Daily Endocrinology Research Analysis
Three impactful endocrinology-related studies stood out today. A nationwide RCT (NUDGE-CKD) found that electronic nudge letters did not increase uptake of guideline-directed CKD therapies. A proteome-wide Mendelian randomization study identified plasma proteins (LIF, IL7RA, CD226, TNFSF11, JUND) causally linked to autoimmune thyroid disease. A large registry cohort suggested an optimal HbA1c range of 6.7–7.1% for people with diabetes and severe CKD to minimize complications.
Summary
Three impactful endocrinology-related studies stood out today. A nationwide RCT (NUDGE-CKD) found that electronic nudge letters did not increase uptake of guideline-directed CKD therapies. A proteome-wide Mendelian randomization study identified plasma proteins (LIF, IL7RA, CD226, TNFSF11, JUND) causally linked to autoimmune thyroid disease. A large registry cohort suggested an optimal HbA1c range of 6.7–7.1% for people with diabetes and severe CKD to minimize complications.
Research Themes
- Implementation science for cardio-renal-metabolic care
- Proteomic genomics to uncover autoimmune thyroid disease mechanisms
- Personalizing glycemic targets in advanced CKD with diabetes
Selected Articles
1. A Nationwide Factorial Randomized Trial of Electronic Nudges to Patients With Chronic Kidney Disease and Their General Practices for Increasing Guideline-Directed Medical Therapy: The NUDGE-CKD Trial.
In a nationwide 2×2 factorial randomized implementation trial involving 22,617 CKD patients, electronic letters to patients and general practices did not increase filled prescriptions for RAS inhibitors or SGLT2 inhibitors over 6 months versus usual care. The null result suggests simple informational nudges are insufficient to change prescribing or uptake.
Impact: A large, pragmatic RCT in Circulation delivering a definitive negative result on a widely proposed low-cost intervention informs policy and resource allocation in cardio-renal-metabolic care.
Clinical Implications: Electronic letter nudges alone are unlikely to improve uptake of GDMT (RAS inhibitors, SGLT2 inhibitors) in CKD. More intensive, tailored, and system-level strategies (e.g., default prescribing, pharmacist-led protocols, decision support) are needed.
Key Findings
- 22,617 CKD patients randomized at patient level; 1,540 practices at provider level in a 2×2 factorial design.
- Primary endpoint (filled RASi/SGLT2i within 6 months): 65.1% with patient-directed nudge vs 65.9% usual care (difference −0.79 pp; 95% CI −2.03 to 0.45).
- Provider-level informational letters similarly did not improve medication uptake.
- Nationwide registry linkage enabled pragmatic outcome assessment.
Methodological Strengths
- Nationwide, pragmatic 2×2 factorial randomization with large sample size
- Objective outcome via prescription fill data from administrative registries
Limitations
- Short follow-up (6 months) may miss delayed behavior change
- Intervention lacked personalization or system redesign; outcome limited to fill data
Future Directions: Test multi-component, behaviorally informed strategies (default orders, pharmacist outreach, incentive alignment), leverage EHR decision support, and evaluate equity impacts and long-term clinical outcomes.
2. Proteome-wide Mendelian randomization reveals causal associations between plasma proteins and autoimmune thyroid disease.
Using proteome-wide MR and colocalization across multiple large datasets, the study identified 11 plasma proteins with causal links to AITD, five of which (LIF, IL7RA, CD226, TNFSF11, JUND) also showed colocalization. LIF and IL7RA increased AITD risk, whereas CD226, TNFSF11, and JUND were inversely associated.
Impact: Provides mechanistic leads and potential biomarkers/targets for autoimmune thyroid disease, moving beyond association to inferred causality via genetic instruments.
Clinical Implications: Findings prioritize specific proteins (e.g., LIF, IL7RA) for translational validation as diagnostic or prognostic biomarkers and as candidate therapeutic targets in AITD.
Key Findings
- Proteome-wide MR leveraging UKB-PPP and deCODE identified 11 plasma proteins with causal associations to AITD.
- Colocalization supported shared causal variants for five proteins: LIF, IL7RA, CD226, TNFSF11, and JUND.
- Genetically predicted LIF and IL7RA levels increased AITD risk; CD226, TNFSF11, and JUND were inversely associated.
- Triangulation across SMR, Wald Ratio, and IVW strengthened causal inference.
Methodological Strengths
- Use of two large independent proteomic GWAS resources and two AITD outcome GWAS meta-datasets
- Colocalization to mitigate confounding by linkage and strengthen causality
Limitations
- Potential residual horizontal pleiotropy cannot be fully excluded
- Plasma protein levels may not reflect thyroidal or immune tissue microenvironments; clinical validation is needed
Future Directions: Validate prioritized proteins in prospective cohorts and interventional models; develop assays for clinical translation; explore pathway-targeted therapeutics.
3. The Association Between Hemoglobin A1c and Complications Among Individuals With Diabetes and Severe Chronic Kidney Disease.
In 27,113 adults with diabetes and severe CKD (eGFR <30), HbA1c showed a U-shaped association with adverse outcomes. Risks increased at HbA1c ≥7.2% and also at <5.8%; hypoglycemia-related hospitalizations rose from ≥6.7%. Data support an optimal HbA1c range of 6.7–7.1% for minimizing complications.
Impact: Provides large-scale, contemporary, registry-based evidence to refine glycemic targets in a high-risk population where RCT data are scarce.
Clinical Implications: For patients with diabetes and severe CKD, aiming for HbA1c around 6.7–7.1% may balance risks of macro/microvascular events and hypoglycemia. Consider CGM metrics and individual risk factors when setting targets.
Key Findings
- U-shaped association: MACE risk increased at HbA1c ≥7.2% and <5.8% versus 6.3–6.6%.
- Microvascular complications increased at HbA1c ≥7.2%.
- Hypoglycemia hospitalizations increased at HbA1c ≥6.7%.
- Patterns were consistent across CKD severity reference cohorts.
Methodological Strengths
- Large nationwide cohort with age/sex-matched reference groups
- Standardized 1-year risk estimation using multivariable Cox models
Limitations
- Observational design with potential residual confounding and indication bias
- HbA1c accuracy may be affected in advanced CKD; unmeasured factors (e.g., anemia, carbamylation) could influence associations
Future Directions: Randomized trials of glycemic targets in advanced CKD; incorporate CGM-derived metrics (time-in-range, hypoglycemia burden) into outcome models.