Moderate · human
This observational study used two target-trial emulations to compare cardiovascular outcomes among commercially insured U.S. adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) who initiated tirzepatide, dulaglutide, or semaglutide between June 2022 and December 2024. Using propensity-score (PS) 1:1 matching to reduce confounding, the researchers formed two cohorts: 9,233 tirzepatide–dulaglutide pairs and 25,266 tirzepatide–semaglutide pairs. The primary outcome was a modified MACE composite (nonfatal myocardial infarction, nonfatal stroke, and all-cause death). The study found that tirzepatide initiators had a statistically significantly lower rate of modified MACE compared with dulaglutide initiators (HR 0.80; 95% CI 0.65–0.99), largely driven by reduced all-cause mortality (HR 0.60; 95% CI 0.43–0.83); tirzepatide was also associated with fewer pneumonia-related hospitalizations versus dulaglutide. No significant difference in modified MACE was observed between tirzepatide and semaglutide initiators (HR 1.03; 95% CI 0.90–1.17). Key limitations include the observational design, potential residual confounding, reliance on administrative claims data, and a relatively short follow-up window.
Diabetes care · May 2026DOI ↗ Limited · human
This pharmacovigilance study used the U.S. FDA Adverse Event Reporting System (FAERS) database (Q2 2022–Q2 2025) to examine whether specific GLP-1 receptor agonists (GLP-1 RAs) — exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide — differ in their association with alopecia and reproductive or endocrine-related adverse events. Researchers identified 1,276 alopecia-related and 759 reproductive/endocrine-related cases, then applied disproportionality analyses using crude and adjusted reporting odds ratios (cROR/aROR) from logistic regression, controlling for potential confounders. Sensitivity analyses with positive and negative control drugs were used to validate signal robustness. The study found that semaglutide was significantly associated with disproportionate reporting of alopecia (aROR 1.23) and several hormonal conditions, including polycystic ovary syndrome (aROR 6.59) and menstrual abnormalities. By contrast, dulaglutide and tirzepatide showed negative or non-significant associations for several reproductive outcomes. Important limitations include the inherent biases of spontaneous reporting systems (e.g., underreporting, notoriety bias, inability to establish causation), lack of denominator data, and absence of clinical detail. The authors conclude that agent-specific differences in endocrine and dermatologic safety profiles may warrant personalised prescribing decisions and ongoing surveillance.
Diabetes/metabolism research and reviews · May 2026DOI ↗ Review
This review examines the perioperative safety implications of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug class increasingly used for type 2 diabetes and obesity management. The authors focus on the mechanism by which GLP-1 RAs delay gastric emptying and how this pharmacological effect may elevate the risk of pulmonary aspiration during general anesthesia—specifically at induction and emergence—even when patients have followed standard preoperative fasting protocols. The review distinguishes between short-acting GLP-1 RAs, which reportedly cause more pronounced gastric emptying delays, and long-acting agents, whose residual effects may vary by dose and duration of treatment. The authors also survey updated guidance issued by international anesthesia societies in response to these concerns. Key limitations acknowledged include the overall scarcity and inconsistency of available clinical evidence. The review concludes by advocating for individualized, interdisciplinary perioperative management involving collaboration between endocrinologists and anesthesiologists. As a narrative review, it does not generate new primary data, and the conclusions are constrained by the quality of the underlying literature.
The Korean journal of internal medicine · May 2026DOI ↗ Review
This state-of-the-art review synthesizes available evidence on how glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — drugs used for type 2 diabetes and weight management — affect blood pressure (BP). The authors examined data across populations including people with diabetes, obesity, and high cardiovascular risk. The review reports that GLP-1 RAs are associated with modest systolic BP reductions, typically in the range of 2–5 mm Hg, which the authors attribute primarily to weight loss, with potential additional contributions from weight-independent mechanisms such as natriuresis (increased urinary sodium excretion), improved endothelial function, and reduced vascular inflammation. The review notes that while these reductions are smaller than those achieved with traditional antihypertensive medications, they may translate to meaningful cardiovascular risk reduction at a population level and may offer additive benefit alongside conventional therapies. The authors also highlight that small increases in heart rate and possible interactions with volume-regulating medications may require clinical monitoring. Limitations acknowledged include the indirect and heterogeneous nature of the synthesized evidence. The review concludes by calling for further research as newer GLP-based therapies emerge to better inform integrated cardiometabolic care strategies.
American journal of hypertension · May 2026DOI ↗ Review
This review examines the emerging role of GLP-1-based medications (such as GLP-1 receptor agonists) in the prevention and treatment of heart failure (HF), with a particular focus on heart failure with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF). The authors summarize and discuss findings from recent clinical studies reporting HF-related outcomes with these agents. The review highlights the strong pathophysiological connections between type 2 diabetes, obesity, and heart failure, positioning GLP-1-based therapies as potentially beneficial across these overlapping conditions. The authors conclude that accumulating evidence supports beneficial effects on HF outcomes—particularly in HFpEF and possibly HFmrEF—while noting that the utility of these medications in heart failure with reduced ejection fraction (HFrEF) remains unclear and requires further investigation. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and its conclusions are therefore dependent on the quality and scope of the studies it includes. It does not establish causality or provide definitive clinical guidance on specific patient populations.
Medicina (Kaunas, Lithuania) · May 2026DOI ↗ Insufficient
TRANSCEND-CKD (NCT05936151) is a double-blind, placebo-controlled Phase 2b mechanistic trial evaluating retatrutide — a triple agonist of the GIP, GLP-1, and glucagon receptors — in adults with overweight or obesity and chronic kidney disease (CKD). The publication describes the trial's rationale, design, and baseline characteristics of the 146 randomized participants (out of 367 screened). Participants had a mean age of 65.1 years, mean BMI of 35.7 kg/m², and mean measured GFR of 49.3 mL/min/1.73 m² (eGFR range 25–75). Roughly 38% had type 2 diabetes. Participants were randomized 1:1 to once-weekly retatrutide (maximum tolerated dose up to 12 mg) or matched placebo. The primary endpoint is change in measured GFR via iohexol clearance at 24 weeks; secondary endpoints include MRI-assessed kidney hemodynamics, volumes, and perirenal/renal sinus fat. The study is explicitly designed as a mechanistic precursor to the larger cardio-kidney outcomes trial TRIUMPH-Outcomes. Because this paper reports only design and baseline data — with no efficacy or safety outcomes yet — no conclusions about retatrutide's effects on kidney function can be drawn from it.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · May 2026DOI ↗ Review
This narrative review evaluates the emerging evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) — a drug class established for type 2 diabetes and obesity — as potential treatments for alcohol use disorder (AUD), a condition with currently limited pharmacological options. The authors searched PubMed, Google Scholar, and ClinicalTrials.gov, ultimately including 13 preclinical studies, 14 clinical studies, and 4 published interventional trials, while noting 19 additional trials in progress or completed but unpublished. The review describes convergent signals from both animal models and human studies suggesting that GLP-1RAs may reduce alcohol consumption and improve alcohol-related outcomes. Mechanistic preclinical work is highlighted to contextualize how these agents might modulate reward-related pathways. Clinical evidence includes observational studies drawing on real-world and electronic health record data, as well as a small number of randomized controlled trials. The authors acknowledge that the existing RCT evidence base remains limited and that further trials are needed to firmly establish efficacy. Mechanistic studies are also called for to more fully explain how GLP-1RAs may reduce alcohol intake. Case reports, commentaries, and preprints were excluded. This review does not itself generate new primary data.
Alcohol, clinical & experimental research · May 2026DOI ↗ 🧪 TrialInsufficient
Registered Phase 1 interventional trial (recruiting). Background: Glucagon-like peptide 1 (GLP-1) agonist drugs are used to treat diabetes and aid weight loss. They may also help reduce cravings for drugs and alcohol. Researchers want to know if a GLP-1 drug (tirzepatide) can lessen the urge to drink in people with alcohol use disorder (AUD). Objective: To learn how the brains of people with AUD respond to a GLP-1 drug. Eligibility: People aged 21 to 65 years with AUD who are non-treatment seeking. They must be enrolled in protocol 14-AA-0181. Healthy volunteers are also needed. Design: This s
ClinicalTrials.gov · Apr 2026View trial ↗ Insufficient
This analytical chemistry study examined compounded tirzepatide products combined with vitamin B12 analogs that are widely marketed in the United States as alternatives to FDA-approved tirzepatide. Researchers collected samples from multiple U.S. market sources and subjected them to various analytical methods to assess peptide-related impurity profiles and potency. The key finding was the identification of a previously unknown chemical impurity generated by a reaction between tirzepatide and certain B12 analogs. This impurity was described as widespread across the tested samples and present at substantial levels. The authors note that compounded tirzepatide-B12 combinations are mass-marketed without undergoing formal evaluation of potency or impurity profiles, unlike FDA-approved products. The study does not characterize the clinical effects of the identified impurity, which remains unknown. Limitations include the absence of clinical outcome data, lack of information on the specific analytical thresholds used, and no assessment of patient exposure or harm. The authors conclude that the findings highlight quality-control risks associated with compounded therapies marketed outside the drug-approval regulatory framework and reinforce the rationale for pre-market testing and FDA oversight.
Expert opinion on drug safety · Apr 2026DOI ↗ Limited · human
This pharmacovigilance study examined safety signals associated with potentially counterfeit semaglutide products by conducting a descriptive and disproportionality analysis of Individual Case Safety Reports (ICSRs) submitted to the European pharmacovigilance database EudraVigilance between January 2018 and December 2025. Researchers identified 234 ICSRs linked to suspected counterfeit semaglutide, of which 73.5% involved female patients and 35.5% involved adults. Notably, 89.3% of reported suspected adverse drug reactions (ADRs) were classified as serious. The most commonly reported suspected ADRs were vomiting, nausea, and hypoglycemia. Disproportionality analysis revealed a statistically higher reporting frequency for hypoglycemia, product use in an unapproved indication, malaise, and drug ineffectiveness compared with reports involving non-counterfeit semaglutide. The authors suggest these signals may reflect contamination, incorrect active ingredients, or subtherapeutic dosing in counterfeit products. Limitations include the inherent biases of spontaneous pharmacovigilance reporting (underreporting, lack of denominator data, and inability to confirm causality), reliance on database classifications of "counterfeit," and the descriptive nature of the analysis. The study concludes that pharmacovigilance databases can play a useful role in detecting safety concerns related to counterfeit medicines, and calls for further research.
Frontiers in pharmacology · Apr 2026DOI ↗ In vitro
This cell-culture study investigated whether the endogenous tripeptide Lysine-Proline-Valine (KPV), derived from α-melanocyte-stimulating hormone, could protect liver cells from fat accumulation. Using the human hepatocellular carcinoma cell line HepG2, researchers induced a hepatic steatosis model by exposing cells to oleic acid (OA), which mimics lipid overload seen in non-alcoholic fatty liver disease (NAFLD). The study found that OA treatment increased intracellular lipid deposits and upregulated fatty acid synthase (FAS), a key enzyme in fat production. KPV treatment was reported to attenuate these effects without causing cytotoxicity. Mechanistically, the authors propose that KPV reduced reactive oxygen species (ROS), which in turn blunted activation of ERK, reduced AKT/mTORC1 phosphorylation, and normalized phosphorylation of PPARγ — a transcription factor central to de novo lipogenesis — ultimately suppressing FAS expression. The study is limited to a single in vitro cell line model, with no animal or human data, meaning findings cannot yet be extrapolated to living organisms. Concentrations used in cell culture do not translate directly to physiological dosing. Results are hypothesis-generating and require further validation in vivo.
Cytotechnology · Apr 2026DOI ↗ Moderate · human
This study aimed to indirectly compare the efficacy and safety of injectable tirzepatide (a dual GIP/GLP-1 receptor agonist) with oral semaglutide (a GLP-1 receptor agonist) for weight management in adults with overweight or obesity but without type 2 diabetes. Because no head-to-head trial exists, researchers used multilevel network meta-regression (ML-NMR) to adjust for baseline differences in sex, ethnicity, and outcome measures between two pivotal trials: SURMOUNT-1 (tirzepatide, 72 weeks) and OASIS 1 (oral semaglutide, 68 weeks). After adjustment, the analysis found that tirzepatide at two of the three doses studied was associated with statistically significantly greater reductions in body weight and waist circumference compared with oral semaglutide. Tirzepatide was also associated with higher odds of achieving clinically meaningful weight-loss thresholds (≥5%, ≥10%, ≥15%, and ≥20% body weight reduction). Cardiometabolic outcomes and safety profiles were reported as improved or broadly comparable for tirzepatide versus oral semaglutide. Key limitations include the indirect nature of the comparison, differences in trial duration and populations, and the inability to fully control for all confounders across separate trials. The findings should be interpreted cautiously pending direct head-to-head evidence.
Diabetes, obesity & metabolism · Apr 2026DOI ↗ InsufficientPreprint
This study analyzed a large, publicly available independent testing dataset of 6,441 samples spanning fourteen peptide compounds sold through largely unregulated gray market channels directly to consumers. Compounds examined included BPC-157, semaglutide, tirzepatide, PT-141, TB-500, thymosin beta-4, and others marketed for purposes such as injury recovery, muscle growth, fat loss, and athletic performance. Researchers applied two quality acceptance frameworks — one approximating standards for 503A compounded medications and a stricter model reflecting FDA-approved drug production standards — to assess purity, measured abundance, and endotoxin burden. The study found that between 41.6% and 71.1% of samples failed to meet basic quality criteria depending on the framework applied, and measurable endotoxin contamination was detected in 15% of samples. Gray market peptides were consistently cheaper than FDA-approved alternatives, though cost differentials varied widely (e.g., 72.8% higher for tirzepatide vs. 3,850% higher for PT-141 when comparing FDA-approved options). The authors concluded that consumer-directed third-party testing improves transparency but captures only a fraction of the full safety profile relevant to patients self-administering injectable compounds. Key limitations include reliance on a secondary dataset not collected under controlled research conditions and the inability to assess many other safety dimensions beyond purity and endotoxin levels.
Unknown journal · Apr 2026DOI ↗ Limited · humanPreprint
This prospective cohort study investigated whether adjunctive thymosin alpha 1 (Thα1) combined with intravenous immunoglobulin (IVIG), initiated 8–10 days after rituximab, could reduce pulmonary adverse events (PAEs) in 379 patients with B-cell lymphoma (BCL) receiving R-CHOP chemotherapy. Patients were assigned to either standard R-CHOP alone (n=164) or R-CHOP plus Thα1-IVIG (n=215); the study was conducted over approximately 11 years. The study found that the Thα1-IVIG group had a notably lower rate of overall PAEs (13.0% vs. 31.7%), with reductions in both infectious pulmonary events and interstitial pulmonary disease. Five-year event-free survival also appeared to favor the adjunctive group. Multivariable Cox proportional hazards models were used to identify independent risk and protective factors. Key limitations include the non-randomized, observational design (patients were not randomly assigned), potential for selection bias and confounding, the preprint status of the manuscript (not yet peer-reviewed), the single-study nature of the findings, and the lack of blinding. These factors substantially limit causal interpretation of the results, and findings should be considered hypothesis-generating pending confirmatory randomized controlled trials.
Unknown journal · Apr 2026DOI ↗ Review
This paper argues that body image has been largely overlooked in research on glucagon-like peptide-1 receptor agonists (GLP-1s) such as semaglutide and tirzepatide, despite its central relevance to why people seek these treatments and how they psychologically adjust to the bodily changes that follow. Drawing on existing literature across body image, weight loss interventions, weight stigma, and cosmetic procedures, the authors conceptualise body image not simply as an outcome of GLP-1 use, but as a motivator, mediator, and moderator across the entire treatment trajectory. The paper identifies several critical research gaps, including the absence of prospective and longitudinal studies tracking body image before, during, and after GLP-1 use, as well as limited understanding of individual vulnerability factors and heterogeneity in psychological responses. The authors also highlight broader societal concerns, including the potential reinforcement of weight stigma, inequities in access to these medications, and the role of media representation. They call for body image-informed psychological support for people using GLP-1s, as well as professional education and training. As a narrative review, the paper does not present new empirical data and its conclusions are based on inference from adjacent literatures rather than direct evidence.
Body image · Apr 2026DOI ↗ Review
This narrative review compared tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a selective GLP-1 receptor agonist) across weight loss, glycemic control, cardiometabolic, and safety outcomes by synthesizing evidence from clinical trials, real-world observational studies, and cardiovascular outcome analyses. The authors found that in completed head-to-head randomized trials, tirzepatide consistently produced greater reductions in body weight and HbA1c compared with semaglutide in people with obesity or type 2 diabetes. Regarding cardiovascular outcomes, the review noted that semaglutide currently holds the most mature evidence for cardiovascular risk reduction, supported by the SUSTAIN-6, PIONEER-6, and SELECT trials. Tirzepatide's SURPASS-CVOT trial demonstrated non-inferiority to dulaglutide for cardiovascular outcomes along with improvements in cardiometabolic risk factors, but direct cardiovascular superiority data versus semaglutide remain limited. Real-world studies on cardiovascular outcomes were characterized as heterogeneous. The authors concluded that treatment selection should be individualized. Key limitations include the narrative (non-systematic) methodology, potential for selection bias in literature inclusion, and the absence of a completed direct head-to-head cardiovascular outcomes trial between the two agents.
Frontiers in medicine · Apr 2026DOI ↗ Preclinical
This study developed a multifunctional injectable hydrogel called HCG@CDs designed to treat radiation-induced skin injury (RISI), a common complication of cancer radiotherapy. The hydrogel was constructed by cross-linking carboxymethyl chitosan (CMCS) with oxidized hyaluronic acid (OHA) conjugated to a Glycyl-L-Histidyl-L-Lysine-Copper(II) complex (GHK-Cu²⁺) via dynamic Schiff-base bonds, with carbon dots (CDs) possessing superoxide dismutase (SOD)-like activity dispersed throughout the network. The system was designed for sequential, pH-responsive drug release: CDs are rapidly released in the acidic wound environment to scavenge reactive oxygen species (ROS) and reduce early oxidative stress, while GHK-Cu²⁺ is released more gradually to promote inflammation modulation, cell migration, proliferation, and collagen deposition. Both in vitro cell-based assays and in vivo animal model experiments were conducted, with results reportedly showing reduced oxidative damage, attenuated inflammatory responses, and accelerated wound healing. Limitations include reliance on preclinical models (cell culture and animal studies), with no human clinical data presented. The translational relevance to human RISI treatment remains to be established through further clinical investigation.
Bioactive materials · Apr 2026DOI ↗ Limited · humanPreprint
This bioinformatics study investigated the role of melatonin-related genes in coronary heart disease (CHD) by analyzing two publicly available gene expression datasets (GSE179789 and GSE113079). Using differential expression analysis and validation, the researchers identified two genes—MAP2K2 (a mitogen-activated protein kinase kinase) and PGD (phosphogluconate dehydrogenase)—as candidate CHD biomarkers, both showing significant upregulation in CHD samples across both datasets. Gene set enrichment analysis (GSEA) linked these genes to pathways including ribosome function, prion diseases, and Parkinson's disease. The study also mapped complex regulatory networks involving lncRNAs, miRNAs, and transcription factors; notably, four lncRNAs (NEAT1, AP000766.1, LINC02381, and XIST) were found to regulate PGD via hsa-let-7e-5p, and 29 transcription factors co-regulated both biomarkers. Drug-target network analysis predicted 41 drugs targeting MAP2K2 and 3 targeting PGD. Biomarker expression was further validated in clinical samples via RT-qPCR. Limitations include the observational and computational nature of the study, reliance on public datasets, small clinical validation cohorts typical of such designs, and the absence of functional or mechanistic experiments confirming causal roles. The study is reported as a preprint and has not undergone formal peer review.
Unknown journal · Apr 2026DOI ↗ Animal only
This mouse study investigated whether potassium-competitive acid blockers (P-CABs), sometimes empirically used for eosinophilic gastrointestinal diseases, might worsen eosinophilic enteritis (EoN) under psychological stress conditions. Researchers established an EoN model in BALB/c mice using ovalbumin sensitization and challenge, then exposed animals to water avoidance stress (WAS) or sham stress, with or without P-CAB administration. Compared to the WAS-only group, WAS combined with P-CAB significantly worsened multiple disease markers, including diarrhea incidence, villus/crypt ratio, eosinophil and mast cell counts, Th2 cytokine expression (mRNA and protein), OVA-specific IgE levels, and ileal permeability measured via Ussing chamber. The study further found that larazotide acetate, a zonulin inhibitor targeting gut tight junctions, reduced ileal inflammation and permeability in WAS + P-CAB-treated EoN mice, suggesting a permeability-mediated mechanism. Key limitations include exclusive use of a mouse model, which may not fully replicate human eosinophilic gastrointestinal disease, and the artificial nature of the stress and sensitization protocols. These findings raise important cautions about P-CAB use in patients with EoN who may be under psychological stress, though human clinical evidence is still lacking.
Digestion · Apr 2026DOI ↗ Limited · human
This large-scale observational study used a federated biomedical data platform to analyze 135,349 individuals treated with GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Wegovy) and tirzepatide (Zepbound) formulations — to characterize differences between "super responders" (>15% weight loss), "moderate responders" (5–15% weight loss), and a "minimal weight-loss" group. The study found substantial heterogeneity in weight-loss outcomes across patients receiving the same therapies. Notably, super responders to Zepbound showed reduced risk of developing certain comorbidities, including conditions at relative risks as favorable as 0.5 for osteoarthritis (P = .001), while Wegovy super responders showed an association with psoriasis (RR = 2.5, P = .03). The authors conclude that differences in weight trajectories likely reflect a combination of biological, behavioral, and social factors. Key limitations include the observational, retrospective design (which cannot establish causation), the reliance on federated real-world data (subject to coding variability), and lack of randomization. The authors call for prospective studies to develop more individualized weight-loss strategies.
Biology methods & protocols · Apr 2026DOI ↗