Daily Endocrinology Research Analysis

BACKGROUND: The CONFIDENCE (COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR Endpoint) trial investigated the safety and efficacy of simultaneously initiating finerenone and empagliflozin for patients with chronic kidney disease (CKD) and type 2 diabetes. This prespecified analysis aimed to determine if the predicted risk of kidney disease progression, based on KDIGO risk categories, influenced the benefits and safety of this combination therapy. METHODS: The double-blind, double-dummy trial randomized 818 adults with CKD and type 2 diabetes [urine albumin-creatinine ratio (UACR) ≥100 to <5000 mg/g] to receive once-daily finerenone plus empagliflozin, finerenone alone or empagliflozin alone, all in addition to a renin-angiotensin system inhibitor. The relative change in UACR from baseline to day 180 (primary endpoint) and a >30% reduction in UACR (secondary endpoint) across KDIGO risk categories was assessed. RESULTS: At baseline, among 781 with available data, 11.3% of participants were classified as low/moderate risk, 29.6% as high risk and 59.2% as very high risk. At 180 days, combination therapy significantly reduced UACR levels across all KDIGO risk categories (low/moderate: -61.7%; high: -60.7%; very high: -52.4%). This reduction was consistently greater than that achieved with either monotherapy alone. More than half of patients on combination therapy experienced UACR reductions of >30% (low/moderate: 58.1%; high: 74.2%; very high: 70.6%), again outperforming monotherapies across all risk groups. While hyperkalemia was more common with combination therapy, early eGFR declines (>30% within 30 days) were less frequent in individuals with higher KDIGO risk compared with lower risk. Overall, the safety profile of combination therapy remained consistent across all KDIGO risk categories, with no unexpected safety signals. CONCLUSIONS: The CONFIDENCE trial demonstrates that the relative efficacy and safety of simultaneous finerenone and empagliflozin combination therapy are consistent across a wide spectrum of predicted kidney disease risk. CLINICAL TRIAL REGISTRATION: NCT05254002; EudraCT 2021-003037-11.

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major atherosclerotic cardiovascular events in individuals living with either diabetes or obesity. Since the turnover of vascular regenerative (VR) stem and progenitor cells has been demonstrated to modulate vessel repair and atherothrombotic risk, this study aimed to determine the effect of the GLP-1RA semaglutide on the levels of circulating VR cells. METHODS: SEMA-VR CardioLink-15 was a randomized translational trial of usual care vs. semaglutide for 6 months in 46 participants with either type 2 diabetes and/or obesity plus atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors. VR cells were enumerated using multi-parametric flow cytometry for high aldehyde dehydrogenase activity (ALDHhi) and lineage-specific cell surface marker expression. The primary endpoint was the 6-month change in VR cell content. RESULTS: Compared to usual care (n = 24), semaglutide (n = 22) led to a greater increase in the number of VR cells (ALDHhiSSClow: +0.8% vs. +34.8%, P = .036), pan-haematopoietic myeloid progenitors (ALDHhiSSClowCD45+: +2.8% vs. +40.1%, P = .017), and endothelial precursors (ALDHhiSSClowCD34+CD133+CD45-: -2.3% vs. +66.2%; P = .037) from baseline. Semaglutide also decreased granulocyte precursors (ALDHhiSSChi: +0.3% vs. -50.8%, P = .002), particularly those expressing the neutrophil activation marker CD66b and chemokine receptor CXCR2. Semaglutide downregulated serum proteins over-represented in pro-inflammatory tumor necrosis factor and interleukin signalling pathways. CONCLUSIONS: In people living with either type 2 diabetes or obesity plus ASCVD risk, semaglutide increased circulating VR cell content while reducing pro-inflammatory granulocyte precursors and cytokine production. Collectively, these findings suggest that semaglutide may improve endogenous progenitor cell-mediated blood vessel repair processes.

OBJECTIVE: Premature adrenarche (PA), characterised by pre-pubertal adrenal androgen excess and hyperandrogenic symptoms, is considered a forerunner of polycystic ovary syndrome, which comes with increased metabolic risk. Here, we aimed to systematically evaluate the evidence on surrogate parameters of metabolic risk in children with PA. METHODS: We searched major databases (1990-March 2025) for studies on PA in children analysing body composition and markers of glucose and lipid metabolism. Two reviewers independently selected studies, collected data, and appraised study quality. Results were standardised, tabulated, and pooled for meta-analysis. RESULTS: Twenty-five case-control studies reported on 694 children with PA and 567 healthy controls (boys and girls). Height standard deviation score (SDS), weight SDS, and body mass index SDS were significantly higher in PA than in controls. Children with PA also presented with higher fasting insulin (FI) levels than controls (MD: 15.04, 95% CI: 5.27-24.81 pmol/L; I2 = 91%). These findings persisted after sensitivity analysis for gender and risk of bias assessment. Other markers of metabolic risk, such as fasting glucose, HOMA-IR, mean serum glucose and insulin during the oral glucose tolerance test, and fasting lipids, did not differ between children with PA and controls. CONCLUSIONS: Children with PA are taller, heavier, and have higher FI levels than their healthy peers at presentation. We observed significant heterogeneity of reported outcomes with generally small participant numbers in the included studies. Large-scale studies with comprehensive, unified assessment and long-term follow-up are needed to explore the extent of metabolic dysfunction that may develop over time.