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Cardiovascular adverse event reporting profile of tirzepatide: a real-world pharmacovigilance analysis of heart failure, arrhythmias, and ischemic events.
Front Pharmacol
Daqiu Chen, Zixun Wang, Zhanxiong Xie +3 more
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is highly effective for glycaemic control and weight reduction. However, its real-world cardiovascular adverse event reporting profile remains incompletely characterised.
Incretin-Based Therapies for the Treatment of Binge Eating-A Systematic Review.
Pharmacotherapy
Raechel T White, Penelope Henriquez, Britnee Innocent +2 more
Binge eating disorder (BED) is a common psychiatric condition associated with psychological and cardiometabolic morbidity. Psychotherapy remains a core treatment modality while pharmacologic agents such as lisdexamfetamine, selective-serotonin reuptake inhibitors (SSRIs), and topiramate demonstrate variable efficacy and tolerability. Incretin therapies-specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA-originally developed for type 2 diabetes mellitus (T2DM) and obesity, are an emerging therapy of interest for BED due to their effects on satiety, appetite regulation, and reward-driven eating. This systematic review examines current data surrounding the efficacy of incretin therapies in treating BED and discusses potential mechanisms underlying their effects.
Targeting Multiple Gut-Brain Pathways in Obesity: Rationale for Combination Pharmacotherapy.
Obes Sci Pract
Alexander D Miras, Muzamil Hussain
As a disease of energy dysregulation, obesity involves metabolic, hormonal, and neural factors, the interconnection of which is referred to as the "gut-brain axis."
Obesity pharmacotherapy reimagined: The era of multi-receptor agonists and next-generation metabolic modulators, perspectives and controversies.
Metabol Open
Ioannis G Lempesis, Maria Dalamaga
Obesity affects over 2 billion adults globally, with projections indicating that nearly two-thirds of adults will be affected by 2050. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed obesity treatment, achieving weight loss previously considered attainable only with bariatric surgery. However, GLP-1-based therapies have revealed important limitations, including weight loss plateaus, substantial inter-individual variability, and weight regain upon discontinuation, underscoring the need for next-generation approaches. Existing reviews have focused predominantly on approved GLP-1RAs, with limited synthesis of emerging multi-receptor agonists, oral formulations, and body composition-targeted agents, while guidance on treatment personalization and sequencing strategies remains limited. This review examines the evolving landscape of obesity pharmacotherapy beyond injectable GLP-1RAs. Oral GLP-1 agonists, including orforglipron, offer comparable efficacy to injectables while potentially improving global accessibility by eliminating cold-chain requirements and simplifying manufacturing. Multi-receptor agonists represent the most transformative developments: triple agonists such as retatrutide achieve weight reductions of 20-24%, while dual GLP-1/glucagon agonists like survodutide and mazdutide show strong efficacy with particular promise for metabolic-associated steatotic liver disease. Maridebart cafraglutide, combining GLP-1 agonism with glucose-dependent insulinotropic polypeptide (GIP) antagonism, enables once-monthly dosing. The amylin pathway has re-emerged through long-acting analogs (cagrilintide, eloralintide) and unimolecular co-agonists (amycretin), achieving weight reductions up to 24% via distinct neuroendocrine circuits. Body composition optimization through agents like bimagrumab addresses lean mass preservation during potent anorectic therapy. Personalized approaches, including setmelanotide for monogenic obesity, exemplify precision pharmacotherapy. Collectively, these advances signal a shift from appetite-centric weight loss toward integrated metabolic, neuroendocrine, and body-composition-focused disease modification. The next epoch of obesity pharmacotherapy will be defined by multi-receptor strategic combinations, targeted approaches to preserve lean mass, and personalized treatment algorithms. Critical priorities include phenotype-stratified trials, long-term safety surveillance, pediatric obesity research, and implementation science to ensure equitable global access. Balancing pharmacologic innovation with sustainable, equitable implementation remains the defining challenge ahead.
Reversible Nephrogenic Diabetes Insipidus Induced by Lithium: A Case Report.
Case Rep Nephrol
Sevil Uygun İlikhan, Gülin Dilken, Gökhan Hazıroğlu +2 more
Lithium is an effective mood stabilizer but may cause nephrogenic diabetes insipidus (NDI) by impairing the renal collecting duct response to arginine vasopressin (AVP). We report a 52-year-old woman on long-term lithium therapy who presented with diarrhea, fatigue, polyuria, and confusion. Initial evaluation showed hypernatremia (serum sodium 156-159 mmol/L), low urine osmolality (101 mOsm/kg) despite serum osmolality of 286 mOsm/kg, daily urine output of 6.5-7.5 L, and a lithium level of 1.65 mmol/L. Renal function was preserved. Intravenous 5% dextrose was administered for free-water replacement. Bicarbonate and potassium supplementation were initiated based on blood gas and biochemical findings consistent with metabolic acidosis (pH: 7.33 and serum bicarbonate: 22.1 mmol/L) and hypokalemia, requiring potassium supplementation. Lithium was discontinued, and a thiazide-containing regimen was initiated. Without desmopressin, serum sodium normalized to 140 mmol/L within 72 h, urine output decreased to approximately 2 L/day, and mental status fully recovered. This case demonstrates that timely recognition and management of lithium-induced NDI may allow recovery of urinary concentrating ability.
Comparative Efficacy and Safety of Resmetirom and Efruxifermin for Metabolic Dysfunction-Associated Steatohepatitis: A Network Meta-Analysis of Randomized Controlled Trials.
Endocrinol Diabetes Metab
Doha Jaber, Inas Jaber, Ayah Abu Lehia +2 more
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver condition and a major cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. Resmetirom, a thyroid hormone receptor β agonist, and Efruxifermin, a fibroblast growth factor 21 analogue, have shown promise in improving hepatic fat fraction (HFF) and liver enzyme levels. This study systematically compares the efficacy and safety of Resmetirom and Efruxifermin in treating MASH.
Efficacy of GLP-1 analog peptides, semaglutide, tirzepatide, and retatrutide on MC4R deficient obesity and their comparison.
Int J Obes (Lond)
Kosuke Hitaka, Takumi Sugawara, Mitsuharu Matsumoto +1 more
Melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus, playing a key role in regulating feeding behavior and energy homeostasis. MC4R is integral to the POMC-MC4R and leptin-MC4R pathways, which control food intake and body weight. Mutations in the POMC gene lead to severe early-onset obesity and increased food consumption. Recently, glucagon-like peptide-1 (GLP-1) analogs, including semaglutide, tirzepatide, and retatrutide, have been explored as potential anti-obesity therapies.
High-linear energy transfer radiation disrupts natural killer cell surveillance of senescent intestinal cells in the mouse intestine.
Mol Biomed
Santosh Kumar, Shubhankar Suman, Heng-Hong Li +3 more
High-Linear Energy Transfer (LET) ion radiation, such as 28Si ions, is densely ionizing and poses a significant risk to astronauts during long-duration space missions. We previously showed that mice exposed to high-LET ionizing radiation (IR) exhibit greater accumulation of senescent cells in the intestine than those exposed to equivalent doses of low-LET γ-rays. However, the mechanisms driving this persistent senescence remain unclear. Given the role of Natural killer (NK) cells in senescent cell clearance, we investigated the impact of IR on intestinal NK cell function. At 60 days post-irradiation, intestinal tissues from 28Si-exposed mice showed a significant reduction in NKp46⁺ NK cells and decreased expression of molecules associated with NK activation and epithelial interactions. NK cell subtype analysis further revealed a decline in functionally mature populations involved in recognizing stressed cells. In parallel, intestinal epithelial cells (IECs) displayed altered expression of NK cell regulatory ligands, including reduced activating signals and increased inhibitory signaling associated with Qa-1b (non-classical MHC class Ib). Mechanistically, these changes were linked to activation of p38 Mitogen-Activated Protein Kinase (MAPK) signaling. Using irradiated intestinal organoids, we observed that pharmacological inhibition of the p38 MAPK pathway decreased Qa-1b expression and enhanced NK cell cytotoxic activity. Causality experiments further demonstrated that Qa-1b directly regulates NK cell-mediated cytotoxicity against senescent IECs. Collectively, these findings indicate that high-LET IR compromises intestinal immune surveillance by impairing NK cell function through a p38 MAPK-Qa-1b signaling axis, providing mechanistic insight into radiation-induced immune dysregulation.
Galectin-9high Neutrophils Exacerbate Radiation-Induced Frailty.
Aging Cell
Zhuo Cheng, Le Ma, Yan Chen +11 more
Local radiation injury-induced frailty seriously impacts the quality of life of patients undergoing radiotherapy or nuclear accident casualties and causes a significant medical and economic burden. However, the underlying mechanisms of the frailty remain unknown. In this study, a unique population of hyperactive GAL-9high neutrophils is identified with characteristics of elevated ROS, NETs, and IFN-γ, prolonged lifespan, etc. These neutrophils infiltrate into multiple organs to induce injuries, also disrupt the bone marrow microenvironment, drive sustained bone marrow myeloid-biased differentiation, and resist clearance by bone marrow macrophages, serving as a crucial factor to exacerbate frailty. GAL-9 protein is demonstrated to play a vital role in the regulation of neutrophil hyperactivity. EccDNA shedding after skin radiation injury is shown to activate the JAK1/2-STAT1 pathway in splenic GMP cells, which is a potential origin of GAL-9high neutrophils. In summary, our results highlight the significance of the previously unrecognized hyperactive GAL-9high neutrophils to exacerbate frailty through a 'skin-spleen-bone marrow-multiple organs' axis after local radiation injury.
DNA O-MAP uncovers the molecular neighborhoods associated with specific genomic loci.
Elife
Yuzhen Liu, Christopher D McGann, Conor P Herlihy +14 more
The accuracy of crucial nuclear processes such as transcription, replication, and repair depends on the local composition of chromatin and the regulatory proteins that reside there. Understanding these DNA-protein interactions at the level of specific genomic loci has remained challenging due to technical limitations. Here, we introduce a method termed 'DNA O-MAP', which uses programmable peroxidase-conjugated oligonucleotide probes to biotinylate nearby proteins. We show that DNA O-MAP can be coupled with label-free or sample multiplexed quantitative proteomics, targeted chemical perturbations, and next-generation sequencing to quantify DNA-proximal proteins and DNA-DNA interactions at specific genomic loci in human and murine cells. Furthermore, we establish that DNA O-MAP is applicable to both repetitive and unique genomic loci of varying sizes, from kilobase HOX gene clusters to megabase alpha-satellite repeats, and that DNA O-MAP can measure proximal molecular effectors in a homolog-specific manner.
Semaglutide-Induced Weight Loss Is the Main Determinant for the Improvement of Hepatic Biochemistry and Elastographic Repeated Measurements with FibroScan® in Patients with Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease.
Metab Syndr Relat Disord
Savvoula Savvidou, Elektra Augousti-Varela, Aikaterini Damianakou +2 more
Semaglutide is currently being investigated for its effectiveness in metabolic dysfunction-associated steatotic liver disease (MASLD), irrespective of type 2 diabetes mellitus (T2DM) presence, even though its action on hepatic fibrosis is still debated. The aim of this study was to examine the effect of semaglutide on hepatic parameters in patients with both T2DM and MASLD in real-world clinical practice, and to further assess the significance of weight loss during treatment.
Preoperative GLP-1 Receptor Agonists and Thromboinflammatory Markers in Patients Undergoing Abdominoplasty: A Prospective Monocentric Study.
Aesthetic Plast Surg
Agostino Bruno, Marco Schirosi, Riccardo Foti
Abdominoplasty in patients with obesity carries a heightened risk of venous thromboembolism (VTE) due to a proinflammatory and hypercoagulable baseline. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for weight loss and have demonstrated anti-inflammatory and antithrombotic properties, but their role in aesthetic surgery remains unexplored.
Molecular Characterization of the Effect of Glucagon-Like Peptide-1 Receptor Agonist Semaglutide in the Nephrotoxic Serum Nephritis Mouse Model.
Kidney360
Jaime Moreno Martinez, Maria Ougaard, Tanya Grancharova +7 more
CKD is a significant public health issue, affecting approximately half a billion people globally. Key risk factors for CKD include obesity, hypertension, cardiovascular diseases and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are effective treatments for obesity and diabetes. The FLOW trial recently showed that treatment with the GLP-1RA semaglutide significantly reduced the incidence of clinically important kidney outcomes in patients with type 2 diabetes and CKD, likely via beneficial effects on kidney blood flow, inflammation and fibrosis as well as effects mediated by improvement of glycemic control. This study aimed to characterize the effects of semaglutide in the mouse nephrotoxic serum nephritis model, a non-obese and non-diabetic mouse model of CKD.
Real-World Clinical Evidence of Tirzepatide for Metabolic Abnormalities in Subjects With Type 2 Diabetes: The Multicenter Retrospective Observational Hokkaido-TZP Study.
Diabetes Obes Metab
Fumika Maruyama, Hiroya Kitsunai, Naoyuki Kitao +12 more
Tirzepatide has demonstrated potent glucose-lowering efficacy and metabolic benefits in subjects with type 2 diabetes (T2D) in Phase III clinical trials. However, its efficacy in real-world clinical practice, particularly among patients receiving various antidiabetic therapies, remains to be elucidated.
Early intervention with tirzepatide or semaglutide influences anti-atherosclerotic effects in ApoE knockout mice.
Sci Rep
Kazunori Dan, Junpei Sanada, Tomohiko Kimura +10 more
This study aimed to investigate the anti-atherosclerotic properties of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, in comparison with semaglutide, a selective GLP-1 receptor agonist. ApoE knockout mice were divided into early diabetes (dosed from 10 to 22 weeks of age), late diabetes (dosed from 18 to 30 weeks of age), and non-diabetic groups after streptozotocin treatment, and each group received semaglutide, tirzepatide, or saline for 12 weeks. In the early diabetes group, both agents significantly suppressed aortic plaque formation compared with control, while modestly improving glycemia and lipid levels. No significant vascular effects were observed in late diabetes or non-diabetic groups. Tirzepatide markedly reduced inflammatory mediators, including Mcp-1, Il-6, I-cam, and Cd68, whereas semaglutide showed partial overlap. Notably, these anti-inflammatory effects were also detected in non-diabetic mice, suggesting vascular protection may involve arterial actions independently of metabolic control. Taken together, our findings demonstrate that tirzepatide exerts anti-atherosclerotic effects comparable to semaglutide, supporting the concept that GIP and GLP-1 signaling can confer vascular benefits. These results highlight the potential clinical relevance of dual incretin receptor agonism for cardiovascular risk reduction, although further studies are required to clarify the specific role of GIP signaling.
Analyzing Vital Sign Variability in Remote Monitoring as a Predictor of 31-Day Heart Failure Readmission: A Retrospective Cohort Study.
Telemed J E Health
Adeel Arif, Anshul Kumar, Michelle Elsener +2 more
Heart failure (HF) is a major cause of morbidity and early hospital readmission in the United States. Remote patient monitoring (RPM) is increasingly used to support postdischarge care, but evidence remains mixed, and the prognostic value of day-to-day vital sign variability is unclear. This study evaluated whether physiologic variability and patient engagement during RPM were associated with 31-day HF readmission.
Tirzepatide-induced ketoacidosis with hyperglycemia in a patient without diabetes.
Arch Endocrinol Metab
Mendel Shloush, Vania Rodriguez, Victor Guillen +1 more
Tirzepatide,a dual GLP-1 and GIP receptor agonist, is increasingly used for weight management in both patients with diabetes and patients without diabetes. While gastrointestinal side effects such as nausea are common, severe metabolic complications like ketoacidosis are rare and often overlooked. We report the case of a 38-year-old woman with congenital heart disease who developed acute ketoacidosis with hyperglycemia following five months of tirzepatide therapy. Laboratory findings confirmed high anion gap metabolic acidosis, elevated ketones, and significant hyperglycemia. With supportive care, including intravenous fluids, insulin infusion, and electrolyte replacement, she recovered fully. This represents a rare case of tirzepatide-induced hyperglycemic ketoacidosis in a patient without diabetes. In contrast, the two previously reported cases by Singh and cols. and Iqbal and cols. involved patients without diabetes who developed euglycemic ketoacidosis with normal glucose levels while on tirzepatide. This case underscores the importance of vigilant monitoring for metabolic complications, including hyperglycemia and ketoacidosis, in patients without diabetes, particularly those with comorbidities.
Beyond the HPA axis: Synaptic circuits of PVNCRH neurons in stress-related psychiatric disorders.
Pharmacol Res
Jiayuan Zheng, Na Yue, Zhanzhuang Tian +2 more
Chronic psychosocial stress is a major risk factor for anxiety, depression and related disorders, yet a hypothalamic-pituitary-adrenal (HPA) axis centric framework alone is insufficient to explain stress-induced vulnerability and phenotypic heterogeneity. Paraventricular nucleus corticotropin-releasing hormone (PVNCRH) neurons are classically regarded as the neuroendocrine entry point for driving glucocorticoid secretion. However, accumulating evidence indicates that, beyond this endocrine role, they also use fast transmitters and CRH co-transmission to form functional projections to diverse brain regions and pre-sympathetic circuits, thereby regulating stress dimensions that extend beyond HPA axis output, including defensive behaviors, reward and motivation, arousal-sleep regulation, autonomic output and glucose homeostasis. In this review, we integrate anatomical, electrophysiological, and behavioral evidence across representative PVNCRH pathways, compare their stress-related functional specialization and shared mechanisms across synaptic and endocrine timescales, and discuss translational implications for circuit-informed pharmacological and neuromodulatory strategies in stress-related psychiatric disorders.
Absent nocturnal cortisol decline in Pheochromocytoma: A retrospective study.
Steroids
Yahan Sun, Mitsuhiro Kometani, Ko Aiga +5 more
Pheochromocytoma is a catecholamine-producing tumor that may exhibit atypical hormonal profiles. Emerging evidence suggests an association with cortisol dysregulation in the absence of overt Cushing syndrome; however, systematic cortisol evaluation is not routinely performed. This study investigated the prevalence and clinical characteristics of absent nocturnal cortisol decline in pheochromocytoma. This retrospective study included 53 patients with histologically confirmed pheochromocytoma treated between 2011 and 2024. All eligible patients diagnosed during the study period were included. Among them, 22 had paired morning (8:00 AM) and midnight serum cortisol measurements for analysis of nocturnal cortisol decline. Adrenocorticotropic hormone (ACTH) and the 1-mg dexamethasone suppression test (DST) were assessed when available. Patients were stratified by midnight cortisol level (≥1.8 µg/dL vs < 1.8 µg/dL). Among the 22 patients, 18 (82%) had elevated midnight cortisol, indicating absent nocturnal decline (mean midnight, 5.1 µg/dL; mean morning, 13.7 µg/dL). The elevated group (n = 18) was older than the normal group (n = 4) (median, 64 vs 43 years). Metabolic comorbidities were more frequent in the elevated group, including diabetes (50% vs. 25%), dyslipidemia (61% vs. 25%), and cardiovascular disease (44% vs. 0%). DST was performed in 10 patients and showed adequate suppression in 7 of 8 patients with paired cortisol measurements, arguing against autonomous cortisol secretion. No patients had clinical features of overt Cushing syndrome. Absent nocturnal cortisol decline was common and may reflect a pseudo-Cushing state associated with catecholamine excess. These findings support further evaluation of cortisol regulation and its clinical implications.
Ectopic ACTH-dependent Cushing syndrome due to mature ovarian teratoma.
BMJ Case Rep
Naseem Eisa
Ectopic adrenocorticotropic hormone (ACTH) secretion accounts for 10%-20% of ACTH-dependent Cushing syndrome, with ovarian teratomas being an exceptionally rare source. We present a female in her early 40s with severe Cushing syndrome due to ectopic ACTH secretion from a mature ovarian teratoma. She presented with progressive weight gain, moon facies, dorsocervical fat pad, proximal muscle weakness, hypertension and new-onset diabetes. Biochemical evaluation confirmed ACTH-dependent hypercortisolism with elevated cortisol, plasma ACTH, late-night salivary cortisol, urinary free cortisol and failure of dexamethasone suppression. Bilateral inferior petrosal sinus sampling (IPSS) confirmed an ectopic source. After negative pituitary and thoracoabdominal imaging, pelvic imaging identified a large right ovarian mass. Laparoscopic salpingo-oophorectomy was performed, and histopathology confirmed a mature cystic teratoma with ACTH-positive neuroendocrine cells. Postoperatively, the patient achieved complete clinical and biochemical remission with full hypothalamic-pituitary-adrenal axis recovery at 1 year follow-up. This case underscores the systematic diagnostic approach required for ectopic ACTH syndrome-including biochemical confirmation, IPSS to distinguish pituitary from ectopic sources and comprehensive imaging-as well as the importance of considering uncommon tumour sites, including ovarian teratomas, when standard thoracoabdominal imaging is unrevealing.