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 ↗ 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.
Review
This review examines the expanding cardiovascular applications of glucagon-like peptide-1 (GLP-1) receptor agonists, a class of peptide-based agents originally developed for type 2 diabetes management. The authors synthesize molecular mechanistic data alongside clinical evidence from major cardiovascular outcome trials (CVOTs) to characterize how GLP-1 agonists may reduce risk across conditions including atherosclerosis, heart failure, stroke, and vascular dementia. Proposed mechanisms discussed include anti-inflammatory, anti-atherogenic, endothelial-protective, and direct cardioprotective effects. The review highlights findings from multiple CVOTs reporting reductions in major adverse cardiovascular events (MACEs), myocardial infarction, stroke, and cardiovascular mortality. Notably, the SELECT trial is cited as evidence extending potential benefit to non-diabetic individuals with obesity and established CVD. The review also addresses emerging dual GLP-1/GIP agonists such as tirzepatide and its own CVOT data. The authors acknowledge important limitations, including high drug costs, unresolved long-term safety questions, and real-world implementation barriers. As a narrative review, this paper does not generate primary data and is subject to the inherent risk of selective literature synthesis. It provides a useful conceptual overview but does not independently establish causality or efficacy.
Journal of clinical medicine · Sep 2025DOI ↗ Review
This scoping review examined the potential role of incretin mimetics — specifically GLP-1 receptor agonists (e.g., semaglutide), dual GLP-1/GIP receptor agonists (e.g., tirzepatide), and the investigational triple agonist retatrutide — as treatments for polycystic ovarian syndrome (PCOS). Following PRISMA guidelines and drawing on literature from EBSCO Medline and PubMed, the authors explored how these agents compare to traditional PCOS pharmacotherapy such as metformin and estradiol-progesterone combination pills. The review found that all three classes of incretin mimetics were associated with meaningful improvements in weight loss and insulin sensitivity relative to conventional treatments. Dual- and triple-acting agonists, which additionally target the GIP receptor, appeared to produce greater reductions in weight and improvements in insulin sensitivity than GLP-1-only agents. Some included studies also reported PCOS-specific symptom improvements, such as reductions in dysmenorrhea and changes in ovarian morphology. The authors note that the precise mechanisms by which incretin mimetics may address the hormonal dysregulation of PCOS remain unclear, and they call for further research to optimize the integration of these agents with existing standard-of-care therapies. Key limitations include the scoping review design, heterogeneity of included studies, and limited long-term human trial data.
Moderate · human
This meta-analysis systematically reviewed the evidence on GLP-1 receptor agonists (e.g., semaglutide, liraglutide) in patients undergoing spinal fusion surgery. Following Cochrane guidelines, the authors searched five major databases and included 11 studies encompassing 14,344 participants, assessing outcomes such as pseudoarthrosis, readmission, acute kidney injury (AKI), cerebrovascular accidents, and deep vein thrombosis. Quality assessment used the Newcastle-Ottawa Scale, and statistical analysis was performed with RevMan 5.4 using risk ratios for dichotomous outcomes. The study found that GLP-1 receptor agonist use was associated with a statistically significant reduction in pseudoarthrosis at both six months (RR = 0.63) and 12 months (RR = 0.64), but this benefit was not sustained at 24 months (RR = 1.03). GLP-1 receptor agonists were also associated with a significantly increased risk of AKI (RR = 1.30). No significant differences were observed for readmission, stroke, deep vein thrombosis, or reoperation rates. Subgroup analysis by diabetic status provided additional insights. Key limitations include the absence of randomized controlled trials among included studies, significant heterogeneity in several outcomes, variability in outcome definitions, and relatively short follow-up periods. The authors call for larger, well-designed RCTs to confirm these findings.
In vitro
This study developed a dual-mode semi-preparative anion-exchange chromatography (AEX) method to fractionate and characterize charge variants of dulaglutide, a GLP-1 receptor agonist used in type 2 diabetes management. Because dulaglutide is an acidic Fc-fusion protein with complex charge heterogeneity, standard characterization methods are technically challenging. The researchers isolated acidic, main, and basic charge variant fractions and subjected them to comprehensive downstream analyses, including assessments of sialic acid content, post-translational modifications (phosphorylation, sialylation, deamidation, oxidation), size heterogeneity, aggregation, truncation, and biological activity. A key finding was that aggregates in basic variants are primarily held together by non-covalent interactions, while acidic variants contain covalently linked aggregates—a structurally meaningful distinction. Charge variants showed only slight differences in biological activity, potentially linked to aggregate presence. A comparative analysis between the innovator product Trulicity® and a biosimilar candidate revealed minor differences in acidic variants, likely attributable to variations in phosphorylation and sialylation profiles. Limitations include the in vitro nature of the biological activity assessments and the absence of in vivo or clinical data. The study provides a detailed analytical framework for characterizing charge heterogeneity in complex biopharmaceuticals.
International journal of biological macromolecules · Sep 2025DOI ↗ Review
This review paper examines survodutide, a dual glucagon and glucagon-like peptide-1 (GLP-1) receptor agonist, and its potential role in cardiometabolic disease management. The authors synthesize findings from Phase 2 clinical trials, which reported weight loss of up to 18.7% and HbA1c reductions of up to -1.71%, suggesting survodutide may outperform semaglutide on weight outcomes while achieving comparable glycemic control. The paper also discusses Phase 2 evidence showing improvements in liver fat content and fibrosis markers in patients with metabolic dysfunction-associated steatohepatitis (MASH), alongside proposed mechanisms for cardiovascular benefit, including reductions in visceral and epicardial adiposity, systemic inflammation, and fibrosis-related remodeling. Early signals of renal benefit are noted. Limitations acknowledged include higher rates of gastrointestinal adverse events and modest heart rate increases compared to some comparators, contributing to elevated discontinuation rates. The authors emphasize that definitive evidence from cardiovascular outcomes trials is still lacking, with the ongoing SYNCHRONIZE-CVOT trial expected to address this gap. As a narrative review relying primarily on Phase 2 data, the paper does not establish long-term cardiovascular efficacy or safety.
Cardiology in review · Sep 2025DOI ↗