Daily Endocrinology Research Analysis

BACKGROUND: In the SURPASS-CVOT trial, tirzepatide, a dual incretin agonist that targets the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, was shown to be non-inferior to dulaglutide for the primary composite cardiovascular outcome in people with type 2 diabetes and atherosclerotic cardiovascular disease. Here, we report the results of a pre-specified exploratory analysis of SURPASS-CVOT that aimed to assess major kidney events in the overall population, low-to-moderate-risk chronic kidney disease population, and high-risk chronic kidney disease population. METHODS: SURPASS-CVOT was a randomised, active comparator-controlled, double-blind trial that enrolled people with type 2 diabetes and atherosclerotic cardiovascular disease at 640 sites in 30 countries. Participants aged 40 years or older with type 2 diabetes and atherosclerotic cardiovascular disease, HbA FINDINGS: Between May 29, 2020, and June 27, 2022, 16 979 participants were screened and 13 299 (2948 with high-risk chronic kidney disease) were randomly assigned. After excluding 134 participants randomly assigned in error, 6586 were assigned to tirzepatide and 6579 were assigned to dulaglutide. At baseline, 4142 (32·0%) of 12 954 participants had microalbuminuria and 1491 (11·5%) of 12 954 had macroalbuminuria, and 2928 (22·5%) of 13 004 had an eGFR less than 60 mL/min per 1·73 m INTERPRETATION: Among people with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was associated with a reduced risk of major kidney events compared with dulaglutide, primarily driven by a reduction in new-onset macroalbuminuria in people with low-to-moderate-risk chronic kidney disease, and slowed decline in kidney function in people with high-risk chronic kidney disease. FUNDING: Eli Lilly and Company.

The global prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising, driven by a complex interplay of metabolic disturbances, inflammation, and fibrosis, yet effective treatment options remain limited. This study examined the relationships among intestinal microbial dysbiosis, ammonia production, and hepatic CD8+ T cell activity in MASH, and assessed the therapeutic potential of DT-109, a glycine-based tripeptide. We investigated the gut-liver axis across human cohorts and both non-human primate and mouse MASH models. Multi-omics approaches were used to characterize ileal microbiota, ammonia levels, and hepatic immune and metabolic pathways. Causality was verified through microbiota transplantation, C. perfringens NirA-knockout mutants, and functional validation in vitro and in vivo. The efficacy of DT-109 was evaluated in non-human primates and mice. Our results revealed a significant increase in the ammonia-producing gut bacterium C. perfringens, which led to elevated intestinal ammonia and disruption of the intestinal barrier in MASH. Elevated ammonia levels triggered FosB-mediated upregulation of chemokine C-C motif ligand 5 (CCL5) in CD8+ T cells, which in turn drove T cell cytotoxicity in the liver. Notably, DT-109 effectively lowered C. perfringens abundance, reduced intestinal ammonia, restored intestinal barrier integrity, and alleviated CD8+ T cell dysregulation in MASH. These results identify a distinct mechanism in which gut-derived ammonia drives CD8+ T cell-mediated MASH and demonstrate that DT-109 effectively targets this axis by inhibiting C. perfringens and reducing ammonia, ultimately ameliorating MASH.

BACKGROUND: Biopsy of phaeochromocytomas and paragangliomas (PPGLs) is discouraged due to the perceived risk of catecholamine-related complications. However, a systematic review showed that this recommendation is primarily supported by case reports. We aimed to assess the safety of percutaneous biopsy in patients with PPGLs. METHODS: This international, multicentre, retrospective study included patients of any age with PPGLs referred to participating centres who had had percutaneous core-needle biopsy or fine-needle aspiration. Biopsies of head and neck paragangliomas were excluded. Participating centres completed standardised data-collection forms. The primary outcome was biopsy-related mortality rate for all patients who had biopsies performed at participating centres, given that biopsies done elsewhere that had fatal outcomes would be unlikely to be referred. Secondary outcomes included the incidence of serious catecholamine-related and non-catecholamine-related complications among all included patients. FINDINGS: Between Sep 1, 1993, and May 31, 2025, 222 patients (110 [50%] female, 112 [50%] male) underwent 234 biopsies in 19 hospitals across 11 countries. 139 (67%) of 207 patients had elevated epinephrine or norepinephrine (or metabolites) and 27 (12%) of 232 biopsies were preceded by the administration of α-adrenoceptor blockade. One (mortality rate 0·9% [95% CI 0·0-5·1]) of 106 biopsies led to death due to biopsy-related infection. Serious catecholamine-related complications occurred after four (1·7% [0·5-4·3]) of 233 biopsies and included tachyarrhythmia, hypertensive crisis, and cardiogenic shock. No serious catecholamine-related complications occurred in patients without catecholamine excess (n=59), receiving fine-needle aspiration (n=46), or after biopsy of metastatic lesions (n=114). Serious non-catecholamine-related complications occurred after ten (4·3% [2·1-7·8]) of 233 biopsies, mainly bleeding and infection. INTERPRETATION: Percutaneous biopsy of PPGLs was associated with a low mortality rate. Serious complication rates were also low, most of which were not catecholamine-related. These findings challenge current recommendations that biopsy should be avoided in suspected or confirmed PPGLs, and instead support a personalised, risk-benefit-based approach to the procedure. FUNDING: Cancerfonden. TRANSLATIONS: For the Chinese and French translations of the abstract see Supplementary Materials section.