Moderate · human
This network meta-analysis (NMA) systematically synthesized evidence from 25 randomized controlled trials across 12 interventions to compare the weight-loss efficacy and safety of four advanced anti-obesity medications — tirzepatide, semaglutide, cagrilintide, and the combination CagriSema (cagrilintide + semaglutide) — in adults with overweight or obesity. Searches were conducted across PubMed, Scopus, and Cochrane Central. Using random-effects NMA models, the study found that tirzepatide 15 mg produced the greatest mean percent body weight reduction (−17.97%), closely followed by CagriSema (−17.84%) and semaglutide 7.2 mg (−14.66%). For achieving ≥20% body weight loss, CagriSema showed the highest relative risk (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). All agents increased gastrointestinal adverse events (RR 1.33–1.91) relative to placebo, with the highest treatment discontinuation seen with semaglutide 7.2 mg (RR 3.09). Serious adverse events were comparable to placebo across all regimens. Key limitations include reliance on indirect comparisons due to absence of head-to-head trials, potential heterogeneity across trial populations and follow-up durations, and the emerging/limited trial data for CagriSema specifically. The authors conclude that both tirzepatide and CagriSema represent leading options for substantial weight loss but call for direct comparative trials.
Endocrinology, diabetes & metabolism · Jul 2026DOI ↗ Review
This 2026 American College of Physicians (ACP) living clinical guideline synthesizes systematic reviews on pharmacologic treatments combined with lifestyle modifications for weight management in nonpregnant adults with overweight or obesity in outpatient settings, using the GRADE framework. For adults with obesity (BMI ≥30 kg/m²), the ACP issued conditional recommendations favoring semaglutide and tirzepatide as first-line agents (moderate-certainty evidence), phentermine-topiramate as second-line (low-certainty), liraglutide as third-line (low-certainty), and naltrexone-bupropion as fourth-line (low-certainty). For adults with overweight (BMI ≥27–30 kg/m²) who also have type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease, the guideline conditionally recommends semaglutide and tirzepatide as first-line and liraglutide as second-line. All recommendations are conditional, reflecting the importance of shared decision-making around benefits, harms, costs, access, comorbidities, contraindications (e.g., cardiovascular contraindication and monthly pregnancy-test requirement for phentermine-topiramate; suicidal ideation risk with naltrexone-bupropion), and patient preferences. The living guideline format signals ongoing updates as new evidence emerges.
Annals of internal medicine · Jun 2026DOI ↗ Strong · human
This living systematic review and network meta-analysis, commissioned by the American College of Physicians, synthesized evidence from 69 randomized controlled trials involving 112,511 adults with overweight or obesity (BMI ≥25 kg/m²) to compare pharmacologic weight-management treatments. Drugs examined included GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide), dual agonists (tirzepatide, retatrutide, semaglutide-cagrilintide), and other agents (naltrexone-bupropion, phentermine, phentermine-topiramate, orforglipron), with or without lifestyle intervention. The review found that nearly all studied interventions produced greater weight loss than placebo and/or lifestyle intervention alone. Semaglutide was found to probably reduce mortality and major adverse cardiovascular events (MACE). Semaglutide and tirzepatide demonstrated the greatest weight loss in both pairwise and network meta-analyses. However, nearly all active treatments were also associated with more treatment discontinuations due to adverse events compared with placebo. The authors noted that evidence for critical outcomes such as mortality, MACE, and serious adverse events remained limited, and direct head-to-head comparisons between treatments were scarce. Thirty-seven of the 69 included studies were rated at low risk of bias. The living review design allows for ongoing evidence updates as new trials emerge.
Annals of internal medicine · Jun 2026DOI ↗ Review
This systematic review, conducted for the American College of Physicians, evaluated the cost-effectiveness of pharmacologic treatments for overweight or obesity in U.S. adults. Researchers searched MEDLINE, Embase, and economic databases through October 2025, ultimately including 9 studies encompassing 42 pairwise treatment comparisons. Study quality was assessed using the CHEQUE tool, value was measured via incremental cost-effectiveness ratios (ICERs) against established willingness-to-pay thresholds, and certainty of evidence was graded using GRADE. Key findings from the 6 moderate-certainty studies suggested that liraglutide had low value compared with lifestyle modification, while phentermine-topiramate and tirzepatide showed high value versus lifestyle modification. Semaglutide demonstrated low value compared with naltrexone-bupropion and phentermine-topiramate, but high value compared with liraglutide. Important limitations include that all 9 included studies were model-based rather than empirical trial-based analyses, only 4 of 9 were at low risk of bias, none of the 42 comparisons reached high certainty, and reporting was frequently incomplete. The authors conclude that current U.S. evidence on cost-effectiveness of obesity pharmacotherapy is significantly hampered by poor study quality, restricting the strength of any conclusions that can be drawn.
Annals of internal medicine · Jun 2026DOI ↗ Limited · human
This retrospective, real-world study used the TriNetX federated database to compare oncologic outcomes in postmenopausal women aged ≥50 with obesity (BMI ≥30) and stage 0–III breast cancer, across three groups: GLP-1 receptor agonist (GLP-1RA) users, bariatric surgery patients, and those receiving both interventions. Two propensity score–matched analyses (1:1) adjusted for age, BMI, tumor stage, receptor status, adjuvant therapy, and comorbidities. Study 1 (n=3,438 matched per group) found that GLP-1RA users had a lower instantaneous mortality risk (HR 0.57, 95% CI 0.45–0.73) and lower locoregional recurrence (LRR) rate (1.8% vs. 4.7%; HR 0.52) compared to bariatric surgery alone, despite similar 10-year overall survival (87% vs. 83%). Study 2 (n=1,129 matched per group) found that combined bariatric surgery plus GLP-1RA therapy was associated with higher 10-year overall survival (91% vs. 80%; HR 0.44) and lower LRR (2.5% vs. 5.8%; HR 0.52) versus surgery alone. The authors hypothesize potential anti-inflammatory, insulin-modulating, or other metabolic mechanisms beyond weight loss. Key limitations include the observational design, potential residual confounding, lack of GLP-1RA dose/duration data, and inability to establish causality.
Annals of surgery · Jun 2026DOI ↗ Review
This review examines the evolving medical management of short bowel syndrome intestinal failure (SBS-IF), a condition historically associated with lifelong dependence on home parenteral support (HPS) and, in select cases, intestinal transplantation (iTx). The authors describe how recent pharmacological advances—particularly glucagon-like peptide-2 (GLP-2) analogues and GLP-1 receptor agonists—have been integrated alongside conventional antimotility and antisecretory therapies to promote intestinal adaptation. The review argues that SBS-IF should now be understood as a dynamic and potentially modifiable form of organ failure rather than a static, irreversible condition. According to the authors, GLP-2 analogues represent the first pathophysiology-targeted, pro-adaptive therapies in this disease, while GLP-1 receptor agonists are highlighted as promising adjuncts, especially for patients with high-output phenotypes. The paper contends that multidisciplinary intestinal rehabilitation and gut-directed pharmacotherapy have meaningfully altered the natural history of SBS-IF, reducing HPS dependence and improving patient-centered outcomes. A key implication discussed is that iTx has been repositioned from a default end-stage intervention to a targeted rescue option used after optimized rehabilitation. Limitations include the review format, which synthesizes existing literature without presenting new primary data or meta-analytic pooling.
Current opinion in organ transplantation · Jun 2026DOI ↗ Preclinical
This study investigated why chemotherapy often fails to generate robust anti-tumor immunity and how the endogenous peptide thymosin alpha-1 (Tα-1) might address this gap. The researchers first observed that circulating levels of Tα-1 were reduced after chemotherapy in both cancer patients (across multiple tumor types) and tumor-bearing mice. Mechanistically, the study found that chemotherapy-induced cancer cell death produces apoptotic bodies (ABs) that are poorly immunogenic. Tα-1 was shown to bind to these ABs and interact specifically with AB-associated microRNAs—particularly miR146a-5p—protecting them from degradation by lysosomal RNase A inside dendritic cells (DCs). This protection allowed miR146a-5p to activate Toll-like receptor 7 (TLR7), which in turn licensed DC maturation, migration to tumor-draining lymph nodes, and presentation of tumor antigens to CD8+ T cells. In mouse models, therapeutic Tα-1 supplementation synergized with chemotherapy to suppress established tumors in a TLR7-dependent and miR146a-5p-dependent manner. Limitations include that mechanistic and therapeutic efficacy data are primarily from mouse models, with human data limited to observational measurements of circulating Tα-1 levels.
Cancer research · Jun 2026DOI ↗ InsufficientPreprint
This bibliometric study compared the 100 most-cited articles on GLP-1 receptor agonists (GLP-1RA) with the 100 most-cited articles on metabolic bariatric surgery (MBS), using the Bibliometrix software to analyze citation patterns, journal distribution, and journal impact factors (IF). The study found that GLP-1RA articles accumulated more total citations (91,660 vs. 72,243) and had a higher median citation count (718 vs. 551) than MBS articles. GLP-1RA research was also more internationally collaborative (57% vs. 26%) and appeared more frequently in journals with IF above 40 (41% vs. 25%). The weighted 5-year mean IF was substantially higher for GLP-1RA journals (35.4 vs. 21.6). The authors argue that these differences may reflect a "prestige-journal effect," whereby GLP-1RA trials' placement in flagship journals such as the NEJM and Lancet inflates citation counts relative to MBS research, which is more dispersed across surgical specialty journals. A key limitation is that this study analyzes publication patterns rather than clinical outcomes, and cannot establish whether citation differences reflect true differences in scientific merit. The authors conclude that journal-impact inequalities should be considered when making citation-based comparisons between therapeutic fields.
Unknown journal · Jun 2026DOI ↗ In vitro
This study presents a novel chemical platform for installing carbon-14 (¹⁴C) or tritium (³H) radiolabeled lysine residues directly onto solid-supported peptides, circumventing the high cost and complexity of traditional radiolabeling methods. The researchers developed a two-step workflow: first, a mild hydroformylation reaction converts allylglycine residues — already incorporated into the peptide on a solid support — into a labeled allysine intermediate using either ¹⁴CO (generated from solid precursors) or ³H₂ gas. Second, reductive amination converts allysine into a radiolabeled lysine residue, with the final labeled peptide released upon cleavage from the solid support. The study reports that the optimized conditions are compatible with diverse peptide sequences and were successfully applied to analogs of semaglutide, a complex pharmaceutical peptide. The platform's key advantages highlighted by the authors include late-stage isotope introduction, flexibility in choosing the radiolabel, and avoidance of lengthy multi-step synthesis. Limitations include that this is a synthetic chemistry methods paper with no biological or clinical testing; all work was conducted in vitro at the bench-chemistry level. No pharmacological, pharmacokinetic, or efficacy data in animals or humans are reported.
Nature communications · Jun 2026DOI ↗ Animal only
This systematic review (PRISMA-guided) examined whether GLP-1 receptor agonists (GLP-1 RAs) exert neuroprotective effects in preclinical models of stroke and Parkinson's disease (PD). Researchers searched four major databases (Cochrane CENTRAL, PubMed, Web of Science, Scopus), identifying 1,643 records and ultimately including 13 experimental animal studies published between 2013 and 2026. For stroke, studies primarily used middle cerebral artery occlusion (MCAO) models; the review found that agents such as liraglutide and linagliptin were associated with notable reductions in infarct volume and improved neurological deficit scores in treated animals. For PD models, the included studies reported improvements in motor function, preservation of dopaminergic neurons, and reduced α-synuclein aggregation. Across both disease models, GLP-1 RAs appeared to modulate neuroinflammatory markers (TNF-α, IL-1β, IL-6), oxidative stress indicators (ROS, 4-HNE), and apoptotic pathways (increased Bcl-2, decreased Bax). Risk of bias assessment using the SYRCLE tool rated overall quality as moderate, with four studies flagged as high risk due to small sample sizes and inadequate reporting of randomization and blinding procedures. The authors concluded that while preclinical evidence appears promising, standardized studies and clinical trials are needed before translational conclusions can be drawn.
Disease-a-month : DM · Jun 2026DOI ↗ Animal only
This study developed a targeted nanodelivery system — GLP-1@tMSN (glucagon-like peptide-1 loaded into matrix metalloproteinase-2-targeted mesoporous silica nanoparticles) — designed to mobilize endothelial progenitor cells (EPCs) and promote re-endothelialization following coil embolization of intracranial aneurysms (IAs). Using a rat coiled aneurysm model, the researchers evaluated whether the platform could recruit EPCs to the lesion site and accelerate vascular repair. The study found that GLP-1@tMSN significantly enhanced EPC recruitment and re-endothelialization compared to controls. After 28 days, histological analysis showed formation of mature endothelial-like tissue in treated animals, while controls exhibited fibrous tissue. Immunofluorescence confirmed preferential accumulation of CD34+VEGFR2+ EPCs at the lesion site, alongside activation of the Wnt/β-catenin signaling pathway, which the authors implicate as a key driver of vascular repair. Preliminary biocompatibility assessments suggested an acceptable safety profile. Limitations include the exclusive use of a rat model, a single 28-day follow-up endpoint, small experimental scale, and lack of human translational data. The authors conclude that this nanotherapeutic approach may hold promise for reducing long-term IA recurrence after embolization, though clinical validation is needed.
Journal of neurosurgery · Jun 2026DOI ↗ In vitro
This study presents a novel chemical strategy for delivering protein-degrading molecules (PROTACs) selectively to pancreatic β-cells by exploiting the glucagon-like peptide-1 receptor (GLP-1R). The researchers engineered a modified GLP-1 peptide using a tryptophan-mediated multicomponent Petasis reaction (TMPR), a modular "stapling" technique that locks the peptide into a stable α-helical conformation. This stapled analogue was reported to show enhanced structural stability and improved GLP-1R potency compared with the wild-type peptide. The stapling strategy also incorporated a chemical handle allowing conjugation to a PROTAC — a bifunctional molecule designed to degrade bromodomain-containing protein 4 (BRD4), a transcriptional regulator implicated in various diseases. The resulting GLP-1–PROTAC conjugate reportedly retained GLP-1R agonist activity and selectively induced BRD4 degradation in GLP-1R-expressing cells, consistent with receptor-mediated uptake and intracellular degrader activation. The study was conducted entirely in cellular (in vitro) systems; no animal or human data were reported. Key limitations include the absence of in vivo validation, and the translational relevance to human β-cell biology remains to be established.
Angewandte Chemie (International ed. in English) · Jun 2026DOI ↗ Animal only
This study investigated whether sustained GLP-1 gene delivery could stimulate β-cell regeneration in diabetic rats, and whether regenerative responses differ between neonatal and adult stages. Researchers engineered a third-generation HIV-based lentiviral vector encoding native GLP-1 (LentiGLP-1) under a CMV promoter. Two rat models of type 2 diabetes were used: neonatal rats treated with low-dose streptozotocin (STZ) to exploit developmental pancreatic plasticity, and adult rats subjected to a high-fat diet combined with low-dose STZ. In neonatal diabetic rats, LentiGLP-1 administration markedly promoted differentiation of ductal and progenitor cells into insulin-producing β-cells, accompanied by increased β-cell proliferation. In adult diabetic rats, LentiGLP-1 partially restored β-cell populations via activation of residual progenitors and stimulation of existing β-cell replication, with improvements in glycemic control and insulin sensitivity. Acinar cells were not observed to contribute to β-cell regeneration in either model. A key limitation is that findings are entirely in rodents, and the translational relevance to human β-cell biology remains unestablished. The study provides mechanistic insight into developmentally regulated GLP-1 effects but does not constitute evidence of efficacy in humans.
Journal of molecular medicine (Berlin, Germany) · Jun 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed over 58 million adverse event reports from the FDA Adverse Event Reporting System (FAERS, 2004–2025) and cross-validated findings against the Canada Vigilance Adverse Reaction Online Database (CVARD) to identify drugs associated with delayed gastric emptying and gastroesophageal reflux. Using three signal-detection algorithms — Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN) — the study screened 50 drugs and found 20 with positive signals across all three methods. GLP-1 receptor agonists showed the strongest associations, with semaglutide exhibiting the highest signal for impaired gastric emptying (ROR: 80.27). Other drug classes flagged included insulin formulations (notably insulin degludec), bisphosphonates, angiotensin receptor blockers, and trofinetide. Weibull time-to-onset analysis further characterized temporal patterns, ranging from very early onset (trofinetide, median ~6.6 days) to markedly delayed onset (immunoglobulin G, median ~535 days). Key limitations include the inherent reporting biases of spontaneous pharmacovigilance databases, inability to establish causality, and potential confounding by indication or co-medications. The authors suggest findings should inform enhanced pharmacovigilance and clinical monitoring strategies.
Limited · human
This case report describes a woman in her 50s who developed Boerhaave's syndrome (spontaneous full-thickness esophageal perforation) in the context of GLP-1 receptor agonist (GLP-1 RA) use — specifically semaglutide restarted abruptly at the maximum weekly dose after several months off therapy. She presented with vasopressor-dependent shock, respiratory failure, pneumomediastinum, and bilateral pleural effusions. An esophagram confirmed a contained esophageal perforation. Initial management included endoscopic stent placement, nasojejunal feeding, and chest tube drainage with early improvement. Two months later she was readmitted with necrotizing pneumonia, esophagopleural fistula, stent migration, and abscess, requiring left thoracotomy, decortication, abscess drainage, lung wedge resection, and intercostal muscle flap repair. At 10-month follow-up, the esophagus had healed on endoscopy. The authors propose that GLP-1 RA–induced gastroparesis contributed to forceful emesis and transmural rupture. Key limitations include the inherent inability to establish causality from a single case, and the absence of a control group or systematic population-level data linking GLP-1 RAs to esophageal perforation.
Journal of cardiothoracic surgery · Jun 2026DOI ↗ Review
This article provides practical, evidence-informed clinical guidance on incorporating oral semaglutide — the first oral glucagon-like peptide-1 (GLP-1) receptor agonist — into obesity management. The authors draw on data from clinical trials, including the OASIS 4 trial, as well as expert clinical insights. The paper highlights that oral semaglutide has demonstrated weight loss outcomes comparable to subcutaneous GLP-1 therapies, with associated improvements in cardiometabolic risk factors, and has received regulatory approval for obesity management and cardiovascular risk reduction in adults. A central focus is the formulation's strict administration requirements, which are necessary to optimize absorption and bioavailability. The article emphasizes the importance of person-centered consultations between healthcare professionals and patients prior to treatment initiation, covering realistic expectations, adherence strategies, and adverse event management. Key limitations include that this is a guidance/review article rather than a primary clinical trial, meaning its conclusions reflect the authors' synthesis and interpretation of existing evidence rather than new experimental data. It does not establish independent causal efficacy and is subject to potential expert bias.
Postgraduate medicine · Jun 2026DOI ↗ Limited · human
This retrospective cohort study examined how the timing of preoperative semaglutide discontinuation affects short-term surgical outcomes in patients undergoing aesthetic lipoabdominoplasty. Eighty non-diabetic patients were divided into four groups: those who continued semaglutide until the day of surgery (Group A), those who discontinued 2 weeks prior (Group B), those who discontinued 4 weeks prior (Group C), and semaglutide-naïve controls (Group D). Groups were matched for age, BMI, and surgical technique, and 30-day postoperative complications were tracked. The study found that Group A had the highest complication rate at 45%, encompassing wound dehiscence, infection, and seroma formation. Group B showed a moderate reduction (30%), while Group C's complication rate (10%) was comparable to the control group (10%). Gastrointestinal intolerance and prolonged drain duration were also more common among patients with recent or ongoing semaglutide use. No reoperations or readmissions were recorded. The authors concluded that a 4-week preoperative discontinuation window effectively normalizes complication rates. Key limitations include the retrospective design, small sample size (n=80 across four groups), and the absence of randomization, blinding, or long-term follow-up.
Aesthetic plastic surgery · Jun 2026DOI ↗ Limited · human
This cross-sectional pharmacovigilance study analyzed 142,705 adverse event (AE) reports for GLP-1 receptor agonists (GLP-1 RAs) from the FDA Adverse Event Reporting System (2015–2025), focusing on 4,090 reports linked to obesity indications. The authors found gastrointestinal events were most common, 76% of reports involved female patients, and most events onset within 0–30 days. Semaglutide showed a distinct distribution including a higher proportion of late-onset events (≥360 days), while tirzepatide showed negative reporting odds ratios for several gastrointestinal events. Strong disproportionality signals were identified for biliary, pancreatic, renal, and coagulation events. Separately, the study constructed herb-compound-target-AE networks using HERB 2.0 and the Comparative Toxicogenomics Database, applying graph convolutional network (GCN) modeling to identify herbal candidates—including Liquorice Root, Mulberry Leaf, Dahurian Angelica Root, Danshen Root, and Ginkgo Leaf—potentially associated with GLP-1 RA AE profiles. GCN performance was moderate (AUC-ROC 0.666–0.798). The authors explicitly note findings are exploratory and hypothesis-generating, with results limited by spontaneous reporting biases and computational modeling constraints. Independent experimental and clinical validation is required before any clinical application.
Scientific reports · Jun 2026DOI ↗ InsufficientPreprint
This study investigates GHK-Cu — a copper-based amino acid complex — as an interfacial modifier inserted between the perovskite layer and the Spiro-OMeTAD hole-transport layer (HTL) in perovskite solar cells (PSCs). The researchers found that GHK-Cu's molecular flexibility and polarity-responsive coordination chemistry allowed it to expose multiple functional groups (─C=O, ─COOH, and ─NH₂) that interact with undercoordinated ionic defects via coordination bonds and hydrogen bonding. These interactions drove GHK-Cu to self-assemble into a mesoporous architecture at the interface, which then reorganized Spiro-OMeTAD into a hybrid mesoporous@Spiro-OMeTAD HTL. The authors report that this structure creates continuous hole-transport channels, reduces thermomechanical stress, and suppresses ion migration. Devices incorporating this interlayer reportedly achieved a power conversion efficiency (PCE) of 26.72%, with a certified PCE of 26.34%, and retained 95% of initial efficiency after 1,600 hours of maximum power point tracking at 85°C. Limitations include the preprint status of the work, meaning it has not yet undergone formal peer review, and the results reflect a specific device architecture that may not generalize broadly.
Unknown journal · Jun 2026DOI ↗ Moderate · humanPreprint
This Bayesian network meta-analysis systematically evaluated the dose-dependent efficacy and safety of mazdutide — a dual GLP-1 receptor and glucagon receptor agonist — in adults with obesity or overweight, with or without type 2 diabetes. Researchers searched five major databases through January 2026 and included nine randomized controlled trials comprising 2,292 participants. The study found that, compared with placebo, multiple mazdutide doses were associated with statistically significant improvements across a broad range of cardiometabolic outcomes, including body weight, waist circumference, BMI, HbA1c, fasting plasma glucose, blood pressure, LDL cholesterol, and liver enzymes (ALT). Subgroup analyses suggested that weight loss effects were more pronounced in non-diabetic individuals, while glycemic benefits were greater in those with type 2 diabetes. Gastrointestinal adverse events were notably more frequent with mazdutide relative to placebo, though serious adverse events were not significantly elevated. Key limitations include the relatively small number of included trials (n=9) and total participants, the indirect comparisons inherent to network meta-analysis methodology, potential heterogeneity across trial populations, and the preprint status of this work, meaning it has not yet undergone formal peer review.
Unknown journal · Jun 2026DOI ↗