Daily Endocrinology Research Analysis

BACKGROUND: Many individuals with chronic kidney disease (CKD) face a considerable but modifiable risk of cardiovascular and renal outcomes because of suboptimal implementation of guideline-directed medical therapy (GDMT). We investigated whether electronic letter-based nudges delivered to individuals with CKD and their general practices could increase GDMT uptake. METHODS: This was a nationwide 2×2 factorial implementation trial with randomization at the patient and general practice level and analyzed at the patient level. All Danish adults with a hospital diagnosis of CKD and access to the official Danish electronic letter system were individually randomized at a 1:1 ratio to usual care (no letter) or to receive an electronic letter-based nudge on GDMT for CKD; general practitioners of individuals with CKD were independently randomized (1:1) to receive no letter or an electronic informational letter on GDMT. Intervention letters were delivered on August 19, 2024. Data were collected through the Danish administrative health registries. The primary end point was a filled prescription of a renin-angiotensin system inhibitor or a sodium-glucose cotransporter 2 inhibitor within 6 months of intervention delivery. RESULTS: A total of 22 617 patients with CKD were randomized to the patient-level intervention, with 11 223 allocated to receive the electronic nudge letter and 11 394 to usual care. Separately, 1540 general practices caring for 28 069 patients with CKD were randomized to the provider-level intervention, with 774 practices (13 959 patients) allocated to the intervention and 766 practices (14 110 patients) to usual care. During follow-up, 7303 (65.1%) allocated to the patient-directed nudge had filled a prescription for a renin-angiotensin system inhibitor or sodium-glucose cotransporter 2 inhibitor compared with 7505 (65.9%) in usual care (difference, -0.79 percentage points [95% CI, -2.03 to 0.45]; CONCLUSIONS: In this nationwide pragmatic, 2×2 factorial implementation trial, electronic letter-based nudges on GDMT delivered to patients with CKD or their general practice did not increase the uptake of a renin-angiotensin system inhibitor or sodium-glucose cotransporter 2 inhibitor as compared with usual care. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06300086.

Autoimmune thyroid diseases (AITD) are the most common autoimmune disorders. Identifying new biomarkers and therapeutic targets in plasma proteins is crucial. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analysis to determine plasma proteins causally associated with AITD. Proteome-wide summary-level genome-wide association studies (GWAS) were collected from the UK Biobank Pharma Proteomics Project (UKB-PPP) and deCODE genetics, encompassing 2922 and 4719 plasma proteins, respectively. Genetic associations with AITD were derived from an AITD GWAS meta-analysis study (30,234 cases and 725,172 controls) and the FinnGen database (40,926 cases and 274,069 controls). MR analysis, including summary-data-based Mendelian randomization (SMR), Wald Ratio, and IVW methods, was employed to estimate the causal effects between plasma proteins and AITD. Colocalization analysis was used to assess whether identified proteins and AITD shared the common causal variants. Genetically predicted levels of 11 plasma proteins were found to have a causal association with AITD. Colocalization analysis revealed that five of these proteins had evidence of colocalization, including leukemia inhibitory factor (LIF), interleukin-7 receptor subunit alpha (IL7RA), CD226, tumor necrosis factor ligand superfamily member 11 (TNF11), and transcription factor junD (JUND). Genetically predicted levels of LIF and IL7RA were associated with an increased risk of AITD, whereas CD226, TNF11, and JUND were inversely related to AITD risk. This study has identified multiple candidate plasma proteins causally associated with AITD. Among these proteins, LIF, IL7RA, CD226, TNF11, and JUND are considered to have potential as disease biomarkers and therapeutic targets, but further clinical and experimental validation is still necessary in the future.

OBJECTIVE: The optimal glycemic target for individuals with severe chronic kidney disease (CKD) remains unclear. We investigated the association between HbA1c and complications in individuals with diabetes and severe CKD. RESEARCH DESIGN AND METHODS: In a Danish nationwide registry-based cohort study, we included 27,113 individuals ≥18 years old with diabetes and severe CKD (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) between 2010 and 2022. As reference groups, we included an age- and sex-matched cohort of 80,131 individuals with diabetes and mild-to-moderate CKD (eGFR 30-59 mL/min/1.73 m2) and 80,797 individuals with diabetes and no-to-mild CKD (eGFR ≥60 mL/min/1.73 m2). Multiple Cox regressions were used to estimate the standardized 1-year risk of major adverse cardiovascular events (MACE), microvascular complications, and hospitalizations due to hypoglycemia across strata of HbA1c levels. RESULTS: For individuals with severe CKD, the risk of MACE significantly increased at HbA1c levels ≥7.2% (55 mmol/mol) (P < 0.01) and <5.8% (40 mmol/mol) (P < 0.001), compared with an HbA1c level of 6.3-6.6% (45-49 mmol/mol). The risk of microvascular complications significantly increased at HbA1c levels ≥7.2% (55 mmol/mol) (P < 0.001), and the risk of hospitalization due to hypoglycemia significantly increased at HbA1c levels ≥6.7% (50 mmol/mol) (P < 0.001). The association patterns between HbA1c and outcomes were similar in the severe CKD cohort compared with the matched cohorts with mild-to-moderate CKD and no-to-mild CKD. CONCLUSIONS: Our data suggest an HbA1c range of 6.7-7.1% (50-54 mmol/mol) to be most favorable for reducing long-term complications in this high-risk population.