Liraglutide

Targeting Multiple Gut-Brain Pathways in Obesity: Rationale for Combination Pharmacotherapy.

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."

Incretin-Based Therapies for the Treatment of Binge Eating-A Systematic Review.

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.

Glucagon-like peptide-1 receptor agonist use and clinical outcomes after posterior cervical spinal fusion for degenerative pathologies: A large cohort retrospective analysis.

Christian Rajkovic, Ankita Jain, Mahnoor Shafi +6 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as potentially impactful agents in improving spinal fusion outcomes. While several recent studies have investigated the effect of these agents on lumbar spinal procedures, the current evidence of the impact of these agents on cervical spinal fusion is limited. This study aims to investigate the impact of GLP-1RA use on perioperative clinical outcomes of posterior cervical spinal fusion.

Real-World Effectiveness and Safety of Tirzepatide, Semaglutide, and Liraglutide in Adults with Overweight or Obesity without Diabetes: A Comparative Study.

Serap Cetiner

Obesity is a chronic metabolic disease associated with substantial cardiometabolic risk and long-term morbidity. Although randomized controlled trials have demonstrated the efficacy of incretin-based therapies, real-world comparative data in adults with overweight or obesity without diabetes remain limited. Real-world studies provide complementary evidence by capturing treatment effectiveness, tolerability, dose escalation, and adherence in routine clinical practice.

Tirzepatide-Induced Liver Injury: A Rare Complication.

Lauren D Spaeth, Kim M Jordan, Mariah P Barlow +1 more

Tirzepatide is widely prescribed and generally considered safe. The objective of this report is to describe a patient with tirzepatide-induced liver injury and increase awareness of this rare complication.

Weight Loss With GLP-1 Agonists in Nondiabetic Adults: Systematic Review and Network Meta-Analysis.

Michael Lim, Pooja Gokhale, Akwasi Akosah +1 more

Two glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (semaglutide and liraglutide) and one dual agonist (tirzepatide) are FDA-approved for weight loss in adults with obesity without type 2 diabetes mellitus. This systematic review and network meta-analysis aims to compare the efficacy of these agents against each other.

GLP-1 receptor agonists and immune checkpoint inhibitor therapy: a narrative review on mechanistic and clinical evidence.

Connor Frey

Obesity paradoxically increases sensitivity to immune checkpoint inhibitors (ICIs) despite elevating cancer risk, creating a clinical opportunity where metabolic dysfunction may generate a target-rich immune microenvironment. However, immunosuppressive mechanisms, including regulatory T-cells, myeloid-derived suppressor cells, and pro-inflammatory macrophages, can limit durable anti-tumor responses. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond metabolic comorbidity management, functioning as metabolic-immunologic adjuvants capable of reprogramming the tumor microenvironment in obese patients receiving ICIs. A literature search was conducted in PubMed/MEDLINE through December 2025 using MeSH headings related to glucagon-like peptide-1 receptor agonists and immune checkpoint inhibitors. Mechanistically, GLP-1R signaling activates cAMP-PKA-AMPK pathways that suppress NF-κB-driven inflammation and promote macrophage repolarization, improving CD8 T-cell metabolic fitness, enhancing central memory formation, and reducing lipid-induced T-cell exhaustion. Real-world observational data across renal cell carcinoma, non-small cell lung cancer, colorectal cancer, and neuroendocrine neoplasms suggest improved overall survival, fewer immune-related adverse events, and lower cardiometabolic complications with concurrent GLP-1RA and ICI therapy. Pharmacovigilance concerns regarding pancreatitis, ICI-induced diabetes, and immune-related toxicities remain incompletely characterized. This review critically appraises mechanistic insights, real-world evidence, and safety considerations, proposing a translational-clinical research agenda to prospectively validate GLP-1RAs as rational adjuncts to checkpoint blockade.

Benchmarking size-exclusion chromatography columns for the analysis of therapeutic peptides and model oligonucleotides.

Mathias Buff, Alexandre Goyon, Kelly Zhang +1 more

Eleven modern size-exclusion chromatography (SEC) columns, including prototype columns designed to minimize non-specific interactions, were systematically evaluated for the analysis of peptides and oligonucleotides. Column physical properties and chromatographic performance were assessed under various mobile phase conditions. Notably, a reduced plate height close to 1 was achieved for one prototype column, representing a marked improvement over typical SEC performance (2 < hmin < 3). Mobile phase composition was optimized to balance chromatographic efficiency and analyte denaturation. The most denaturing conditions (30 % acetonitrile, 0.1 % trifluoroacetic acid) provided the best performance for linear, macrocyclic, disulfide-constrained, and lipid-conjugated peptides by effectively suppressing hydrophobic and ionic interactions. Columns with pore sizes ≥ 100 Å showed optimal performance, with UP-SW2000, Biozen dSEC-1, and BioCore SEC-120 columns (100-125 Å) yielding the best results. Column and mobile phase selection were particularly critical for hydrophobic peptides such as liraglutide and semaglutide; for these analytes, a phosphate-based mobile phase containing 20 % isopropanol was proposed to limit denaturation and potentially enable the characterization of non-covalent aggregates. For oligonucleotides, mobile phase composition had a limited impact, whereas stationary phase chemistry was decisive. Only two columns (UP-SW2000 and ACQUITY Premier SEC 125 Å) provided acceptable separations, enabling resolution of n-2 and n-3 shortmer impurities of 20-mer linear and structured oligonucleotides with resolutions close to 1. Coupling two 150-mm SEC columns in series further enhanced shortmer separation within 30 min.

Glucagon-like peptide-1 receptor agonists reduce experimental atherosclerosis progression, inflammatory biomarkers and cardiovascular events, irrespective of hyperglycaemia and obesity.

Mohamad B Kassab, Haitham Khraishah, Andrew Thrapp +16 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular events. However, their impact on atherosclerosis and inflammation, regardless of diabetes or obesity, is unknown. Here, GLP-1 RA effects were investigated on (i) atherosclerosis burden and inflammation in vivo in rabbits and (ii) inflammatory biomarkers and major adverse cardiovascular events (MACE) in clinical subjects, adjusted for glycaemic and obesity status.

The Role of GLP1 Receptor Agonists and Multi-agonist Incretin Therapies for Specific Obesity-related Health Conditions: Evidence and Rationale for Prioritisation.

Christo Albor, Oluwaseun Anyiam, Luke D Boyle +17 more

Impact of GLP-1 and dual agonists on the incidence of new cases of physician-reported sleep apnea: a real-world study.

Beatriz S Prado, Diego R Mazzotti, André Franci +5 more

Previous studies have shown that glucagon-like peptide-1 (GLP-1) agonists and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) agonists (tirzepatide) reduced severity of sleep apnea. However, whether these medications impact incidence of new cases of physician-reported sleep apnea (PRSA) is unknown.

Efficacy of Glucagon-Like Peptide-1 Receptor Agonists for Psychological Well-Being and Depressive Symptoms: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Tsung-Hsuan Hung, Chyi-Rong Chen, Chih-Wei Hsu +5 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic disorders. Howeve, their effects on depressive symptoms and psychological well-being remain uncertain.

Potential Antiarrhythmic Mechanisms of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs).

Jianhong Li, Kun Fu, Jiaqian Zhao +9 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a novel class of glucose-lowering agents that offer benefits beyond glycemic control and weight loss and are increasingly recognized for their cardioprotective benefits, including protective effects against hypertension, heart failure, myocardial infarction, and arrhythmias. Notably, GLP-1RAs have demonstrated a significant capacity to reduce arrhythmia risk not only in animal models but also in large-scale clinical trials. However, the antiarrhythmic mechanisms of GLP-1RAs remain incompletely understood. This mechanistic review synthesizes current preclinical and clinical evidence to delineate the key pathways through which GLP-1RAs may exert their antiarrhythmic effects. The primary mechanisms discussed include the attenuation of cardiomyocyte death, improvement of myocardial metabolism, and inhibition of the inflammatory response. Additional mechanisms, such as the promotion of autophagy, maintenance of ion homeostasis in cardiomyocytes, and modulation of the autonomic nervous system, are also examined. By clarifying these mechanisms, this review aims to offer novel therapeutic strategies for arrhythmia prevention, especially in the high-risk population with cardiometabolic diseases.

Emulating the LEADER trial in China: a regulatory science case study on non-interventional research.

Jun Zhao, Xiaona Xin, Yuanyuan Song +4 more

Integrating real-world evidence (RWE) into regulatory decision-making requires validation against pivotal randomized controlled trials for the same estimand. We emulated the LEADER trial using Chinese claims data to evaluate liraglutide's cardiovascular safety, assessing RWE-RCT concordance and examining the methodological adaptations and operational challenges encountered when emulating RCTs with claims data.

Cardiovascular Outcomes and Safety of GLP-1 Receptor Agonists in Elderly Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Weifei Gao, Xiaoming Cai, Xiaolu Wang +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, evidence specific to elderly patients remains limited. Elderly patients with diabetes are associated with high cardiovascular (CV) risk and increased susceptibility to adverse events. Therefore, this study systematically evaluated the CV outcomes and safety of GLP-1 RAs in elderly patients with T2DM.

A septal inhibitory circuit constrains alcohol reward and mediates liraglutide's suppressive effects on alcohol intake in mice.

Yu Tian, Yutong Liu, Haiyang Jing +10 more

Alcohol use disorder (AUD) lacks effective brain-targeted treatments. Here, using mouse models, we show that glucagon-like peptide-1 receptor (GLP-1R) signaling in the dorsal lateral septum (dLS) regulates alcohol consumption and reward. Systemic administration of the GLP-1R agonist liraglutide decreased alcohol intake and ethanol-evoked dopamine release in the nucleus accumbens, requiring GLP-1R expression in the dLS. Alcohol consumption suppressed dLSGLP-1R neuronal activity, whereas liraglutide prevented alcohol-induced suppression of transient calcium dynamics. Inactivation of these neurons increased alcohol consumption and abolished the behavioral effects of liraglutide, whereas chemogenetic activation suppressed alcohol-directed behavior. Circuit-level analysis identified a local inhibitory projection from dLSGLP-1R neurons to estrogen receptor 1-expressing neurons in the ventral lateral septum (vLSEsr1 neurons), and targeted manipulation of this circuit confirmed its role in regulating alcohol intake. Together, these findings delineate a septal inhibitory circuit through which GLP-1R signaling modulates alcohol-related behaviors and highlight the dLS as a therapeutic target for AUD.

Exposure-adjusted safety and efficacy of GLP-I and GLP-1/GIP receptor agonists compared with non-GLP-I for weight management and type 2 diabetes: Based on FDA medical and statistical reports of 34 280 safety and 36 312 efficacy subjects.

Aishwarya Prasad, Anshu Arora, Arun Arora +2 more

This work aimed to contextualize glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists safety and efficacy regarding weight management (WM); we analysed Food and Drug Administration (FDA) Medical Reviews to analyse 14 medications using patient-exposure year normalization and compared GLP-1 RAs with older WM medications.

Psychiatric Adverse Events and Administration Challenges Associated with GLP-1 Receptor Agonists for Weight Loss: A Real-World Analysis.

Ali Hindi, Mohamed Mekkawy, Hala Shokr

Background: Glucagon-like peptide-1 receptor agonists are increasingly prescribed for weight loss, but concerns remain regarding adverse events beyond gastrointestinal, renal, and pancreatic effects. Understanding these risks is essential to guide safe clinical application and public health policy. The study aims to characterize psychiatric risks, administration-related adverse events, and patterns of inappropriate use associated with semaglutide, liraglutide, and tirzepatide for weight management. Methods: Disproportionality analysis using proportional reporting ratios and reporting odds ratios was conducted to detect significant signals in adverse event reports within the U.S. Food and Drug Administration Adverse Event Reporting System, identifying semaglutide, liraglutide, or tirzepatide as drugs used for weight loss while excluding gastrointestinal, renal, and pancreatic adverse events. Results: Among 40,253 adverse event reports (68.6% female; median ages: semaglutide, 62 years; liraglutide, 59 years; tirzepatide, 53 years), semaglutide demonstrated the strongest disproportionality signal for psychiatric adverse events, notably anxiety (PRR 1.34, 95% CI 1.18-1.51), depression (PRR 1.83, 95% CI 1.62-2.07), and suicidal ideation (PRR 3.44, 95% CI 2.98-3.97). Tirzepatide showed markedly higher signals for injection-site reactions (PRR 7.98, 95% CI 7.8-8.18) and inappropriate use, including incorrect dosing and off-label administration (PRR 5.98, 95% CI 5.9-6.06). Conclusions: In real-world use, semaglutide is disproportionately associated with psychiatric adverse events, whereas tirzepatide demonstrates higher rates of injection-site complications and misuse. Liraglutide presents a comparatively lower risk profile. These findings underscore the need for vigilant psychiatric monitoring, patient education on injection technique and dosing, and stronger regulatory oversight to reduce misuse of GLP-1 receptor agonists for weight loss.

New Drugs on the Block: Dietary Management and Nutritional Considerations During the Use of Anti-Obesity Medication.

Eleni C Pardali, Kalliopi K Gkouskou, Christos Cholevas +4 more

Incretin-based pharmacotherapy has rapidly transformed obesity management. However, despite its efficacy, gastrointestinal (GI) adverse events (AEs) are common and represent a major driver of treatment discontinuation. Symptoms such as nausea, vomiting, acid reflux, diarrhea, and constipation, not only impair the quality of life, but also compromise adherence, thereby limiting the real-world effectiveness of these agents. Targeted nutritional strategies may play a pivotal role in mitigating these symptoms and supporting sustained treatment. However, most clinical trials have relied on generalized lifestyle advice combined with hypocaloric dietary prescriptions, with limited integration of structured, mechanism-based nutritional counseling tailored to the physiological actions of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs. Consequently, practical guidance for clinicians and dietitians remains fragmented. The present review synthesizes the available evidence on GI AEs associated with incretin-based therapies and examines whether structured, targeted nutritional management can meaningfully reduce symptom burden. We also outline key monitoring strategies and focus on important clinical aspects for physicians and dietitians, aiming to optimize patient outcomes. In addition, we provide detailed information on the spectrum of GI AEs to guide effective management and limit intolerance. By bridging pharmacology with applied clinical nutrition, we aim to provide a pragmatic framework for improving tolerability, sustaining adherence, and translating trial efficacy into durable real-world effectiveness.

GLP-1 Receptor Agonists at the Crossroads of Circadian Biology, Sleep, and Metabolic Disease.

Ayush Gandhi, Ei Moe Phyu, Kwame Koom-Dadzie +2 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. This narrative review synthesizes current preclinical and clinical evidence examining the bidirectional relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and circadian biology. A structured literature search was conducted in PubMed using combinations of the terms 'GLP-1,' 'circadian,' 'chronobiology,' 'sleep,' 'obesity,' and 'type 2 diabetes' through January 2026. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep-wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Emerging data suggest that GLP-1 signaling is under circadian regulation and may, in turn, influence central and peripheral clock systems. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies. We propose that GLP-1 receptor agonists may function as chronometabolic modulators, with potential implications for personalized chronopharmacological strategies in metabolic disease.

Resistant and Refractory Obesity: The Complexity of Anti-Obesity Therapy Failure.

Michał Nicze, Maciej Borówka, Adrianna Dec +3 more

Pharmacotherapy is a key component of obesity management, yet treatment failure remains a prevalent challenge in clinical practice. Such failure may present as insufficient pharmacological response, early discontinuation, or post-treatment weight regain, underscoring the discrepancy between clinical trial efficacy and real-world outcomes. The effectiveness of anti-obesity medications (AOMs) is influenced by psychiatric comorbidities, including depression, anxiety, and disordered eating patterns, as well as environmental and socioeconomic factors such as limited healthcare access, weight-related stigma, and high medication costs. Individual characteristics, including physical activity, body composition, visceral adiposity, and microbiome profile, further modulate treatment outcomes. Pharmacokinetic and pharmacotherapeutic limitations such as drug-phenotype mismatch, route of administration, suboptimal formulations, and exposure to counterfeit products also compromise efficacy. No less important are genetic and immunological factors, comprising pharmacogenomic variants of both incretin and melanocortin receptors along with antidrug antibodies (ADAs), which may constitute therapy resistance. Concomitant medications and comorbid endocrine disorders can additionally attenuate weight-loss effects. The objective of this review is to characterize the multifactorial nature of resistance and refractoriness to anti-obesity therapy, and the importance of identifying pretreatment predictive factors for recognizing individuals at risk of inadequate or lack of response, thereby enabling personalized management strategies and improving long-term clinical outcomes, particularly in "difficult-to-treat" patients.

Comparative Effectiveness of Liraglutide and Dulaglutide in Heart Failure with Preserved Ejection Fraction: A Propensity Score-Matched Real-World Study.

Ibrahim Khalil, Imran Hossain, Pallab Sarker +6 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve outcomes in heart failure with preserved ejection fraction (HFpEF), but no head-to-head study has compared liraglutide and dulaglutide, two widely used GLP-1 RAs; we aimed to address this gap.

The Therapeutic Potential of Glucagon-Like Peptide-1 Receptor Agonists in Psoriasis and Hidradenitis Suppurativa.

Joshua K Morales, Jennifer Keelin, Toan N Vu +6 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), commonly prescribed for type 2 diabetes and obesity, have demonstrated potential anti-inflammatory and immunomodulatory effects that may be beneficial in chronic inflammatory skin conditions such as psoriasis and hidradenitis suppurativa (HS). A systematic review of the literature was conducted, focusing on prospective studies, case reports, and systematic reviews that evaluated the impact of GLP-1 RAs on these diseases. In psoriasis, GLP-1 RAs, particularly liraglutide, have been associated with improvements in the Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI), especially among patients with T2D. Reported benefits include enhanced glycemic control, weight reduction, and decreased levels of inflammatory markers, suggesting that GLP-1 RAs may modulate immune pathways and proinflammatory cytokine activity involved in the pathogenesis of psoriasis. Similarly, in HS, GLP-1 RAs such as liraglutide and semaglutide have shown promising results, including decreased lesion severity, improved quality of life, and reduced systemic inflammation. Weight loss induced by these agents may also contribute to symptom improvement by reducing mechanical stress in intertriginous areas and mitigating inflammatory responses associated with HS. Although preliminary evidence suggests that GLP-1 RAs may play a role in managing psoriasis and HS through both metabolic and immunologic mechanisms, current data are limited to early-phase studies and case reports. Further large-scale randomized controlled trials, some of which are ongoing, with diverse study populations are necessary to better understand their efficacy, safety, and long-term impact in the treatment of these chronic inflammatory skin conditions.

Weight Changes With Tirzepatide and Concomitant Weight-Inducing Medications: Post Hoc Analysis of Randomized Clinical Trials.

Rodolfo J Galindo, Kimberly A Gudzune, Michelle Look +5 more

Given the common use of weight-inducing (WI) medications, it is crucial to understand the potential association of these medications with the effectiveness of obesity treatments.

Glucagon-like Peptide-1 Receptor Agonists in Liver Transplant Recipients: A Retrospective Cohort Study.

Hesham Sheashaa, Ramzi Ibrahim, Amani Elshaer +14 more

Liver transplant recipients face high risks of cardiometabolic events after transplant, driven by posttransplant weight gain, diabetes, hypertension, as well as immunosuppression-related side effects. Glucagon-like peptide-1 receptor agonists (GLP1RAs) improve metabolic and cardiorenal outcomes in nontransplant populations, but their role in liver transplant recipients remains understudied.