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 ↗ 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 ↗ 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 ↗ Moderate · human
This updated systematic review and meta-analysis evaluated the efficacy and safety of semaglutide — a GLP-1 receptor agonist — in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). Following PRISMA guidelines and registered on PROSPERO, the authors searched multiple databases through January 2026, ultimately pooling data from 10 studies comprising 1,908 participants. The primary outcomes were histological MASH resolution without worsening of fibrosis and improvement in fibrosis stage; secondary outcomes included liver stiffness and biochemical markers. The meta-analysis found that semaglutide was significantly associated with MASH resolution without fibrosis worsening (OR 3.48; 95% CI: 2.68–4.53). However, the anti-fibrotic effect appeared to be both stage-dependent and time-dependent, with meaningful histological fibrosis reversal observed primarily in non-cirrhotic patients within the durations of the included trials. Improvements in liver stiffness and biochemical markers were also reported. Limitations include the relatively short durations of the constituent trials and heterogeneity across included studies, which may limit generalizability to advanced or cirrhotic disease stages.
British journal of clinical pharmacology · Jun 2026DOI ↗ Animal onlyPreprint
This mouse study investigated the effects of semaglutide, a GLP-1 receptor agonist (GLP-1 RA), administered from preconception through lactation in dams fed either a high-fat diet (HFD) or a standard diet. Researchers assessed metabolic outcomes in both the treated mothers and their offspring, who were weaned onto a standard diet. The study found that semaglutide improved body composition and glucose metabolism in HFD-fed dams during pregnancy, and these benefits persisted approximately 10 weeks after weaning even after treatment was discontinued. Offspring born to HFD-fed, untreated dams showed impaired glucose homeostasis and hepatic steatosis (fatty liver) at 18 weeks of age. These metabolic disturbances were attenuated in offspring whose mothers received semaglutide. Notably, semaglutide treatment did not adversely affect conception rates or fetal viability. The authors conclude that GLP-1 RA therapy during the perinatal period may improve both maternal and offspring metabolic health in an obesity mouse model, and they call for further investigation into GLP-1–based therapies in this context. Key limitations include the exclusive use of a mouse model, limiting direct translation to human pregnancy, and the fact that this appears to be a preprint not yet formally peer-reviewed.
Unknown journal · Jun 2026DOI ↗ Limited · human
This retrospective federated cohort study used the TriNetX US Collaborative Network to examine whether GLP-1-based therapy (semaglutide or tirzepatide) was associated with lower rates of ICD-10-documented heart failure (HF) or respiratory failure (RF) in non-diabetic adults with rheumatoid arthritis (RA) and obesity (BMI ≥30 kg/m²). Patients were required to have baseline disease-modifying antirheumatic drug (DMARD) use, and those with diabetes or overlapping systemic autoimmune diseases were excluded. After propensity score matching on 68 covariates (1:1), 3,483 patients remained per cohort. The study found that GLP-1-based therapy was associated with a substantially lower hazard of first post-landmark composite HF or RF events during days 91–365. In absolute terms, the primary composite occurred in 0.7% of GLP-1 users versus 1.8% of never-users, corresponding to roughly one fewer event per 100 patients. Heart failure and respiratory failure analyzed separately showed directionally consistent lower hazards, though individual event counts were small. The authors acknowledge that the findings are hypothesis-generating only, are limited by the retrospective, administrative-data design and potential residual confounding, and require prospective validation before informing clinical practice.
Clinical rheumatology · Jun 2026DOI ↗ Limited · human
This prospective, matched controlled study used continuous glucose monitoring (CGM) via FreeStyle Libre to characterize glycaemic patterns during Ramadan 2025 in 54 adults with insulin-treated diabetes. Three matched groups of 18 participants each were compared: type 2 diabetes on basal-bolus insulin alone (BB), type 2 diabetes on basal-bolus insulin plus adjunctive semaglutide or tirzepatide (BB+), and type 1 diabetes on basal-bolus insulin. CGM data were collected over 28 days pre-Ramadan and 29 days during Ramadan. The study found that dysglycaemia was predominantly driven by the post-iftar (meal-breaking) period. The BB group showed marked deterioration in glycaemic control during non-fasting hours. In contrast, the BB+ group demonstrated significantly better time-in-range (74.4% vs. 36.8%), a lower glucose management indicator (6.9% vs. 8.3%), and an approximately 61% reduction in post-iftar glucose excursions, without increased hypoglycaemia or treatment discontinuations. Limitations include a relatively small matched sample size, a single Ramadan observational period, and non-randomized group assignment, which may introduce residual confounding despite matching.
Diabetes research and clinical practice · Jun 2026DOI ↗ Limited · humanPreprint
This retrospective, propensity-score matched observational study used de-identified federated U.S. electronic health record (EHR) data to examine real-world associations of semaglutide (n=1,424) and tirzepatide (n=578) use in adults with type 1 diabetes (T1D) compared to 1:1 matched T1D controls (n=2,002) who did not receive these agents, over a study period from 2018–2025. Neither drug is approved for T1D. The study found that both agents were associated with statistically significant reductions in total daily insulin dose, HbA1c, and body weight at 12 and 24 months compared to controls. Greater insulin reductions were observed in semaglutide users who achieved higher weight loss or dose escalation. The pre-vs-post safety analysis identified predominantly gastrointestinal adverse events; DKA, severe hypoglycemia, pancreatitis, and retinopathy did not increase significantly overall, though patients with >30% insulin dose reduction had higher DKA rates. Semaglutide and tirzepatide exposure was associated with lower all-cause mortality and major adverse cardiovascular events versus matched controls. Key limitations include the observational design, EHR data quality constraints, off-label prescribing confounding, and preprint status, meaning findings have not yet undergone peer review.
Unknown journal · Jun 2026DOI ↗ Review
This systematic review examined existing evidence on the use of second-generation incretin analogs — specifically semaglutide (a GLP-1 receptor agonist) and tirzepatide (a dual GLP-1/GIP receptor agonist) — in adults with type 1 diabetes (T1D) or latent autoimmune diabetes in adults (LADA). Researchers screened 3,053 records from six major databases and ClinicalTrials.gov, ultimately identifying 11 eligible publications. These comprised two systematic reviews, one post hoc subgroup analysis, six narrative or consensus reviews, and two LADA case reports. Three key themes emerged from the synthesis: (1) LADA is frequently misdiagnosed or diagnosis is delayed due to its heterogeneous presentation; (2) both tirzepatide and semaglutide show potential benefits in LADA and in certain T1D subtypes, particularly in individuals retaining residual beta-cell function; and (3) existing clinical management frameworks may guide practice while robust trial data are awaited. The authors concluded that current evidence is promising but moderate in quality, and that well-designed, adequately powered randomized controlled trials in clearly defined LADA and T1D populations are needed to establish long-term efficacy and safety. Notable limitations include the small number of eligible studies, the predominance of review-level and narrative publications, and only two primary patient-level reports.
Journal of the American Association of Nurse Practitioners · Jun 2026DOI ↗ Strong · human
The REIMAGINE 2 trial was a phase 3, double-blind, randomised, placebo- and active-controlled study evaluating the fixed-dose combination of cagrilintide (an amylin receptor agonist) and semaglutide (a GLP-1 receptor agonist), known as CagriSema, in 2,713 adults with inadequately controlled type 2 diabetes and overweight or obesity across 30 countries. Participants were on background metformin with or without an SGLT2 inhibitor and were followed for 68 weeks. The primary endpoint was change in HbA1c from baseline. The study found that the higher-dose CagriSema combination produced a statistically significantly greater reduction in HbA1c compared with semaglutide alone (-1.91 vs. -1.75 percentage points; treatment difference -0.16 percentage points; p=0.0035). Adverse events were more frequent in the combination group (86.9%) than in the semaglutide monotherapy group (81.2%), with gastrointestinal disorders being the most common across active treatment arms. Limitations include the relatively modest absolute difference in HbA1c reduction, a predominantly White study population, and industry funding by Novo Nordisk, which may introduce sponsorship bias.
The lancet. Diabetes & endocrinology · Jun 2026DOI ↗ Moderate · human
REIMAGINE 1 was a randomised, double-blind, placebo-controlled phase 3a trial evaluating once-weekly subcutaneous cagrilintide-semaglutide (CagriSema) — a combination of an amylin receptor agonist (cagrilintide) and a GLP-1 receptor agonist (semaglutide) — in 189 adults with type 2 diabetes inadequately controlled by diet and exercise alone. Conducted across 42 sites in six countries over 40 weeks, participants were assigned to one of two active dose levels or matched placebo. The primary endpoint was change in HbA1c from baseline to week 40. The study found that both active dose levels produced statistically significant and clinically meaningful reductions in HbA1c compared to placebo (estimated treatment differences of −1.7 and −1.4 percentage points for the higher and lower doses, respectively; p<0.0001 for both). Body weight reduction was a notable secondary finding. The safety profile was described as consistent with the GLP-1 receptor agonist class. Key limitations include the relatively small sample size (n=189), short 40-week duration, an early-stage diabetes population not on background glucose-lowering medications, and industry funding from Novo Nordisk, which may introduce bias. These results suggest CagriSema may be a promising therapeutic option for early-stage type 2 diabetes.
The lancet. Diabetes & endocrinology · Jun 2026DOI ↗ Strong · human
The REIMAGINE 3 trial investigated the combination of cagrilintide and semaglutide (CagriSema) as a weekly add-on to daily basal insulin in adults with type 2 diabetes and suboptimal glycaemic control (HbA1c 7.0–10.5%). In this 40-week, double-blind, placebo-controlled phase 3 study conducted across 46 centres in six countries, 274 participants were randomised to one of two active dose combinations (2.4 mg each or 1.0 mg each) or pooled placebo. The primary endpoint—change in HbA1c from baseline to week 40—was significantly greater with both CagriSema doses (–2.33% and –2.10%, respectively) compared with placebo (–0.66%). Both active groups also achieved substantial bodyweight reductions versus placebo, and no additional hypoglycaemia risk was observed. The safety profile was consistent with the GLP-1 receptor agonist class. Limitations include a relatively short 40-week duration, a moderately sized sample, and industry funding by Novo Nordisk. The study authors conclude that CagriSema meaningfully improved glycaemic control when added to basal insulin, without increasing hypoglycaemia risk.
Lancet (London, England) · Jun 2026DOI ↗ Animal only
This mouse study investigated the molecular mechanisms by which tirzepatide (TZP), a dual GIP/GLP-1 receptor agonist, affects the liver in metabolic dysfunction-associated steatotic liver disease (MASLD). Male C57BL/6J mice (n=32) were fed a high-fat, high-fructose (HFHFr) diet to induce MASLD and then randomized to receive no treatment, semaglutide (Sema), or TZP. Researchers combined RNA sequencing and liquid chromatography-mass spectrometry (LC-MS) to generate hepatic transcriptomic and proteomic profiles, with key targets validated by PCR and immunoblotting. The study found that HFHFr feeding produced hyperglycemia, insulin resistance, elevated liver enzymes, and hepatic steatosis and inflammation. Both TZP and Sema were associated with improvements in these parameters; TZP was associated with reductions in pro-inflammatory markers (MCP-1, IL-1β, TNF-α, GSDMD) and partial restoration of IL-10. Integrated omics analysis implicated the CCL2/CCR2 chemokine axis and PI3K-AKT signaling pathway as key molecular signatures associated with TZP's hepatic effects. Key limitations include the exclusive use of an animal model, a small sample size, and the mechanistic (non-causal) nature of omics associations.
BMC gastroenterology · Jun 2026DOI ↗