Animal only
This study investigated whether milk-derived small extracellular vesicles (sEVs) could serve as oral delivery vehicles for two GLP-1 receptor agonists (GLP-1RAs): semaglutide and tirzepatide. Researchers loaded both peptides onto sEVs in vitro and administered them orally to diabetic db/db mice—a well-established mouse model of type 2 diabetes. The study found that both peptides were efficiently incorporated into the sEV carrier system and that oral administration of the loaded vesicles effectively reduced blood glucose levels in the diabetic mice. The authors compared this approach to the existing SNAC (sodium N-[8-(2-hydroxybenzoyl) amino] caprylate) technology used in the commercially approved oral semaglutide formulation (Rybelsus), arguing that sEVs offer broader applicability across multiple peptide drugs, not just semaglutide. Key limitations include the exclusive use of an animal model with no human pharmacokinetic or efficacy data, a relatively small and homogeneous study design, and the early-stage, preclinical nature of the platform. Translation to humans remains undemonstrated.
Journal of extracellular biology · Nov 2025DOI ↗ Review
This scoping review examines the biological rationale and existing evidence for using glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of psoriatic disease (PsD), a chronic systemic inflammatory condition frequently accompanied by cardiometabolic comorbidities such as obesity, type 2 diabetes mellitus, and cardiovascular disease. The authors explored three main areas: (1) how obesity, diabetes, and cardiovascular disease influence PsD severity and treatment resistance; (2) the established efficacy of GLP-1RAs in managing these comorbidities; and (3) early evidence from rheumatologic and dermatologic conditions including rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, and hidradenitis suppurativa. The review highlights shared immunopathogenic mechanisms — particularly Th1/Th17-driven cytokines such as TNF, IL-6, and IL-17 — as a rationale for GLP-1RA use beyond metabolic indications. The authors report that early clinical and preclinical data suggest GLP-1RAs may reduce systemic inflammation and PsD burden, but acknowledge this evidence is preliminary. Key limitations include the scoping review design (which maps available evidence rather than synthesizes effect sizes), reliance on preclinical and indirect data, and the absence of dedicated randomized controlled trials in PsD populations. The authors conclude that further clinical trials are needed to establish disease-modifying potential.
Inflammation research : official journal of the European Histamine Research Society ... [et al.] · Nov 2025DOI ↗ 🧪 TrialInsufficient
Registered N/A interventional trial (completed). Obesity is a chronic condition linked to numerous health risks and affects more than one billion people worldwide. While pharmacological treatments such as incretin-based therapies are available, they may have side effects, are not suitable for all patients, and adherence can be limited. Dietary supplements that influence appetite and satiety may represent an alternative or complementary approach. This study will evaluate whether a dietary supplement containing plant extracts stimulates the intestinal incretin response. The primary focus is the
ClinicalTrials.gov · Nov 2025View trial ↗ Insufficient
The DREAMS-3 trial is a randomized, open-label Phase 3 study designed to compare the efficacy and safety of mazdutide (a glucagon receptor/GLP-1 receptor co-agonist) versus semaglutide (a GLP-1 receptor agonist) in Chinese adults with type 2 diabetes (T2D) and obesity. This publication reports the trial's rationale, design, and baseline characteristics rather than outcome results, as the study is ongoing with an expected completion date in early 2026. A total of 349 participants (mean age 42.4 years; 44.7% male) were randomized 1:1 to either treatment arm for a 32-week active-controlled period followed by a 24-week extension. At baseline, participants had a mean HbA1c of 8.0%, body weight of 90.5 kg, and BMI of 33.0 kg/m². The mean T2D duration was 1.8 years, and approximately 39.5% were on metformin. The primary endpoint is the proportion of participants achieving HbA1c targets. Notably, comorbidities such as metabolic-associated fatty liver disease and gout/hyperuricemia showed strong associations with BMI. As a design and baseline data paper, no efficacy or safety outcomes are yet available, limiting current evidence value.
Contemporary clinical trials · Nov 2025DOI ↗ Review
This paper examines the socioeconomic and systemic barriers that limit equitable access to glucagon-like peptide-1 (GLP-1) receptor agonist medications as obesity treatments. The authors note that obesity disproportionately burdens socioeconomically disadvantaged populations, yet the high cost and limited supply of GLP-1 agonists mean these effective therapies remain largely accessible only to those who can afford to pay privately. The paper frames this disparity through Julian Tudor Hart's "inverse care law," which describes how access to effective healthcare tends to be inversely correlated with clinical need. The authors argue that current rollout patterns risk deepening existing health inequalities rather than alleviating them. They call for evidence-informed policies to prioritize access based on clinical need, equitable global distribution strategies, and complementary investment in preventive and population-level public health measures. As a narrative review and commentary, the paper does not present original clinical data or trial results, and its conclusions are based on synthesized existing evidence and policy analysis rather than empirical study. Its primary value is as a framework for health policy discussion around GLP-1 access equity.
Review
This review synthesizes current scientific understanding of ghrelin, a hormone originally characterized primarily for its role in appetite stimulation and growth hormone release. The authors trace the full arc of ghrelin biology: from its biosynthesis (preproghrelin processing and O-acylation by the enzyme GOAT to produce the active acyl-ghrelin form), through its receptor pharmacology at GHSR1a, to its wide-ranging physiological roles. The review highlights that des-acyl ghrelin—the predominant circulating form—can exert effects independently of or with lower potency at GHSR1a, and that truncated "mini-ghrelins" may act as competitive antagonists. Recent cryo-EM structural data on GHSR1a are discussed as a framework for understanding biased signaling and drug design. The authors also review ghrelin's roles in glucose regulation, gastric function, cardiovascular tone, bone remodeling, renal hemodynamics, innate immunity, and the central nervous system—including links to neuroprotection, depression, Alzheimer's disease, and addiction. Translational topics covered include ghrelin stabilization strategies, synthetic ligands (agonists, antagonists, inverse agonists), LEAP-2-based approaches, and GOAT inhibitors. As a narrative review, the paper does not generate new experimental data, so primary evidence quality depends on the underlying cited studies.
International journal of molecular sciences · Nov 2025DOI ↗ Insufficient
SYNCHRONIZE™-2 is an ongoing double-blind, randomized, placebo-controlled Phase 3 trial evaluating survodutide — an investigational dual glucagon receptor/GLP-1 receptor agonist — for weight reduction in adults with obesity and type 2 diabetes (T2D). This paper reports only the baseline characteristics of the 752 enrolled participants across 133 sites in 19 countries; efficacy and safety results are not yet available. Participants were randomized 1:1:1 to one of two doses of weekly subcutaneous survodutide or placebo, alongside diet and physical activity guidance. At baseline, the cohort had a mean age of 55.7 years, mean BMI of 36.5 kg/m², mean body weight of 104.1 kg, and mean HbA1c of 7.4%; roughly half were female. Common comorbidities included hypertension (69%), dyslipidaemia (68%), and obstructive sleep apnoea (17%). The geographic distribution included participants from Europe, North America, and East Asia, suggesting reasonable diversity. Primary endpoints are percentage change in body weight and achievement of ≥5% weight loss at Week 76. A key limitation of this publication is that it presents only baseline data — no outcomes are yet reported — so no conclusions about efficacy or safety of survodutide can be drawn from this paper alone.
Diabetes, obesity & metabolism · Nov 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 1 interventional trial (recruiting). The purpose of this study is to investigate how the duration of fasting and temporary stopping of Glucagon-Like-Peptide 1 (GLP-1) medications affect the amount of food left in the stomach in people using liraglutide (injected), semaglutide (taken by mouth) or semaglutide (injected). The length of participants participation in the study will depend on the type of GLP-1 RA treatment participants are already using.
ClinicalTrials.gov · Nov 2025View trial ↗ Moderate · human
This systematic review, following PRISMA 2020 guidelines, examined the frequency, severity, and types of gastrointestinal (GI) adverse effects associated with anti-obesity medications in non-diabetic adults with obesity. Researchers searched PubMed, Google Scholar, BMJ, and Web of Science through July 2025, ultimately including 12 studies from 733 screened articles. The evidence base included one large cohort of 18,386 participants alongside smaller randomized and observational trials. The review found that nausea, vomiting, diarrhea, and constipation were the most frequently reported GI symptoms, occurring predominantly with GLP-1 receptor agonists such as semaglutide and tirzepatide, particularly during dose escalation phases. Orlistat was commonly associated with steatorrhea and flatulence, while phentermine was linked to reduced GI motility. Newer investigational agents, including retatrutide and orforglipron, also demonstrated notable GI side effect profiles. Natural products and other investigational agents reported fewer adverse events but lacked long-term data and standardized reporting. Key limitations include heterogeneity in study designs and inconsistent GI outcome reporting across included studies. The authors concluded that GI side effects are common but generally mild to moderate, and that standardized reporting and proactive clinical management strategies may improve patient adherence and tolerability.
Medicina (Kaunas, Lithuania) · Nov 2025DOI ↗ Insufficient
This paper reports the baseline characteristics of participants enrolled in SYNCHRONIZE-1, a multinational, randomized, double-blind, placebo-controlled Phase 3 trial evaluating survodutide — a dual glucagon receptor and GLP-1 receptor agonist — for weight management in adults with obesity but without type 2 diabetes. A total of 725 participants from 14 countries were randomized 1:1:1 to receive once-weekly subcutaneous injections of survodutide (up-titrated to 3.6 mg or 6.0 mg) or placebo over 76 weeks. At baseline, participants had a mean age of 47.1 years, mean BMI of 37.9 kg/m², and mean waist circumference of 115.2 cm; 59.4% were female. Common obesity-related complications included hypertension (40.0%), dyslipidaemia (33.7%), and prediabetes (30.2%). The primary endpoints are percent body weight change and achievement of ≥5% body weight reduction from baseline to Week 76. As this publication covers only baseline data, no efficacy or safety outcomes are yet reported. The study's key limitation at this stage is that it describes enrollment characteristics only, with no outcome data available.
Diabetes, obesity & metabolism · Nov 2025DOI ↗ Limited · human
This multicenter retrospective observational study used the TriNetX database (2018–2021) to examine whether adding a GLP-1 receptor agonist (GLP-1 RA) to an SGLT2 inhibitor (SGLT2i) provides additional benefit over SGLT2i monotherapy in adults with both heart failure (HF) and type 2 diabetes (T2D). From nearly 929,000 eligible patients, 25,989 received combination therapy and 54,619 received SGLT2i monotherapy; after propensity score matching, each group contained 23,240 patients. Over one year, the study found that the combination group had a significantly lower rate of all-cause death (2.8% vs. 6.3%) and hospitalization compared with the monotherapy group. While propensity score matching was used to balance baseline characteristics, the retrospective and observational design limits causal inference, as unmeasured confounders (e.g., prescribing patterns, disease severity, medication adherence) may have influenced outcomes. The TriNetX database also relies on real-world electronic health records, which can have coding inaccuracies. The authors conclude that combination SGLT2i and GLP-1 RA therapy was associated with lower all-cause mortality and hospitalization risk in this HF and T2D population, but prospective randomized trials are needed to confirm these findings.
BMJ open diabetes research & care · Nov 2025DOI ↗ Review
This review examines the role of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) in kidney protection among people living with type 2 diabetes and obesity. The authors trace the evolution of GLP-1 research from its original characterization as a metabolic hormone—regulating insulin secretion, suppressing glucagon, and reducing insulin resistance partly through weight loss—toward a broader understanding of its effects on kidney physiology and clinical outcomes. The review summarizes preclinical data alongside landmark clinical trial findings, noting that renoprotective effects have been observed despite only modest GLP-1 receptor expression in the kidney. Key clinical outcomes discussed include changes in albuminuria, estimated glomerular filtration rate decline, and cardiovascular-renal endpoints drawn from large outcomes trials. The authors frame GLP-1 RAs as an area of intensive ongoing investigation for chronic kidney disease management in the relevant patient population. As a narrative review, this paper does not conduct original data collection or meta-analysis, and conclusions are therefore subject to the selection and interpretation choices of the authors. It provides a useful synthesis of the existing evidence base but does not itself constitute primary clinical trial data.
The Journal of clinical investigation · Nov 2025DOI ↗ Review
This review examines the relationship between glucagon-like peptide-1 (GLP-1) receptor agonists — a class of drugs used to treat obesity and type 2 diabetes — and cancer risk. The authors note that obesity and type 2 diabetes are established risk factors for several cancers, and that GLP-1 receptor agonists have become transformative treatments for these conditions. The review synthesizes current clinical evidence across multiple cancer types, including thyroid, pancreatic, gastrointestinal, and hormone-dependent malignancies. The authors report that recent meta-analyses generally do not support an increased cancer incidence with GLP-1 receptor agonist use, and suggest a potential risk-lowering effect in some cancer types. Preclinical studies are also discussed, with findings pointing to possible anticancer mechanisms even in non-obese models, including immune-modulating effects that may reflect direct action on immune cells or stem from improved metabolic function. The review highlights ongoing clinical trials and identifies key gaps in translational research, including questions about treatment timing, duration, concurrent anticancer therapies, and the distinction between cancer risk versus progression models. As a narrative review, it does not generate new primary data, and conclusions depend on the quality of the underlying studies reviewed.
The Journal of clinical investigation · Nov 2025DOI ↗ Strong · human
This systematic review and network meta-analysis examined the renal effects of three classes of novel antidiabetic agents—DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors—in adults with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Researchers searched four major databases through July 2025 and identified 20 randomized controlled trials enrolling 80,670 participants, with a minimum follow-up of 24 weeks. Key outcomes assessed were composite renal outcomes, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR). The study found that several agents significantly reduced composite renal outcomes compared with placebo; dapagliflozin demonstrated the largest effect (high-certainty evidence), followed by canagliflozin, empagliflozin, and select GLP-1 agonists (efpeglenatide, sotagliflozin, semaglutide, dulaglutide). Canagliflozin most strongly reduced UACR, while dapagliflozin showed no significant effect on this measure. No agent significantly altered eGFR. DPP-4 inhibitors showed no renal benefit. Certainty of evidence, assessed via GRADE, was high for direct placebo-controlled comparisons but fell to low or very low for indirect network estimates. A key limitation is that conclusions about head-to-head drug comparisons rely on indirect evidence, which carries greater uncertainty.
Diabetes, obesity & metabolism · Oct 2025DOI ↗ Animal only
This study describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for measuring tirzepatide — a dual GIP/GLP-1 receptor agonist — in rat plasma. Researchers used protein precipitation with methanol for sample preparation, a peptide C18 column for chromatographic separation, and positive electrospray ionization with multiple reaction monitoring for detection, using semaglutide as an internal standard. The method demonstrated good linearity (1–1000 ng/mL), with intra- and inter-day accuracy and precision meeting regulatory criteria. Stability under various storage and handling conditions was also confirmed. The validated method was then applied to a pharmacokinetic study in rats administered tirzepatide intravenously and subcutaneously at 0.3 mg/kg. The study reports terminal half-lives of approximately 10 hours via both routes and estimates subcutaneous bioavailability at roughly 62%. Key limitations include the exclusive use of a rat model, a single dose level, and a small number of animals typical of preclinical PK studies, meaning findings may not translate directly to humans. The authors suggest the method could be adapted for quantifying other structurally similar peptide therapeutics.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · Oct 2025DOI ↗ Moderate · humanPreprint
This meta-analysis pooled data from four randomized controlled trials (n = 918) to evaluate the efficacy of mazdutide — a dual GLP-1 and glucagon receptor agonist — in nondiabetic adults with overweight or obesity. Researchers searched PubMed, Scopus, and Web of Science and applied a random-effects model to analyze primary outcomes including body weight, BMI, and waist circumference, along with secondary cardiometabolic markers. The pooled analysis found that, compared with placebo, mazdutide was associated with statistically significant reductions in body weight (mean difference: −7.72 kg), BMI (−2.84 units), waist circumference (−5.76 cm), HbA1c (−0.30%), LDL cholesterol (−10.59 mg/dL), total cholesterol (−18.61 mg/dL), and triglycerides (−49.87 mg/dL). The authors concluded that mazdutide shows promise as a pharmacotherapy option for this population. Key limitations include the small number of included trials (n = 4), the relatively modest total sample size, the lack of long-term follow-up data, and the preprint status of this analysis, meaning it has not yet undergone formal peer review. Findings should therefore be interpreted with caution pending publication.
Unknown journal · Oct 2025DOI ↗ Review
This review paper examines the potential role of nutrient-stimulated hormone-based therapies (NuSHs) — particularly GLP-1 receptor agonists — in the prevention and management of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC). The authors contextualize MASH as the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now the most prevalent chronic liver disease in Western populations. The review synthesizes emerging clinical and preclinical evidence suggesting that NuSHs can resolve MASH without worsening fibrosis, primarily through weight loss and improved insulin sensitivity. However, the authors note that benefits appear less pronounced in cirrhotic patients, implying greater utility in early disease stages. Preclinical models suggest NuSHs may reduce MASH-related HCC incidence and tumor burden through systemic metabolic improvements rather than direct anti-cancer mechanisms. Observational data from bariatric surgery populations further support a preventive role for weight loss. The authors also propose that integrating NuSHs into post-locoregional HCC treatment pathways could delay systemic therapy, improve immunotherapy synergy, and enhance transplant eligibility. Key limitations include the indirect nature of evidence, inconsistent fibrosis regression data, and an absence of trials with oncological primary endpoints.
Journal of clinical and translational hepatology · Oct 2025DOI ↗ In vitro
This study investigated PapB, a radical S-adenosyl-l-methionine (rSAM) enzyme involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs). Classically, RiPP maturase enzymes require an N-terminal leader sequence on the precursor peptide to guide substrate recognition and modification. The researchers discovered that PapB can function in a "leader-independent" manner — meaning it can process peptide substrates that entirely lack canonical leader sequences. To demonstrate the practical utility of this finding, the team applied PapB to three analogues of glucagon-like peptide (GLP-1) pathway agonists — a therapeutically relevant class of peptides — and showed that the enzyme achieved complete conversion of each linear peptide into a thioether-macrocyclized (C-terminally cyclized) product. The study is primarily a biochemical and enzymological characterization conducted in vitro, with no human or animal subjects involved. Limitations include that all work was performed outside of a biological system, and the therapeutic relevance of the resulting macrocyclic GLP-1 analogues in vivo remains to be established. The findings position PapB as a potentially versatile biocatalytic tool for generating conformationally constrained peptide drug candidates.
ACS bio & med chem Au · Oct 2025DOI ↗ Review
This updated narrative review examines the efficacy and safety of anti-obesity medications (AOMs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). The authors synthesize evidence on several pharmacologic classes, with particular focus on incretin-based therapies. GLP-1 receptor agonists, specifically liraglutide and semaglutide, are reported to reduce hepatic steatosis, improve liver enzyme profiles, and attenuate fibrosis progression. Tirzepatide, a dual GLP-1/GIP agonist, is noted to produce superior weight loss compared to GLP-1 monotherapy, though data on hepatic histological outcomes in MASLD/MASH remain limited. Retatrutide, a triple GLP-1/GIP/glucagon agonist, showed the most pronounced metabolic effects overall, but its liver-specific histological impact is described as underexplored. The review also flags safety concerns with other AOMs such as bupropion-naltrexone and phentermine-topiramate, citing potential hepatotoxicity risks. The authors note that advanced MASLD may alter drug pharmacokinetics, complicating treatment decisions. Key limitations include the review's narrative design, heterogeneity of cited primary studies, and a general lack of large-scale, liver-histology-focused trials for newer agents.
World journal of gastroenterology · Oct 2025DOI ↗ Review
This article is a regulatory milestone review summarizing the development history of mazdutide (Xinermei®), a dual glucagon receptor (GcgR) and glucagon-like peptide-1 receptor (GLP-1R) agonist co-developed by Eli Lilly and Innovent Biologics. The review traces the compound's path to its first regulatory approval in China in June 2025 for long-term body weight management in adults with obesity (BMI ≥28 kg/m²) or overweight with comorbidities (BMI ≥24 kg/m²), alongside diet and physical activity. A subsequent Chinese approval for glycemic control in type 2 diabetes followed in September 2025. The article also notes ongoing clinical investigations into metabolic dysfunction-associated fatty liver disease, obstructive sleep apnea, and alcohol use disorder. As a "First Approval" narrative review, it consolidates developmental milestones rather than presenting original trial data. It does not independently report clinical outcomes, efficacy effect sizes, or safety data from primary studies, limiting the ability to assess the strength of underlying evidence directly from this article alone.