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Weight-loss dynamics with tirzepatide versus semaglutide.
PNAS Nexus
A J Venkatakrishnan, Karthik Murugadoss, Venky Soundararajan
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for obesity and type 2 diabetes, yet substantial variability in weight-loss response remains poorly understood. We conducted a retrospective cohort study using de-identified electronic health records and performed 1:1 propensity matching on age, sex, type 2 diabetes status, baseline BMI and weight, index year, and follow-up duration. The matched cohorts included 10,339 tirzepatide-treated and 10,339 semaglutide-treated patients. Patients were categorized by maximum weight loss over 2 years into five response groups. Adverse events were identified through AI-enabled curation of clinical notes. Weight-loss trajectories, demographic patterns, adverse-event profiles, and pre- to posttreatment disease-prevalence changes were compared across drugs. Patients treated with tirzepatide lost more weight than those treated with semaglutide (mean reduction, 14.7 vs. 10.8%; P < 0.001). High-response rates (≥15% weight loss in year 1) were nearly doubled with tirzepatide (42.6 vs. 21.6%; P < 0.001), accompanied by faster monthly weight-loss velocity (2.54 vs. 2.18%). AI-enabled curation showed that tirzepatide was associated with lower prevalence of gastrointestinal and systemic adverse events. For both tirzepatide and semaglutide, women were more represented among high responders than the minimal weight-loss group (<5% weight loss) and White patients were more represented among high responders, whereas Black and Hispanic patients were more represented among the minimal weight-loss group. In this large, propensity-matched real-world cohort, tirzepatide was associated with greater and faster weight loss than semaglutide, with marked demographic variations in outcomes, highlighting the need for next-generation obesity clinical trials and routine care decisions to incorporate the growing body of evidence from widespread use of incretin therapies across diverse patient populations.
Swiss obesity clinical practice guidance.
Swiss Med Wkly
Philipp A Gerber, Tinh-Hai Collet, Lucie Favre +8 more
Obesity is a chronic, relapsing, and multifactorial disease that poses a significant public health challenge in Switzerland, where approximately 43% of adults are overweight or obese. This new clinical practice guidance establishes a structured, multidisciplinary framework for healthcare professionals, emphasising that assessment, treatment and care should focus on improving overall health metrics, resolving comorbidities and achieving functional gains, rather than solely on numerical weight loss. Crucially, the guidance mandates a non-stigmatising, empathetic approach to combat weight bias, reduce internalised stigma and build therapeutic trust. Accurate diagnosis and risk stratification begin with measuring body mass index (BMI), using adjusted cutoffs for specific ethnic populations. However, since BMI alone may not fully capture cardiometabolic risk, we recommend integrating waist circumference and body composition analyses. Physicians must conduct a comprehensive assessment to identify mechanical and metabolic comorbidities - spanning cardiometabolic, respiratory, gastrointestinal, musculoskeletal and mental health domains, among others - and systematically evaluate the patient's daily functioning and health-related quality of life. Care is organised across a tiered system. Primary care physicians play a central role in screening, initial management, and long-term monitoring. Patients with a BMI of 35 kg/m² or higher, or those with severe obesity-related complications, should be referred to specialised medical obesity services. The foundation of all weight management is a multimodal lifestyle intervention. This intervention includes medical nutrition therapy favouring minimally processed, nutrient-dense diets, such as the Mediterranean pattern; individualised physical activity plans targeting 150-300 minutes of moderate aerobic exercise per week alongside resistance training; and behavioural strategies, such as cognitive behavioural therapy, to address emotional eating and enhance self-efficacy. When lifestyle modifications are insufficient, adjunctive therapies are indicated. The pharmacological landscape has been revolutionised by incretin-based therapies, notably GLP-1 and dual GIP/GLP-1 receptor agonists (e.g. semaglutide and tirzepatide). These medications produce substantial weight reduction and cardiovascular benefits, although clinicians must carefully navigate current reimbursement criteria. For patients with severe or treatment-resistant obesity, bariatric/metabolic surgery, such as Roux-en-Y gastric bypass and sleeve gastrectomy, offers highly effective, durable outcomes but necessitates lifelong interdisciplinary follow-up. Finally, the guidance highlights the necessity of individualised care for special populations, including tailored strategies for children, reproductive-age women and older adults, for whom preserving muscle mass and bone health is prioritised over absolute weight loss.
GLP-1 Agonist Attenuates Nicotine Reward-Related Behavior by Regulating the Prepro-Orexin in the Hypothalamus and Prepro-Glucagon in the Nucleus Tractus Solitarius.
Behav Neurol
M Rahmadi, C Ardianto, R Rodsiri +4 more
Tobacco consumption has significantly increased globally, contributing to various degenerative diseases such as lung cancer and cardiovascular disorders. Nicotine, the primary addictive component in tobacco, exerts its effects by stimulating nicotinic acetylcholine receptors (nAChRs), leading to excessive dopamine release in the ventral tegmental area (VTA) and nucleus accumbens (NAc), which underlies its rewarding and addictive properties. Additionally, nicotine enhances orexin activity in the hypothalamus and prepro-glucagon expression in the nucleus tractus solitarius (NTS), further reinforcing addictive behaviors. This study is aimed at investigating the effects of liraglutide, a GLP-1 receptor agonist, on nicotine-induced reward. Male mice strain ddy were divided into four groups: control, nicotine, nicotine + liraglutide (50 μg/kg), and nicotine + liraglutide (100 μg/kg). The conditioned place preference (CPP) test was used to evaluate nicotine's rewarding effects, whereas RT-PCR assessed the expression of prepro-orexin and prepro-glucagon mRNA in the hypothalamus and NTS, respectively. The results confirmed that nicotine administration (0.5 mg/kg) significantly increased CPP scores, indicating enhanced reward-related behaviors. Correspondingly, nicotine elevated prepro-orexin and prepro-glucagon mRNA expression levels. Treatment with liraglutide (50 and 100 μg/kg) significantly reduced nicotine-induced CPP scores, suggesting an attenuation of addictive behavior. Liraglutide downregulated the expression of prepro-orexin and prepro-glucagon, with the 100 μg/kg dose demonstrating greater efficacy in normalizing prepro-glucagon levels. These findings indicate that liraglutide mitigates nicotine reward by modulating neuropeptide pathways, including orexin and glucagon signaling. The dual impact of liraglutide on behavioral and molecular markers highlights its potential as a therapeutic agent for treating nicotine induce reward-related behavior. Further research is warranted to explore its long-term efficacy and underlying mechanisms in addiction modulation.
Liraglutide-Induced Acute Hepatocellular Injury With Positive Rechallenge: A Case Report and Literature Review.
Clin Med Insights Case Rep
Mohammad Adi, Ahmed Ashraf, Shohsanam Eshimova +1 more
Glucagon-like peptide-1 receptor agonist liraglutide is widely used in type 2 diabetes mellitus and obesity and is generally considered non-hepatotoxic, with only rare reports of idiosyncratic liver injury. We report the case of a 58-year-old obese woman with type 2 diabetes who developed marked hepatocellular injury 12 weeks after initiating liraglutide therapy, with alanine aminotransferase (ALT) 876 U/L and aspartate aminotransferase (AST) 702 U/L after exclusion of alternative causes. Liver enzyme levels improved rapidly following drug discontinuation. A supervised rechallenge resulted in recurrence of severe transaminitis (ALT 1245 U/L, AST 980 U/L) within 10 days, with RUCAM score of 11 supporting a highly probable drug-induced liver injury. This case highlights a rare but definite idiosyncratic hepatocellular injury associated with liraglutide. Prompt recognition, discontinuation, and avoidance of rechallenge are essential. Further pharmacovigilance is warranted to better characterize incidence and mechanisms and guide safe clinical use of GLP-1 therapies in practice settings.
Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: theoretical foundations, regulatory suspension, and translational challenges.
Front Aging
Gang Li, Shusheng Jiao, Yi Zhou +1 more
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological changes in β-amyloid protein deposition, abnormal tau protein phosphorylation neurofibrillary tangles, and chronic neuroinflammation. Recent studies have shown that the glymphatic-meningeal-cervical lymphatic system pathway plays a crucial role in the clearance of intracranial metabolic waste. Dysfunction of this system may lead to a decrease in the clearance efficiency of Aβ and tau proteins. Deep cervical lymphaticovenous anastomosis (DCLVA) has been proposed as a novel surgical approach to enhance cervical lymphatic drainage, reduce Aβ/tau accumulation, and improve cognitive function in patients with AD. However, on 8 July 2025, the National Health Commission of China issued a notice prohibiting the clinical application of "deep cervical lymphaticovenous anastomosis" for the treatment of AD. This article provides a narrative review with critical appraisal of the theoretical basis, surgical mechanisms, and clinical evidence of DCLVA for AD. We objectively evaluate the strengths and limitations of current clinical studies, critically appraise the uncertainty of underlying physiology, and comprehensively analyze the potential risks, safety concerns, and translational obstacles that led to regulatory suspension. We further clarify unresolved scientific questions including pressure gradients, lymphatic contractility, reflux risk, anastomotic patency, and biomarker validation. By framing DCLVA within the context of its clinical prohibition, we provide clinicians and researchers with a balanced appraisal that acknowledges both the procedure's potential and the substantial gaps that must be addressed before widespread application can be justified.
Cyclin-Dependent Kinases 4 and 6 Inhibitors: An Emerging Therapeutic Framework from Growth Suppression to Tumor Clearance.
ACS Pharmacol Transl Sci
Cong Ma, Xuan Ji, Wenqin Huang +5 more
This review explores strategies to overcome the clinical limitations of Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, namely, reversible cytostasis and acquired resistance. We outline an emerging therapeutic framework in which these inhibitors induce specific vulnerabilities, shifting the treatment objective from growth suppression toward tumor clearance. Specifically, we analyze the effects of CDK4/6 inhibitors across four interconnected domains: cellular senescence, compromised DNA damage repair, metabolic reprogramming, and immune microenvironment remodeling. Building upon this framework, we summarize rational combination strategiessuch as pairing with senolytics, poly-(ADP-ribose) polymerase (PARP) inhibitors, or immune checkpoint inhibitors (ICIs)designed to exploit these induced vulnerabilities. To bridge preclinical rationale with clinical application, we discuss key translational determinants, noting that successful implementation depends on biomarker-guided patient selection and optimized dosing schedules (e.g., sequential administration) to mitigate overlapping toxicities. Collectively, the evidence suggests that rational combination strategies could repurpose CDK4/6 inhibitor therapy for more durable tumor control.
Apelin analog treatment reverses severe pulmonary arterial hypertension and right ventricular heart failure.
JCI Insight
Jennie Vu, Pavel Zhabyeyev, Kemar J Brown +18 more
Pulmonary arterial hypertension (PAH) is a progressive vascular syndrome characterized by aberrant signaling, severe pulmonary artery remodeling, and right ventricular (RV) failure, a major driver of morbidity and mortality. Dysregulation of the apelinergic pathway has been implicated in pulmonary vascular remodeling in PAH. Using a sugen-hypoxia rat model of PAH, we assessed the ability of a novel apelin analog, resistant to native peptidase degradation, to reverse the pathological hallmarks of PAH and RV dysfunction. Apelin analog therapy corrected the vascular lesions in the lungs and nearly normalized pulmonary arterial pressures. Early cardiorenal syndrome, RV dilation and dysfunction as well as RV cardiomyocyte and fibroblast activation induced by pressure overload, were also reversed by apelin analog treatment. Single-nucleus RNA sequencing of the lungs and RV revealed apelin-analog treatment activated several protective pathways, including rebalancing protective BMPR2 (bone morphogenetic protein receptor type 2) signaling to counteract excessive pathogenic TGFBR2 (transforming growth factor β receptor 2) activity in PAH. These findings highlight the therapeutic potential of exogenous apelin in reversing pulmonary vascular and cardiac pathologies in PAH and support further investigation to evaluate the clinical benefits of apelin analog treatment in patients with PAH and RV failure.
Prescribing Trajectories in Type 2 Diabetes in the United States, 2019-2024.
Diabetes Obes Metab
Tobias S Lux, Dongkun Lee, Jeff M Phillips +12 more
Clinical guidelines for type 2 diabetes (T2D) provide population-level recommendations, but real-world treatment patterns evolve dynamically and vary across patients. Understanding longitudinal prescribing trajectories may reveal heterogeneity in care not captured by cross-sectional analyses.
Spurious Plasma Adrenocorticotropic Hormone Level in a Patient With Adrenal Cushing Syndrome.
Ochsner J
Sarath Chandran, Alpesh Goyal, Mangesh Mane +2 more
Endogenous Cushing syndrome results from excessive cortisol production by the adrenal glands and is characterized by the loss of circadian rhythm of cortisol secretion and negative feedback regulation of the hypothalamic-pituitary-adrenal axis. This condition is broadly subtyped into adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent types based on ACTH measurement. A plasma ACTH level <5 pg/mL suggests ACTH-independent Cushing syndrome (adrenal source), while a level >15 pg/mL suggests ACTH-dependent Cushing syndrome (pituitary or ectopic source). A certain immunoassay platform (Immulite 1000 [Siemens AG]) has a known positive ACTH bias, so a patient with ACTH-independent Cushing syndrome may be falsely labeled as having ACTH-dependent disease. This misclassification can lead to unnecessary investigations and interventions such as pituitary imaging, inferior petrosal sinus sampling, and even pituitary surgery.
Primary Ovarian Neuroendocrine Neoplasm With Carcinoid Syndrome and Carcinoid Heart Disease.
Ochsner J
Kitti Thammakosol, Prin Vathesatogkit, Surakiat Leelasithorn +1 more
Neuroendocrine neoplasms commonly arise in the midgut, lungs, or pancreas, while primary ovarian neuroendocrine neoplasms are rare and can present with carcinoid syndrome and carcinoid heart disease even in the absence of hepatic metastases.
Rational engineering of a novel cationic LL-37-temporin SHa hybrid peptide with anti-parasitic activity and effects on mitochondrial membrane potential in protozoan parasites.
Microb Pathog
Kiran Khurshid, Muhammad Adnan Sabir Mughal, Jamal Muhammad Khan +3 more
The emergence of drug resistance and host toxicity is associated with conventional antiprotozoal therapies which necessitates development of novel and selective antiparasitic agents. In the present study, novel hybrid peptide which is HP-AP-1 (KRIVQRIDKFLRNFLPLLAKK) was rationally designed and evaluated through combination of LL-37 membrane-active core with a truncated temporin-derived hydrophobic motif followed by C-terminal cationic optimization. Physicochemical analysis revealed 21-amino-acid peptide with molecular weight of 2597.23 Da, high theoretical pI (11.74), +6 net charge, moderate hydrophobicity (GRAVY -0.257) and strong α-helical propensity (>95%). Helical wheel projection confirmed well-defined amphipathic structure. Analytical RP-HPLC verified approximately 97.25% purity and an accurate molecular mass was confirmed through MALDI-TOF MS. Biological evaluation also demonstrated negligible hemolytic activity of <5% at 64 μM and low cytotoxicity toward RAW264.7 macrophages of >75-85% viability. HP-AP-1 has exhibited dose-dependent antiparasitic activity against Tritrichomonas foetus and Leishmania infantum with IC50 values approximately 8-9 μM. Notably, the peptide was significantly reduced intracellular amastigote burden in the infected macrophages. Mechanistic studies revealed concentration-dependent mitochondrial membrane depolarization by suggesting potential membrane-associated effects. Collectively, these findings have demonstrated that rational hybridization of LL-37 and temporin motifs with C-terminal cationic reinforcement yields a selective, amphipathic and mechanistically versatile antiparasitic peptide. HP-AP-1 represents a promising in vitro anti-parasitic peptide candidate requiring further in vivo validation and serves as a rationally designed scaffold for future optimization studies.
Cathelicidin antimicrobial peptides: current progress and future prospects in immunotherapy.
Dev Comp Immunol
Aibo Ding, Zhonghua Lu, Jiajing Wu +5 more
Antimicrobial peptides (AMPs) are small molecules with defensive effects that are crucial in innate immune defense. Cathelicidin AMPs are a major AMP family found in humans and other vertebrates, originating from various cell types such as neutrophils, macrophages, pancreatic β-cells and epithelial cells. Cathelicidin AMPs serve as a vital line of defense for the immune system. With the rise of antibiotic resistance, many studies are paying attention to cathelicidin AMPs, classic distinctive small immunopeptides. This article provides a systematic review of the molecular structure, biological role and mechanism of cathelicidin AMPs, along with its advancement in clinical application for treating both infectious and non-infectious disease. Additionally, this review points out the future research direction and potential application of cathelicidin AMPs, considering the limitation of current study.
Adjunctive GLP1 Receptor Agonists in Patients with Inflammatory Bowel Diseases and Obesity and/or Diabetes: A Target Trial Emulation.
Clin Gastroenterol Hepatol
Kuan-Hung Yeh, Dhruv Ahuja, Sagar B Patel +11 more
We conducted a target trial emulation study to examine the effect of two glucagon-like peptide-1 receptor agonists (GLP1RAs) (semaglutide and tirzepatide) on clinical outcomes in patients with inflammatory bowel diseases (IBD) with obesity and/or diabetes.
A Computational Trial of Dermal Mechanotransduction in GLP-1 Receptor Agonist-Associated Premature Facial Ageing.
Aesthetic Plast Surg
Eqram Rahman, William Richard Webb, Jean D A Carruthers
The efficacy of non-invasive ultrasound skin tightening (e.g., Sofwave) relies on fibroblast mechanotransduction, a process impaired in obesity. The widespread use of GLP-1 receptor agonists (GLP-1RAs) like semaglutide for weight loss introduces a dynamic metabolic variable that may further alter dermal tissue state. The optimal timing between these interventions is unknown and difficult to study clinically.
1-year outcomes of semaglutide, tirzepatide, and sleeve gastrectomy in obesity in type 2 diabetes: a retrospective cohort study.
Lancet Diabetes Endocrinol
Daniel B Leslie, Brian T Steffen, Eric Wise +5 more
Type 2 diabetes and obesity are prevalent, inter-related conditions for which treatment options have expanded substantially, yet direct real-world comparisons of modern pharmacological and surgical interventions remain scarce. We aimed to compare 1-year weight loss, glycaemic outcomes, and selected safety outcomes associated with semaglutide, tirzepatide, and sleeve gastrectomy among adults with obesity and type 2 diabetes in real-world clinical practice.
Profiling the molecular and physiological effects of senolytic treatment on aged mice identifies immune, fibrotic and metabolic remodeling.
Nat Aging
Jing Hou, Kai-Xuan Chen, Qiao-Ni Xiao +17 more
Although senolytics such as dasatinib and quercetin (D+Q) show promise in modulating aging, their tissue-specific efficacy and optimal intervention timing remain poorly understood. Given D+Q's potential off-target effects, incomplete senescent cell clearance and associated hematologic side effects, we performed an unbiased multitissue single-cell analysis in aged mice across different aging phenotypes and tissue contexts. Here through integrative transcriptomics, single-cell technologies, histopathology and molecular profiling, we investigated the influence of D+Q treatment on aging-related phenotypes at the tissue and cellular levels. Specifically, D+Q remodeled immunity by enhancing immune cell function and maintaining population stability, alleviated tissue inflammation and improved metabolic profiles. Furthermore, intervention initiated during early aging and prolonged treatment showed a greater tendency to mitigate readouts of aging compared to shorter, late-stage treatment. Our findings reveal that D+Q systematically attenuates several aging hallmarks in a tissue- and cell-type-specific manner, and support the possibility that early-initiated, long-term intervention may amplify efficacy.
Orange Peel Powder Improves Constipation-Related Phenotypes and Is Associated with Coordinated Colonic and Brain-Related Changes in a Doxorubicin- and Loperamide-Treated Rat Model.
J Nutr
Kun Xu, Yiming Zhang, Gaixia Hou +2 more
This study aimed to determine whether orange peel powder (OP) improves constipation-related phenotypes in a doxorubicin- and loperamide-treated rat model and whether such improvement is accompanied by coordinated histological and molecular changes in colon and brain tissues.
Corticotropin-secreting pheochromocytoma: A case report.
Endocrinol Diabetes Nutr (Engl Ed)
Pedro Iglesias, Juan González González, Emiliano González-Vioque +1 more
Corticotropin (ACTH)-secreting pheochromocytomas are rare neuroendocrine tumors that combine catecholamine and cortisol excess, posing major diagnostic and therapeutic challenges. We report the case of a 38-year-old man with hypertension, episodic adrenergic symptoms, and biochemical evidence of elevated metanephrines and ACTH-dependent hypercortisolism. Imaging revealed a right adrenal mass compatible with pheochromocytoma, but metaiodobenzylguanidine (MIBG) scintigraphy was negative. After preoperative preparation with alpha- and beta-blockade and intraoperative steroid coverage, the patient underwent laparoscopic adrenalectomy. Histopathology confirmed pheochromocytoma with focal ACTH expression and malignant potential (PASS 5). Postoperatively, he required transient glucocorticoid replacement and achieved normotension without antihypertensives. This case illustrates the complexity of diagnosing and managing ACTH-secreting pheochromocytomas, highlights the need for careful preoperative stabilization, and underscores the importance of multidisciplinary follow-up to detect recurrence and manage adrenal insufficiency.
Cholecystokinin coordinates gonadotropin-dependent and independent pathways to orchestrate zebrafish gonadal development.
Nat Commun
Hangyu Li, Faming Yuan, Hongwei Liang +15 more
Cholecystokinin (CCK) is established as a critical regulator of teleost gonadal development, functioning not only as a follicle-stimulating-hormone-releasing hormone (FSH-RH) but also stimulating gonadal development through three distinct mechanisms. Specifically, (1) CCK directly activates pituitary lhb transcription via CCKBRb in a specific bi-hormonal subpopulation, and indirectly enhances hypothalamic gnrh3 expression to regulate LH synthesis and secretion. However, CCK's physiological role in LH regulation requires further investigation, and its effect may involve both direct and indirect mechanisms, including targeting a specific bi-hormonal subpopulation. (2) CCK exerts gonadotropin-independent control over primordial germ cell (PGC) proliferation during embryogenesis, evidenced by significantly reduced PGC numbers in cck1-/-;cck2-/- and cckbrb-/- mutants, a phenotype absent in fshb-/- and lhb-/-;fshb-/- zebrafish. (3) CCK initiates meiosis and maintains gonadal somatic cell survival by suppressing apoptosis; these processes are abrogated in CCK-deficient mutants but remain intact in gonadotropin-deficient lines. Collectively, hypothalamic and peripheral CCK cells regulate gonadal function through gonadotropin-dependent and gonadotropin-independent pathways, respectively, thereby coordinating gonadal development from germline establishment to maturation.
Fine particulate matter and tobacco product exposure exacerbates metabolic syndrome-related colon cancer via regulating oxidative stress and tumor-associated macrophage interactions.
Cancer Metab
Shenghua Zhang, Dongfang Meng, Haibo Zhang +3 more
The incidence of colorectal cancer (CRC) is closely associated with prolonged exposure to fine particulate matter (PM 2.5) and tobacco carcinogens, 4-methylnitrosamino-l-3-pyridyl-butanone (NNK). However, due to a lack of understanding of its intricate pathological processes, there is currently no approved clinical medication or successful treatment plan. Also, tobacco carcinogens and PM 2.5 are implicated in the progression of CRC by the onset of a metabolic disorder. Nonetheless, direct evidence connecting the metabolic disorder to NNK/PM 2.5-mediated CRC development has yet to be developed.