPA was 0.81 (95% CI, 0.70-0.90) in the primary cohort and 0.86 (95% CI, 0.80-0.90) in the validation cohort. CONCLUSION: We propose a new biological-radiological score that could simplify the diagnostic assessment of PA.
3. Comparative cardiovascular outcomes and safety of hypoglycemic drug classes in patients with type 2 diabetes and hypertension: a multicenter cohort analysis.
In T2D patients with hypertension on metformin, add-on GLP-1 RAs, DPP-4 inhibitors, and glinides were associated with lower MACE risk compared with insulin and acarbose, while sulfonylureas had higher MACE risk than DPP-4 inhibitors. Safety signals included lower CKD risk with DPP-4 inhibitors but higher coronary and hypertensive heart disease risks.
Impact: Offers head-to-head real-world comparisons across multiple drug classes in a high-risk subgroup, informing cardiovascular risk-conscious therapeutic choices.
Clinical Implications: When hypertension coexists, prioritize GLP-1 RAs or DPP-4 inhibitors as add-on to metformin to reduce MACE risk; consider individual safety profiles (e.g., CKD benefits vs potential coronary/hypertensive heart disease signals) and patient-specific risks.
Key Findings
- Compared with insulin, GLP-1 RAs (HR 0.48), DPP-4 inhibitors (HR 0.70), and glinides (HR 0.70) were associated with lower 3-point MACE risk.
- Sulfonylureas had higher 3-point MACE risk versus DPP-4 inhibitors (HR 1.30).
- DPP-4 inhibitors, GLP-1 RAs, and glinides had lower 3-point MACE risk than acarbose; similar patterns were seen for 4-point MACE.
- Safety: DPP-4 inhibitors were linked to reduced CKD risk; insulin use to lower risks of inflammatory polyarthritis and insomnia; DPP-4 inhibitors showed higher risks of coronary atherosclerotic diseases and hypertensive heart disease.
Methodological Strengths
- Multicenter EHR-based cohort with propensity score matching and Cox modeling across multiple drug classes.
- Evaluation of both efficacy (3-/4-point MACE) and diverse safety outcomes.
Limitations
- Observational design with potential residual confounding and confounding by indication despite PSM.
- Exact sample size and treatment duration not reported; potential outcome misclassification in EHR data.
Future Directions: Prospective head-to-head randomized trials in T2D with hypertension, mechanistic studies of class-specific CV effects, and subgroup analyses (e.g., CKD, ASCVD) to personalize therapy.
BACKGROUND: Patients with type 2 diabetes (T2D) and hypertension are at increased risk of adverse cardiovascular (CV) events. However, real-world evidence comparing the CV effectiveness and safety of major hypoglycemic drug classes remains limited in this population. This multicenter pooled analysis aims to directly compare the CV outcomes and safety profiles of these key agents in patients with T2D and hypertension. METHODS: We analyzed electronic health records from two databases in a cohort study of T2D patients with hypertension who had initiated metformin as first-line therapy. Propensity score matching (PSM) and Cox proportional hazards models were used to compare the risks of 3-/4-point major adverse cardiovascular events (MACE) and safety outcomes across drug classes added to metformin: insulin, sulfonylureas (SUs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), glinides, acarbose, and sodium-glucose transporter 2 inhibitors (SGLT2is). RESULTS: Compared with insulin, GLP-1 RAs, DPP4is, and glinides were associated with a lower risk of 3-point MACE (HR: 0.48 [0.31-0.76], 0.70 [0.57-0.85], and 0.70 [0.52-0.94], respectively). SUs were associated with a higher risk of 3-point MACE compared with DPP4is (HR: 1.30 [1.06-1.59]). DPP4is, GLP-1 RAs, and glinides showed a lower risk of 3-point MACE compared with acarbose (HR: 0.62 [0.51-0.76], 0.47 [0.29-0.75], and 0.59 [0.43-0.81], respectively). Similar patterns were observed for 4-point MACE. For safety outcomes, DPP4is were associated with a reduced risk of chronic kidney disease, while insulin use was associated with reduced risks of inflammatory polyarthritis and insomnia. However, DPP4is were associated with higher risks of coronary atherosclerotic diseases and hypertensive heart disease. CONCLUSIONS: This study highlights the differential cardiovascular effectiveness and safety profiles of hypoglycemic therapies in real-world settings, providing valuable insights for optimizing T2D management, particularly in patients with comorbid hypertension.