In vitro
This study developed and validated a stability-indicating High-Performance Liquid Chromatography (HPLC) method for the simultaneous quantification of two GLP-1 receptor agonists — Semaglutide (SEM) and Tirzepatide (TIR) — used in the treatment of type 2 diabetes and obesity. The method employed a C18 column with an isocratic mobile phase of 0.1% formic acid and acetonitrile (30:70), achieving rapid separation with retention times of 1.42 min for SEM and 1.68 min for TIR. The method was validated per ICH guidelines, demonstrating strong linearity (1–500 µg/mL, r > 0.9999), sensitivity (LOD: 10 ng/mL for TIR; 16 ng/mL for SEM), accuracy, and precision. The method successfully resolved both compounds from degradation products generated under acidic, basic, oxidative, and photolytic stress conditions. It was also applied to bulk drug, pharmaceutical dosage forms, and spiked rat plasma. A comprehensive six-pronged sustainability assessment was performed using nine analytical greenness, whiteness, blueness, and violet innovation tools. A key limitation is that the plasma work used spiked rat samples rather than real patient samples, meaning no clinical or pharmacokinetic conclusions about humans can be drawn.
BMC chemistry · Jan 2026DOI ↗ Moderate · human
This systematic review and meta-analysis examined the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and heart rate (HR) changes in people with overweight or obesity who do not have diabetes. Researchers searched four major databases (PubMed, Web of Science, Embase, and Cochrane Library) and ultimately included 12 randomized controlled trials. Using both pairwise and network meta-analysis methods, the study calculated mean differences (MDs) in HR compared to placebo. Pairwise meta-analysis found that all analyzed GLP-1RAs — including liraglutide, semaglutide, orforglipron, oral semaglutide, tirzepatide, retatrutide, and the drug class overall — were associated with statistically significant increases in heart rate versus placebo. Network meta-analysis, which allows indirect comparisons across agents, suggested that orforglipron 36 mg was associated with the most pronounced HR increase, while tirzepatide 5 mg showed the least increase (and its result was not statistically significant). Key limitations include the indirect nature of network comparisons, variability in trial designs and follow-up durations, and the restriction to a non-diabetic population, which limits generalizability. The clinical significance of the observed HR increases was not fully addressed.
European journal of medical research · Jan 2026DOI ↗ Limited · human
This retrospective pharmacovigilance study analyzed FDA Adverse Event Reporting System (FAERS) data from Q1 2022 to Q3 2025 to compare gynecological hemorrhagic event reporting between tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a GLP-1 receptor agonist) in female patients. Researchers identified 103,607 female-specific reports—70,768 for tirzepatide and 32,839 for semaglutide—and calculated reporting odds ratios (RORs) using standardized MedDRA queries. The study found that gynecological hemorrhagic events were reported at nearly identical rates (0.60% for tirzepatide vs. 0.62% for semaglutide), with an ROR of 0.97 (95% CI: 0.82–1.14), indicating no statistically significant difference in reporting odds between the two agents. Notably, the authors flagged a substantial difference in reporter source composition: 94.6% of tirzepatide reports originated from consumers versus 53.4% for semaglutide, which may introduce bias and limits direct comparability. The authors concluded that no disproportionate safety signal was detected but emphasized that disproportionality analyses cannot establish causation, and that the consumer-reporting imbalance warrants cautious interpretation. Prospective, controlled studies were recommended to validate these findings.
Review
This commentary is aimed at clinicians and provides practical guidance for counseling patients who are hesitant about starting glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy due to concerns about its perceived "newness" or unproven long-term safety. The paper briefly traces the history of GLP-1, from its discovery in the 1980s through nearly two decades of clinical use, to contextualize these agents as well-established rather than experimental. It distinguishes native GLP-1 from structurally modified agents such as semaglutide and tirzepatide, arguing that modifications prolong drug action without fundamentally changing the hormone's core mechanism. The authors summarize available safety data, noting that known side effects are predominantly mild and transient gastrointestinal in nature, and that there is currently no established evidence linking GLP-1RAs to feared risks such as cancer. The paper includes a practical counseling checklist and sample patient-friendly language intended to support shared decision-making conversations. Key limitations include the absence of original data, lack of systematic literature review methodology, and potential for author bias in evidence selection. Findings and reassurances are the authors' interpretive positions rather than conclusions drawn from a primary study.
American journal of preventive cardiology · Jan 2026DOI ↗ Review
This paper examines the growing use of glucagon-like peptide-1 (GLP-1) receptor agonists — specifically semaglutide and tirzepatide — in the context of obesity management. The authors discuss how these medications have meaningfully shifted the landscape of obesity care, while simultaneously raising important questions about their safety profile, long-term outcomes, and the risks associated with unregulated or compounded versions of these products. The paper highlights the tension between rapidly increasing patient demand and the need for robust clinical oversight. Key concerns addressed include adverse side effects, the consequences of unsupervised use, and the importance of coordinated clinical frameworks to ensure patients access these therapies safely. The authors advocate for structured monitoring systems and regulatory vigilance to keep pace with the surge in prescribing. As a review or commentary piece rather than an original clinical trial, the paper does not generate new primary data; its conclusions are based on synthesis of existing evidence and expert perspective. This limits its ability to independently establish causality or quantify risk with precision, and readers should interpret its claims in that context.
PLoS medicine · Jan 2026DOI ↗ Review
This narrative review synthesizes mechanistic and clinical trial evidence on incretin-based therapies — GLP-1 receptor agonists (GLP-1RA), DPP-4 inhibitors, and newer dual/triple agonists — for cardiovascular (CV) and renal protection in type 2 diabetes (T2DM) and related conditions. The authors draw on multiple pivotal randomized cardiovascular outcome trials (CVOTs), including SELECT (semaglutide in obesity without diabetes), FLOW (semaglutide in chronic kidney disease), SOUL (oral semaglutide in T2DM with ASCVD/CKD), and SURPASS-CVOT (tirzepatide vs. dulaglutide). Key findings attributed to these trials include reductions in major adverse cardiovascular events (MACE), CV and all-cause mortality, heart-failure hospitalization, and hard kidney endpoints across GLP-1RA programs. A 2019 pooled analysis and a 2025 update reportedly confirm these cardiorenal benefits independent of baseline HbA1c. Mechanistically, the review describes GLP-1R signaling via Gs-cAMP/PKA, β-arrestin, and Gq pathways, linked to anti-inflammatory, natriuretic, and antifibrotic effects. Oral small-molecule GLP-1R agonists (e.g., orforglipron) showed phase 2 efficacy but lacked long-term outcome data at time of publication. As a narrative review, it is subject to selection bias and does not conduct formal meta-analytic pooling.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Jan 2026DOI ↗ Review
This review examines the evolving landscape of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies and their role in cardiorenal protection in metabolic diseases, particularly type 2 diabetes (T2D) and obesity. The authors synthesize evidence from clinical and real-world studies demonstrating that GLP-1RAs consistently reduce HbA1c and body weight, and that mounting data support cardiovascular and kidney benefits beyond glycaemic control in high-risk populations. The review highlights that in T2D, GLP-1RAs have been shown to improve hard cardiovascular outcomes and, more recently, kidney outcomes. In individuals with obesity without T2D, semaglutide at a higher dose was reported to reduce body weight by up to 15% and lower major adverse cardiovascular events by approximately 20%. The review also covers next-generation "multi-agonist" molecules combining GLP-1 receptor agonism with activity at GIP, glucagon, and amylin receptors, aiming for complementary or synergistic metabolic effects. Tirzepatide, a dual GLP-1/GIP receptor agonist approved for T2D and obesity, is highlighted as achieving up to 22.5% weight loss in phase 3 trials. Limitations include the inherent constraints of a narrative review: no new primary data are generated, and conclusions depend on the scope and quality of included studies.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · Jan 2026DOI ↗ Limited · human
This case report describes a 61-year-old woman with type 2 diabetes and morbid obesity who developed severe small bowel obstruction after more than a year of tirzepatide therapy. The patient experienced progressive constipation following initiation of tirzepatide, eventually presenting with acute diffuse abdominal pain and dry heaving. CT imaging revealed multiple dilated, fluid-filled small bowel loops with a transition point in the lower pelvis, moderate gastric distention, and free pelvic fluid. Initial conservative management with nasogastric decompression, bowel rest, intravenous fluids, and analgesia was insufficient, and the patient ultimately required laparoscopic adhesiolysis converted to exploratory laparotomy. Intraoperatively, a closed-loop obstruction caused by adhesive disease and an internal hernia was identified, necessitating resection of 25 cm of necrotic bowel. Pathology confirmed ischemic changes. Notably, tirzepatide had produced meaningful metabolic benefits, including hemoglobin A1c reduction and weight loss. The authors propose that tirzepatide's known effects on gastrointestinal motility may have worsened pre-existing constipation and contributed to the obstructive event in this predisposed patient. Key limitations include the single-patient design, the presence of confounding adhesive disease, and the inability to establish direct causation.
Review
This review article examines the evolving landscape of engineered nutrient-stimulated hormonal (NUSH) peptide therapies for obesity and related metabolic conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. The authors describe the mechanistic basis of GLP-1 receptor agonists (GLP-1RAs) and their limitations as monotherapies, then explore how dual and triple co-agonist strategies — combining GLP-1 with GIP, glucagon, amylin, or peptide YY — aim to overcome those gaps. The review highlights clinical and preclinical data for specific agents: tirzepatide (GLP-1/GIP), CagriSema (GLP-1/amylin), and retatrutide (GLP-1/GIP/glucagon), noting reported benefits in weight reduction, glycemic control, liver health, cardiovascular outcomes, and inflammation. The paper also discusses non-peptidyl oral GLP-1 RAs such as orforglipron as adherence-improving alternatives. The authors frame these multi-agonist therapies as a paradigm shift analogous to the pleiotropic hormonal effects of bariatric surgery, and as building blocks for precision metabolic medicine. As a narrative review, it does not generate new primary data, and conclusions depend on the quality and heterogeneity of the underlying cited studies.
Clinical and molecular hepatology · Nov 2025DOI ↗ Review
This narrative review examines the current and emerging landscape of GLP-1 receptor agonists (GLP-1RAs) as treatments for obesity and related metabolic conditions. The authors survey the three FDA-approved agents for obesity—liraglutide, semaglutide, and tirzepatide—alongside off-label options, summarizing evidence for their efficacy in weight reduction and glycemic control. The review also discusses expanding indications, including potential benefits in neurodegenerative disorders, fatty liver disease, dyslipidemia, atherosclerosis, cardiovascular disease, chronic kidney disease, and heart failure. Emerging pipeline agents—such as CagriSema, orforglipron, mazdutide, retatrutide, and survodutide—are highlighted alongside innovations like ultralong-acting formulations, combination therapies, higher-dose oral delivery, and AI-integrated drug development. The authors note that generic liraglutide and evolving insurance coverage may reshape affordability and access. Key limitations acknowledged include adherence challenges, safety concerns, disparities in global access, and the need for long-term data on sustained weight loss and disease modification. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and conclusions are therefore subject to the quality and selection of included studies.
Journal of obesity · Nov 2025DOI ↗ 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 narrative review synthesizes the current landscape of FDA-approved and investigational pharmacotherapies for obesity management. The authors examine six approved long-term agents — orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide — covering their mechanisms of action, pivotal efficacy data, safety profiles, indications, and prescribing considerations. The review notes that semaglutide and tirzepatide have substantially raised expectations for pharmacological weight loss compared to older agents. Emerging investigational compounds, including oral GLP-1 receptor agonists such as orforglipron and multireceptor agonists such as retatrutide, are highlighted as showing even greater early-phase efficacy signals. Common safety considerations discussed include gastrointestinal adverse effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, teratogenicity, and cost and access barriers. The authors emphasize that patient selection should be guided by BMI, comorbidities, and contraindications. Key limitations acknowledged by the review include a lack of direct head-to-head comparative trials, limited long-term cardiovascular outcomes data, and questions about weight durability after treatment discontinuation. The authors identify these gaps as priorities for future research.
Review
This review paper surveys the current landscape of obesity pharmacotherapy, covering both approved and emerging treatment options. The authors outline the clinical burden of obesity, noting its associations with diabetes, cardiovascular disease, hypertension, and hyperlipidemia, and briefly describe non-pharmacological management strategies such as nutritional therapy and exercise. The review catalogues FDA-approved anti-obesity medications — orlistat, setmelanotide, phentermine-topiramate, naltrexone-bupropion, liraglutide, semaglutide, and tirzepatide — and highlights semaglutide as having a favorable clinical and regulatory profile. Emerging agents discussed include orforglipron, a non-peptide oral GLP-1 receptor agonist positioned as a potentially convenient alternative to injectable therapies. The authors also explore adjunctive approaches such as probiotics, prebiotics, fecal microbiota transplantation, and mitochondrial uncouplers. Key barriers to obesity management — including financial constraints, inadequate clinician training, and lack of reimbursement — are identified. The paper concludes by advocating for innovative, multidisciplinary, and patient-centered care models. As a narrative review, the paper does not generate new primary data, and conclusions reflect the authors' synthesis of existing literature rather than independent experimental findings.
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 ↗ 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 ↗ 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 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.
Review
This review paper examines the challenge of preserving muscle mass during weight loss induced by GLP-1–based pharmacotherapies, including GLP-1 receptor agonists (e.g., semaglutide), dual GLP-1/GIP agonists (e.g., tirzepatide), and triple GLP-1/GIP/glucagon agonists (e.g., retatrutide). The authors note that while these agents can produce clinically meaningful weight loss (5–10% or more of body weight), a portion of that loss comes from lean mass, including skeletal muscle, which may contribute to long-term weight regain and increase the risk of sarcopenia. The paper discusses the biology of myokines—over 600 signaling proteins released during muscle contraction identified in human myocyte research—as potentially important targets for protecting or expanding muscle mass. The authors explore emerging anti-obesity agents and their potential combinations with incretin-based therapies to preferentially reduce fat mass while sparing or building muscle. The paper calls for further research to clarify the functional consequences of lean mass changes during weight loss and maintenance. As a narrative review, it synthesizes existing literature without conducting original trials, and no new clinical data are presented. Generalizability is limited by the review format and the evolving evidence base for newer agents.
World journal of diabetes · Sep 2025DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from 25 randomized controlled trials (RCTs) involving approximately 2,600 patients to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) — including liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide, and retatrutide — on metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Across a median treatment period of 24 weeks, the authors reported that GLP-1RAs were associated with a statistically significant mean reduction in liver fat content of 5.21%, with retatrutide showing the largest effect. Histological analyses suggested significant improvements in steatosis, hepatocellular ballooning, and lobular inflammation, though improvements in fibrosis did not reach statistical significance. Liver enzymes (ALT, AST, γ-GT) and liver stiffness also improved significantly, with semaglutide showing the most pronounced effect on stiffness. No liver-related adverse drug effects were identified. Limitations include heterogeneity across trials, variable treatment durations, and the relatively short median follow-up, which may be insufficient to capture fibrosis outcomes. The evidence base is derived entirely from RCTs in human populations.
The Journal of clinical endocrinology and metabolism · Sep 2025DOI ↗