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Therapeutic potential of targeting the orexin (hypocretin) system in sleep disorders.
Nat Rev Endocrinol
Birgitte R Kornum, Alberte Wollesen Breum, Zuzanna Mincikiewicz +1 more
Sleep is emerging as a key health topic in modern society. The prevalence of and focus on sleep-wake disorders is increasing, which has led to a large interest from the pharmaceutical industry to develop new treatments targeting sleep biology (that is, drugs that have the potential to mimic normal sleep-wake physiology). The orexin (also known as hypocretin) system is one of the key targets and regulators of sleep and wakefulness. In this Review, we will discuss the mechanisms by which loss of orexin signalling is involved in narcolepsy type 1 and whether loss and/or disruption of orexin signalling might have a role in other sleep disorders such as narcolepsy type 2, idiopathic hypersomnia and obstructive sleep apnoea. We will also describe current and emerging therapies for sleep disorders involving orexin, such as orexin receptor antagonists for insomnia and orexin receptor agonists for narcolepsy.
Marked and reversible circulating insulin-like growth factor-1 elevation during teprotumumab N01 treatment for thyroid eye disease with limited correspondence to glycemic changes.
Front Endocrinol (Lausanne)
Wei Zhao, Lingli Zhou, Ying Gao +4 more
Insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) inhibitors have changed the treatment landscape for moderate-to-severe thyroid eye disease (TED), but the longitudinal behavior of circulating IGF-1 during and after therapy remains insufficiently characterized. This study aimed to describe serum IGF-1 dynamics in patients with TED treated with IGF-1R inhibitor teprotumumab N01 and to explore their relationship with glycemic changes.
Incorporating estimands into meta-analyses of clinical trials.
Res Synth Methods
Antonio Remiro-Azócar, Pepa Polavieja, Emmanuelle Boutmy +9 more
The estimand framework is increasingly established to pose research questions in confirmatory clinical trials. In evidence synthesis, the uptake of estimands has been modest, and the population, intervention, comparator, and outcome (PICO) framework is more often applied. While PICOs and estimands have overlapping elements, the estimand framework explicitly considers different strategies for intercurrent events. We propose a pragmatic framework for the use of estimands in meta-analyses of clinical trials, highlighting the value of estimands to systematically identify and mitigate key sources of quantitative heterogeneity, and to enhance the applicability or external validity of pooled estimates. Focus is placed on the role of strategies for intercurrent events, within the specific context of meta-analyses for health technology assessment. We apply the estimand framework to a network meta-analysis of clinical trials, comparing the efficacy of semaglutide versus dulaglutide in type 2 diabetes. We explore the impact of a treatment policy strategy for treatment discontinuation or initiation of rescue medication versus a hypothetical strategy for the corresponding intercurrent events. The specification of different target estimands at the meta-analytical level allows us to be explicit about the source of heterogeneity, the intercurrent event strategy, driving any potential differences in results. We advocate for the integration of estimands into the planning of meta-analyses, while acknowledging that potential challenges exist in the absence of subject-level data. Estimands can complement PICOs to strengthen communication between stakeholders about what evidence syntheses seek to demonstrate, and to ensure that the generated evidence is maximally relevant to healthcare decision-makers.
Comparative Cardiovascular Outcomes and Safety Profiles of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Trials.
Cureus
Samih Abdelmutalab Mohamed Abdalla, Hind Osman Ali Mohammed, Eltayeb Osman E Omer +6 more
Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been assessed in several large cardiovascular outcome trials (CVOTs); however, the individual agents differ in molecular structure, pharmacology, and the populations studied, and their reported effects range from neutral to clearly beneficial. This review compares the cardiovascular efficacy and safety of GLP-1 RAs across all eligible randomized, placebo-controlled CVOTs in T2DM and quantitatively pools the primary outcome. Following the PRISMA 2020 statement, ClinicalTrials.gov, MEDLINE, Embase, and the Cochrane CENTRAL were searched from inception to 15 December 2025 for randomized, double-blind, placebo-controlled CVOTs comparing a GLP-1 RA with placebo in adults with T2DM and reporting adjudicated major adverse cardiovascular events (MACE) as a primary or co-primary endpoint. The protocol was not prospectively registered. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment (Cochrane RoB 2), and certainty of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Findings were synthesized narratively and, for the primary MACE outcome, pooled using a DerSimonian-Laird random-effects model on the log-hazard-ratio scale, with heterogeneity quantified by I² and Cochran's Q, leave-one-out sensitivity analysis, and small-study assessment by funnel plot and Egger's test. Nine trials enrolling 69,730 participants met the eligibility criteria. The primary MACE hazard ratio favored the GLP-1 RA in eight of nine trials (range = 0.73-1.02) and reached statistical superiority in five. Random-effects meta-analysis yielded a pooled MACE hazard ratio of 0.86 (95% CI: 0.82-0.92; P < 0.001), corresponding to a 14% relative risk reduction, with moderate heterogeneity (I² = 37%; Cochran's Q = 12.7, P = 0.12) and a 95% prediction interval of 0.75-1.00. The pooled estimate was robust to leave-one-out analysis (0.85-0.88), and no small-study asymmetry was detected (Egger's P = 0.13). The composite benefit was driven by reductions in myocardial infarction and stroke, with a neutral effect on hospitalization for heart failure. Gastrointestinal adverse events were the most common class effect; a class-level excess of gallbladder and biliary disease was also evident, and a diabetic retinopathy signal was observed with subcutaneous semaglutide. Eight trials were judged to be at low risk of bias, and the certainty of evidence was moderate for the principal cardiovascular outcomes. In adults with T2DM, GLP-1 RAs as a class reduce the risk of MACE by approximately 14% with an acceptable safety profile, supporting their role as a cornerstone of cardiovascular risk reduction. Between-agent and between-trial heterogeneity preclude a definitive ranking of individual agents.
Autoantibodies to Extracellular Erythrocyte Band 3 Epitopes Are Associated With Anemia in Plasmodium vivax Infection.
Am J Hematol
Aline Marzano-Miranda, Vanessa G Fraga, Cor Jésus F Fontes +4 more
Plasmodium vivax-associated anemia is a multifactorial clinical outcome, in which the destruction of uninfected red blood cells (uRBCs) plays a major role in disease development and severity. Here, we identified autoantibody targets within the extracellular loops of Band 3 (B3), a major erythrocyte transmembrane protein. In silico epitope prediction identified six of the seven potentially immunogenic extracellular domains of B3. Patients with P. vivax infection who were anemic (n = 79) and non-anemic (n = 95), and 40 healthy donors from a non-endemic area were included as negative controls. In addition, 15 anemic and 15 non-anemic infected individuals were also analyzed immediately before treatment (D0) and on Days 7, 14, and 28 after antimalarial therapy. Synthetic peptides corresponding to the six B3 domains were robustly recognized by autoantibodies from P. vivax-infected patients. Anemic individuals exhibited prominent autoantibody responses, particularly against loops 4 and 6. IgG3 was the predominant subclass targeting these loops and remained detectable up to 28 days post-treatment, suggesting a possible role in the persistence of anemia even after parasite clearance. In contrast, IgG1 was the principal subclass recognizing the peptides corresponding to loops 1, 2, and 3, indicating a significant response to senescent domains during P. vivax infection. Analysis of IgG subclass against full-length B3 confirmed the presence of both IgG1 and IgG3 responses. The pro-inflammatory properties of these IgG subclasses support the hypothesis that anti-B3 autoantibodies contribute to the immunopathogenesis of P. vivax-related anemia. Collectively, these findings identify potential targets for future mechanistic investigations and therapeutic intervention strategies.
Osteoimmune senescence in aging-related bone diseases.
Front Immunol
Huali Li, Yingli Yang, Huanle Zhu
Aging-related bone diseases are increasingly recognized as disorders in which uncoupled bone remodeling remains central but is substantially modified by immune-skeletal interactions. This review consolidates current evidence for osteoimmune senescence, a framework that links senescent skeletal cells, aging immune compartments, chronic SASP signaling, impaired immune clearance, and marrow-niche deterioration to reduced bone strength and repair. Osteoporosis, rheumatoid arthritis-associated erosion, osteoarthritis, periodontal bone loss, and delayed fracture healing are clinically distinct diseases, but they may share overlapping senescence-associated osteoimmune mechanisms while retaining disease-specific endotypes. Senescent osteocytes, osteoblast-lineage cells, and bone marrow stromal cells can increase RANKL/OPG imbalance, suppress osteogenesis, and reshape immune recruitment, whereas remodeled T cells, macrophages, neutrophils, and NK-cell surveillance pathways modify osteoclastogenesis and repair resolution. We also discuss gut-derived metabolites and imaging phenotypes as clinically important but non-specific readouts of this biology. DXA, HR-pQCT, MRI, CBCT, and molecular imaging cannot identify senescent cells directly, but they can anchor molecular hypotheses to tissue-level deterioration. Therapeutic translation will depend on matching senolytics, senomorphics, immune-recalibrating approaches, microbiota-derived metabolites, and bone-targeted delivery systems to disease stage, dominant cell population, and measurable skeletal endpoints.
Failing Fontan following total cavopulmonary connection: extracardiac biomarkers reveal two distinct phenotypes with divergent clinical courses.
Interdiscip Cardiovasc Thorac Surg
Muneaki Matsubara, Havva Aldogan, Thibault Schaeffer +8 more
Failing Fontan is an increasingly recognised complication after total cavopulmonary connection, yet longitudinal biomarker data remain scarce. We aimed to characterise the incidence, biomarker trajectories, and prognostic determinants of failing Fontan.
Acute TRPTI™ (oleoylethanolamide) supplementation enhances incretin hormone responses: a fixed-sequence crossover study.
Front Endocrinol (Lausanne)
David Briskey, Janice Pellow, Pavitra Viswanath +1 more
Oleoylethanolamide (OEA) is an endogenous lipid mediator involved in nutrient sensing and gut-derived hormonal signalling. TRPTI™ is a bioavailable OEA formulation designed to support metabolic and appetite-related pathways. This study evaluated the acute metabolic effects of TRPTI™ in healthy adults under controlled feeding conditions.
Efficacy and Safety of Dual and Triple Glucagon-Like Peptide-1-Based Polyagonists in Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis: A Systematic Review and Meta-Analysis.
Cureus
Rogelio Santos Solis, Armando A Baeza-Zapata, Juan P Negrete-Najar
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are strongly linked to obesity, insulin resistance, type 2 diabetes, and progressive liver fibrosis. Dual and triple glucagon-like peptide-1 (GLP-1)-based polyagonists may provide complementary hepatic and metabolic benefits, but their overall efficacy and safety have not been fully established. This systematic review and meta-analysis evaluated randomized controlled trials comparing dual or triple GLP-1-based polyagonists with placebo in adults with MASLD or MASH. PubMed, the Cochrane Central Register of Controlled Trials, ScienceDirect, and Google Scholar were searched from inception through May 19, 2026. Dichotomous outcomes were pooled as risk ratios (RRs), and continuous outcomes were analyzed as mean differences (MDs), using random-effects models. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Six randomized controlled trials involving 961 participants were included. The included GLP-1-based polyagonists-tirzepatide, survodutide, pemvidutide, retatrutide, and cotadutide-significantly increased MASH resolution or histological improvement without worsening of fibrosis (RR 3.32, 95% CI 2.28-4.84; I² = 20%) and fibrosis improvement without worsening of MASH (RR 1.49, 95% CI 1.15-1.94; I² = 0%). Treatment also produced a greater relative reduction in liver fat content (MD -44.60 percentage points, 95% CI -51.17 to -38.04; I² = 0%) and increased the likelihood of achieving at least a 30% relative reduction in liver fat by magnetic resonance imaging-proton density fat fraction (RR 4.71, 95% CI 3.04-7.30; I² = 22%). Body weight was significantly reduced, although heterogeneity was considerable (MD -9.14 percentage points, 95% CI -17.38 to -0.91; I² = 98%). Nausea, diarrhea, and vomiting were more frequent with polyagonists, but no statistically significant differences were observed in serious adverse events or adverse events leading to treatment discontinuation. In conclusion, dual and triple GLP-1-based polyagonists improve histological and imaging-based hepatic outcomes in MASLD and MASH and may simultaneously address underlying metabolic dysfunction. However, gastrointestinal intolerance, pharmacological heterogeneity, the small number of trials, and limited follow-up warrant cautious interpretation. Larger phase 3 trials are needed to clarify drug-specific efficacy, long-term safety, and effects on liver-related and cardiovascular outcomes.
Design of a metabolically-stable peptide therapeutic with triple-hormone-receptor agonist activity.
J Comput Aided Mol Des
Shubham Vishnoi, Sarah Hudson, Shayon Bhattacharya +1 more
Peptide-based therapeutics such as tirzepatide and semaglutide target the neuroendocrine system to remediate both diabetes and obesity. In addition to integrating the complementary actions of two endogenous metabolically related hormones targeting glucagon-like peptide-1 and glucagon receptors (GLP-1R and GCGR), the synergistic targeting of a third G protein-coupled receptor (GPCR), namely the gastric inhibitory polypeptide receptor (GIPR), may achieve optimal control of blood glucose levels and weight loss in patients with diabetes and obesity. In this work, we harness the predictive power of sequence-derived in silico mutagenesis to rationally design effective single-molecule peptides with triple-receptor-agonist activities. We model the binding profiles of our designed peptides to the GIP, GLP-1 and GCG receptor triad through multiple, long, repeat molecular simulations and effective binding enthalpy calculations to assess their predicted multi-receptor engagement profiles. Our data predict a balanced, highly favourable effective binding enthalpy profile of our newly designed peptides for the three receptors compared to endogenous peptides and the experimental reference peptides, with high targeted specificity for the receptors. The peptides are further engineered to structurally support metabolic stability by substituting sites prone to proteolytic cleavage. The predicted triple-hormone-receptor agonist peptide mechanism opens new avenues for the synthesis and activity testing of multi-targeting peptides with improved stability, offering a computational design strategy for testing the potential reduction of adverse gastrointestinal effects of peptide therapeutics and support future development of lower-dose oral formulations.
Ectopic Adrenocorticotropic Hormone Syndrome in a Patient Diagnosed With Lung Adenocarcinoma and Hospitalized Due to Diabetic Ketonuria: A Case Report.
Case Rep Oncol Med
Murat Ay, Erhan Bozkurt, Esra Özgül
Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is most often a paraneoplastic manifestation of small-cell lung cancer and is rare in lung adenocarcinoma. Its features include a cushingoid appearance, skin hyperpigmentation, muscle weakness, hypertension, glucose intolerance, hypokalemia, and metabolic alkalosis resulting from nonsuppressible, ACTH-driven hypercortisolism. We report a 70-year-old man admitted with pneumonia and diabetic ketonuria without acidosis, in whom EAS secondary to a poorly differentiated lung adenocarcinoma was diagnosed. Key biochemical findings were a markedly elevated 8 a.m. plasma ACTH (149.3 pg/mL), grossly elevated serum cortisol (54.94 μg/dL) with loss of diurnal rhythm, elevated 24-h urinary free cortisol, and failure of cortisol suppression after both low- and high-dose dexamethasone, with a normal pituitary MRI-a profile consistent with an ectopic ACTH source. What distinguishes this case is that the heralding presentation was a refractory metabolic emergency (hyperglycemia with diabetic ketonuria; HbA1c 6.3%, indicating no pre-existing poorly controlled diabetes) rather than the classic cushingoid phenotype. The patient deteriorated rapidly and died on the third day after CT-guided lung biopsy, before tumor-directed therapy or confirmatory ACTH immunohistochemistry could be undertaken. This case highlights that EAS from lung adenocarcinoma may present primarily as a severe metabolic emergency and that early biochemical screening and control of hypercortisolism are critical.
PYY3-36 potentiates Semaglutide‑mediated mitochondrial modulation in MASLD.
Am J Physiol Endocrinol Metab
Niklas Geiger, Alexander Georg Nickel, Michael Kohlhaas +14 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent comorbidity of obesity. Incretins have emerged as promising therapeutics for MASLD, but their exact mechanisms of action remain unclear. In this study with obese rats, we investigated the cellular effects of the GLP 1 receptor agonist semaglutide and the NPY 2 receptor agonist PYY3 36 on hepatic mitochondria with a focus on mitochondrial oxygen consumption and ROS emission.
CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.
Cell
Alex C Y Chen, Keely Y Ji, Cansu Yerinde +19 more
Immune aging impairs T cell-mediated tumor control as well as cancer immunotherapy outcomes. The most important drivers of T cell dysfunction in aged tumors remain unknown. We performed single-cell CRISPR screens to identify Dusp5 and Zfp219 as key regulators of CD8+ T cell persistence and effector differentiation within aged tumors. Loss of Dusp5 increased extracellular signal-regulated kinase (ERK) phosphorylation and globally enhanced T cell proliferation. Conversely, Zfp219 deletion induced epigenetic reprogramming and increased expression of cytotoxic molecules, enhancing antitumor immunity specifically in aging. Levels of the human ortholog ZNF219 were higher within intratumoral CD8+ T cells from older cancer patients, which correlates with worse survival following immunotherapy. Zfp219 ablation synergized with immune checkpoint inhibitors to expand effector-like CD8+ T cells, leading to tumor clearance in aged mice. Our findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction that can be targeted to rejuvenate antitumor immunity in older cancer patients.
GLP-1 Receptor Agonists May Reduce Insulin Requirements in New-Onset Type 1 Diabetes.
Endocrinol Metab Clin North Am
Justin M Gregory
Early stage 3 type 1 diabetes is a period of rapid pathophysiologic change. Flagging beta-cell secretion is accompanied by postprandial hyperglucagonemia, impaired incretin amplification, beta-cell stress, and insulin resistance. Incretin-based therapy may align favorably with these defects by augmenting glucose-dependent insulin secretion, improving postprandial hyperglucagonemia, reducing beta-cell stress and insulin resistance. Randomized trials initiating glucagon-like peptide 1 receptor agonist therapy soon after diagnosis demonstrate lower insulin requirements and better-preserved stimulated C-peptide while on treatment, but these advantages often diminish after discontinuation. Combination approaches pairing immunomodulatory therapy with incretin-based metabolic support may improve durability.
Combination of Glucagon-like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter Inhibitors in Type 1 Diabetes: Why, when and How? An Exploration of the Rationale and Clinical Scenarios for Combining These 2 Adjunctive Agents.
Endocrinol Metab Clin North Am
Husam Ghanim, Sambasiva Rao Srungavarapu, Paresh Dandona +1 more
Even with the most advanced insulin preparations and delivery systems currently available, it is challenging for many people with type 1 diabetes (T1D) to achieve target levels of glycemic management. Adjunct therapy in T1D consists of adding glucose-lowering agents besides insulin with the aim of lowering hemoglobin A1c (HbA1c) and improving other health outcomes, including weight. It is an attractive potential strategy for achieving glycemic targets and other benefits in this T1D subpopulation. While not yet Food and Drug Adminstration (FDA)-approved for this use, incretin-based therapies (glucagon-like peptide-1 receptor agonist-based therapy) and sodium-glucose cotransporter-1/2 (SGLT-1/2) inhibitors are being prescribed off-label for T1D.
The Participation of Prolactin in the Immunopathology of Experimental Pulmonary Tuberculosis.
Neuroimmunomodulation
Dulce Adriana Mata-Espinosa, Gabriel Quintero-Bustos, Daniel Enrique Castillo Baltazar +3 more
Prolactin and its receptor are widely recognized for their roles in lactogenesis and galactopoiesis. However, they have also gained attention for their role in immune pathophysiology, acting as mediators of both innate and acquired immune responses and potentially playing a significant role in chronic infectious diseases such as tuberculosis.
Immunomodulatory Effects of Poly-D,L-Lactic Acid on LL-37-Driven Rosacea-like Inflammation via Suppression of mTORC1 Signaling.
Int J Mol Sci
Kyung-A Byun, Je-Young Park, Seyeon Oh +4 more
Rosacea is a chronic inflammatory skin disorder driven by dysregulated cathelicidin processing and excessive LL-37, which triggers a circuit involving Toll-like receptor 2 (TLR2)/kallikrein-5 (KLK5)-dependent amplification and downstream mechanistic target of rapamycin complex 1 (mTORC1), NF-κB, and NLR family pyrin domain containing 3 (NLRP3) inflammasome pathways. We hypothesized that poly-D,L-lactic acid (PDLLA) could attenuate this inflammatory cascade by inducing macrophage-derived interleukin (IL)-10. PDLLA increased IL-10 secretion from THP-1-derived macrophages in a dose-dependent manner. In LL-37-stimulated HaCaT keratinocytes, LL-37 decreased phosphorylated signal transducer and activator of transcription (pSTAT3)/STAT3, DNA damage-inducible transcript 4 (DDIT4), and phosphorylated AMP-activated protein kinase (pAMPK)/AMPK while increasing phosphorylated protein kinase B (pAKT)/AKT and mTORC1 activation; conditioned media from PDLLA-treated macrophages (CMPDLLA) restored pSTAT3/STAT3, DDIT4, and pAMPK/AMPK, reduced pAKT/AKT, and suppressed pmTOR/mTOR. CMPDLLA attenuated downstream inflammatory responses, including NF-κB nuclear translocation, VEGF production, and NLRP3-inflammasome-mediated IL-18 secretion. These findings were validated using an intradermal LL-37-injected mouse model. Compared with the normal control/saline group, LL-37/saline decreased IL-10, pSTAT3/STAT3, DDIT4, and pAMPK/AMPK while increasing pAKT/AKT, pmTOR/mTOR, pS6K/S6K, TLR2/KLK5/LL-37, NF-κB, VEGF, and NLRP3 inflammasome/IL-18 signaling; PDLLA partially restored the STAT3/DDIT4-AMPK regulatory pattern and suppressed these disease-associated signals. Consequently, PDLLA treatment led to a pronounced reduction in clinical lesion area. Overall, PDLLA may attenuate LL-37-driven cutaneous inflammation by promoting an IL-10-linked STAT3/DDIT4-AKT/AMPK program that suppresses mTORC1 and disrupts cathelicidin amplification, supporting its potential as an injectable immunomodulatory approach for rosacea-like skin inflammation.
GLP-1 receptor agonists in primary care: readiness, equity, and the risk of a two-tiered obesity treatment landscape.
Ther Adv Endocrinol Metab
Mohamed Mustaf Ahmed, Rahmatullah Nazari, Zhinya Kawa Othman +6 more
Glucagon-like peptide-1 receptor agonists have transformed obesity pharmacotherapy by producing substantial weight loss and, for semaglutide in patients with established cardiovascular disease, reducing major cardiovascular events. Integrating these therapies into primary care is constrained by gaps in provider training, clinical inertia, weight bias, high treatment costs, and fragmented insurance coverage. Racial and ethnic minority groups, low-income communities, and publicly insured patients are less likely to receive or fill prescriptions despite the disproportionate burden of obesity-related diseases. This narrative review examines primary care readiness, structural determinants of access, disparities in prescribing and use, real-world adherence, and policy options for these drugs. Without coordinated action, these therapies may reinforce a two-tiered treatment landscape in which access reflects socioeconomic advantages rather than clinical needs. Equitable implementation will require aligned reforms in coverage and pricing, workforce development, person-centered care, and long-term treatment support.
Adult Annular Pancreas Presenting With Gastric Outlet Obstruction Following Semaglutide Initiation: A Case Report.
Cureus
Fatima Gamaleldin, Milind Raje, Solomon K John
Annular pancreas is a rare congenital anomaly that may remain clinically silent until adulthood. Its symptoms can be masked or exacerbated by glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which delay gastric emptying. We report a 55-year-old male with type 2 diabetes who developed progressive postprandial vomiting and nine-kg weight loss following semaglutide initiation. Imaging revealed a partial annular pancreas causing second-part duodenal stenosis without malignancy. Symptoms persisted despite semaglutide discontinuation, supporting a fixed mechanical obstruction as the primary aetiology. The patient underwent successful Roux-en-Y gastrojejunostomy and cholecystectomy; histopathology confirmed benign fibrotic pancreatic tissue. At follow-up, the patient was symptom-free with nutritional recovery. This case emphasises that severe gastrointestinal symptoms in patients on GLP-1 RAs should prompt evaluation for structural pathology rather than being attributed solely to medication side effects, ensuring timely surgical intervention.
A Systematic Review and Meta-Analysis Evaluating the Role of GLP-1 Receptor Agonists in Substance Use Disorders.
Cureus
Indrani Sarma, Krishna P Biswas, Prerna Jagdish +3 more
GLP-1 receptor agonists (GLP-1RAs) have shown preclinical effects on reward-seeking behavior across several substance classes, but human randomized controlled trial (RCT) evidence remains limited. This systematic review and meta-analysis evaluated the effects of GLP-1RAs on substance-use outcomes in adults with substance use disorders. Electronic databases and trial registries were searched from inception to April 30, 2026, for parallel-group or crossover RCTs comparing any GLP-1RA with placebo or control. Outcomes included days without alcohol consumption, cigarettes smoked per day (CPD), and Fagerström Test for Nicotine Dependence (FTND) scores. Five RCTs met the inclusion criteria, including 764 participants with follow-up ranging from six to 52 weeks. Three RCTs contributed alcohol-related outcomes, and four contributed tobacco-related outcomes. Random-effects meta-analysis showed no statistically significant effect on days without alcohol consumption (MD -1.96 days, 95% CI -17.97 to 14.05; I² = 74%), CPD (MD -0.55 cigarettes/day, 95% CI -1.76 to 0.65; I² = 45%), or FTND score (MD 0.02, 95% CI -0.32 to 0.36; I² = 0%). Risk-of-bias assessment using the Cochrane Risk-of-Bias (RoB) 2 tool rated three trials as low risk overall and two as having some concerns. Certainty of evidence assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) ranged from low to moderate. Current pooled RCT evidence does not demonstrate a statistically significant benefit of GLP-1RAs for alcohol or tobacco use outcomes. A possible signal of benefit in patients with comorbid alcohol use disorder and obesity should be interpreted as hypothesis-generating because of the small number of trials, clinical heterogeneity, and imprecision. Adequately powered, long-duration, agent-specific RCTs using standardized substance-use outcomes are required before clinical translation can be recommended.