Review
This review examines the landscape of next-generation glucagon-like peptide-1 (GLP-1)-based therapeutics in clinical development for type 2 diabetes and obesity, building on the established success of semaglutide and tirzepatide. The authors survey a broad range of investigational agents that target multiple gastro-entero-pancreatic hormone receptors simultaneously — including GIP, glucagon, amylin, and peptide YY receptors — to produce synergistic effects on energy intake, storage, and expenditure. Specific agents discussed include maridebart cafraglutide (GLP-1 agonism/GIP antagonism), survodutide and mazdutide (GLP-1/glucagon coagonists), cagrilintide combined with semaglutide (CagriSema), amycretin (amylin/GLP-1 dual agent), and retatrutide (GIP/GLP-1/glucagon triple agonist). The review also highlights the emergence of oral small-molecule GLP-1 receptor agonists such as danuglipron and orforglipron, which resist enzymatic degradation and may improve patient convenience. The paper does not present original clinical trial data; it synthesizes existing preclinical and clinical development evidence. As a narrative review, it does not meta-analytically pool outcomes, and the included agents are largely at Phase 1–3 stages, meaning long-term efficacy and safety data remain limited.
Endocrine reviews · Mar 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled evidence from 21 randomized controlled trials (n = 7,024 participants) to evaluate the weight-loss efficacy of GLP-1 receptor agonists (GLP-1 RAs) compared with placebo or active comparators. Across 16 placebo-controlled trials, the study found that a substantially higher proportion of participants achieved weight loss with GLP-1-based agents (78.54%) than with placebo (26.53%), yielding a pooled odds ratio of 11.37 (95% CI: 8.10–15.98). A frequentist network meta-analysis using SUCRA rankings suggested that tirzepatide and semaglutide demonstrated the greatest relative efficacy among agents evaluated. The authors concluded that GLP-1 RAs significantly increase the likelihood of weight loss and support their role in clinical obesity management. Notable limitations include the use of a fixed-effect model despite potential heterogeneity across trials, a binary primary endpoint (any weight loss) rather than magnitude of weight loss, the absence of a pre-registered protocol, and inclusion criteria restricted to the past five years in English only. These methodological choices may affect the precision and generalizability of the pooled estimates.
Review
This paper examines the ethical landscape surrounding semaglutide (marketed as Ozempic, Rybelsus, and Wegovy), a glucagon-like peptide-1 (GLP-1) receptor agonist manufactured by Novo Nordisk and primarily used to treat type II diabetes. The authors note that semaglutide has garnered widespread attention beyond its diabetic indication due to its effects on appetite suppression and weight loss, earning it the popular label of a "miracle drug." The paper surveys a range of ethical concerns that have been raised in both governmental and public discourse — including issues around drug access and equity, medicalization of obesity, societal body-image pressures, and resource allocation — and critically analyzes whether these concerns are sufficient to advise against prescribing semaglutide for weight loss. The authors ultimately argue that, while many of the ethical objections raised are legitimate and deserve serious consideration, none individually or collectively constitute a conclusive reason to withhold semaglutide prescriptions for weight management purposes. As an ethics and policy review, the paper does not present original clinical trial data and offers no empirical findings on patient outcomes. Its conclusions are based on philosophical argument and literature synthesis rather than experimental evidence.
Journal of medical ethics · Feb 2026DOI ↗ Moderate · human
This systematic review and frequentist network meta-analysis (NMA) examined the comparative cardiovascular efficacy of tirzepatide (a dual GIP/GLP-1 receptor agonist) versus GLP-1 receptor agonists (GLP-1RAs) and placebo in adults with type 2 diabetes (T2D) and established or high-risk atherosclerotic cardiovascular disease (ASCVD). Eleven randomized controlled trials were included — ten evaluating GLP-1RAs and one evaluating tirzepatide (SURPASS-CVOT). In the class-level analysis, the study found that tirzepatide was associated with statistically significant reductions in MACE, cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke compared to placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo and lixisenatide specifically, while appearing broadly comparable to other individual GLP-1RAs. Subgroup and leave-one-out sensitivity analyses were consistent with primary findings. A key limitation is that only one tirzepatide RCT (SURPASS-CVOT) was available, constraining direct head-to-head NMA comparisons between tirzepatide and individual GLP-1RAs and reducing the precision of tirzepatide-specific estimates. The authors concluded that tirzepatide may provide cardiovascular benefit at least comparable to established GLP-1RAs, though this inference is based on indirect comparisons.
Cardiovascular diabetology · Feb 2026DOI ↗ Preclinical
This study investigated whether mazdutide, a dual GLP-1/glucagon receptor agonist previously studied for weight and metabolic management, could reduce early-stage metabolic dysfunction-associated steatotic liver disease (MASLD). Researchers used two model systems: mice fed a high-fat diet for 12 weeks (then treated with subcutaneous mazdutide for 4 weeks) and hepatocytes exposed to free fatty acids in cell culture (then co-treated with mazdutide or an ER stress inhibitor). The study measured blood and liver lipid profiles, liver injury markers, inflammatory cytokines, oxidative stress indicators, and liver histology, as well as protein expression linked to endoplasmic reticulum (ER) stress, inflammation, and lipid metabolism. The authors report that mazdutide treatment was associated with improved lipid metabolism, reduced hepatic steatosis, lower liver injury markers, and decreased inflammation and oxidative stress in both the animal and cell models. Mechanistically, the authors propose that mazdutide acts at least partly by dampening ER stress pathways. Key limitations include the exclusive use of preclinical models (no human subjects), a single mouse strain/diet protocol, and the early-stage disease focus, meaning translation to human MASLD remains unestablished.
Pharmaceuticals (Basel, Switzerland) · Feb 2026DOI ↗ Strong · human
This systematic review and meta-analysis evaluated the efficacy and safety of CagriSema — a dual therapy combining the GLP-1 receptor agonist semaglutide with the amylin analogue cagrilintide — compared to semaglutide monotherapy or placebo in adults with obesity. The authors searched four major databases through July 2025 and identified four eligible randomized controlled trials encompassing 4,419 participants (CagriSema: 3,055; controls: 1,364). Pooled analyses found that CagriSema was associated with significantly greater percent body weight loss (Cohen's d: −1.38; 95% CI: −1.84 to −0.91), greater absolute weight reduction (mean difference: −11 kg), reductions in waist circumference (−9.41 cm), and lower systolic blood pressure (−7.06 mmHg) versus comparators. However, gastrointestinal adverse events occurred more frequently with CagriSema (relative risk: 1.32). Notable limitations include high statistical heterogeneity (I² = 94.8%) across the included trials, the small number of studies (n = 4), and the absence of long-term safety and cardiovascular outcomes data. The authors conclude that CagriSema demonstrates superior weight reduction compared with semaglutide or placebo, but that tolerability monitoring and longer-term evidence are warranted.
The American journal of cardiology · Feb 2026DOI ↗ Limited · human
This real-world pharmacovigilance study analyzed 40,253 adverse event reports submitted to the FDA Adverse Event Reporting System (FAERS) involving semaglutide, liraglutide, and tirzepatide used for weight loss. Researchers applied disproportionality analysis—using proportional reporting ratios (PRR) and reporting odds ratios (ROR)—to identify safety signals beyond the commonly studied gastrointestinal, renal, and pancreatic effects. The study population was predominantly female (68.6%), with median ages varying by drug. Key findings included that semaglutide showed the strongest disproportionality signals for psychiatric adverse events, including anxiety, depression, and suicidal ideation. Tirzepatide was associated with markedly elevated signals for injection-site reactions and indicators of misuse, such as incorrect dosing and off-label administration. Liraglutide showed a comparatively lower overall risk signal across these categories. Important limitations of this study include the inherent biases of spontaneous reporting systems (underreporting, confounding, lack of denominator data), the inability to establish causality, and the possibility that reporting patterns reflect prescribing trends or media attention rather than true pharmacological risk. The authors conclude that psychiatric monitoring and patient education warrant greater attention in clinical practice.
Pharmaceuticals (Basel, Switzerland) · Feb 2026DOI ↗ Review
This review examines the development and clinical progress of long-acting amylin-related peptides as treatments for obesity and type 2 diabetes. It traces the field from the first-generation amylin receptor (AMYR) agonist pramlintide—which acts centrally to induce satiety, suppress glucagon, and reduce post-meal hyperglycemia but had limited use as an insulin adjunct—to a new generation of non-aggregating, long-acting analogues. The authors describe advances in understanding the heterodimeric structure of amylin-calcitonin receptor complexes that have guided the rational design of these newer agents. Highlighted compounds include the dual AMYR/calcitonin-receptor agonist cagrilintide, the combination product CagriSema (cagrilintide plus semaglutide), and the unimolecular tri-agonist amycretin. Several monotherapy candidates (eloralintide, petrelintide, Met-233, AZD6234) are also discussed. The review notes that gastrointestinal side effects—chiefly nausea—are common during initiation but typically resolve with continued use, and highlights emerging preclinical and early clinical signals for potential benefits in fatty liver disease, diabetic kidney disease, and resistant hypertension. As a narrative review, it synthesizes heterogeneous sources and does not itself generate new primary data.
Review
This review provides a broad educational overview of pharmacological agents used in diabetes management, spanning both traditional and newer-generation therapies, with particular attention to their off-label use for weight loss. The authors describe the mechanistic and clinical distinctions between type 1 and type 2 diabetes and survey established drug classes—insulin, metformin, sulfonylureas, and thiazolidinediones—noting their limitations such as hypoglycemia risk and weight gain. The review then highlights the clinical impact of incretin-based therapies, specifically GLP-1 receptor agonists and SGLT-2 inhibitors, which the authors associate with improved glycemic control, weight reduction, and cardiorenal benefits. Newer dual and triple agonists, including tirzepatide, are described as producing HbA1c and body weight reductions approaching those of bariatric surgery. The paper raises concerns about the rising off-label use of antidiabetic agents for weight management, citing gastrointestinal adverse effects and rare motility disorders. Limitations include the review's broad scope and lack of original data or formal systematic methodology. The authors call for ongoing pharmacovigilance, equitable access, and further research into long-term safety and emerging oral non-peptide incretin mimetics.
The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians · Feb 2026DOI ↗ Animal only
This animal study investigated the anti-obesity effects of three GLP-1 receptor agonist peptides — semaglutide, tirzepatide, and retatrutide — in melanocortin 4 receptor knockout (MC4R KO) mice, a model of genetically driven obesity caused by disruption of the POMC-MC4R signaling pathway. All three compounds were administered for 21 days, after which body weight, body composition, metabolic markers, liver health, and gene expression were assessed. The study found that all three GLP-1 analogs produced statistically significant reductions in body weight, with tirzepatide showing the greatest effect (approximately 31.6%), followed by retatrutide (approximately 24.1%) and semaglutide (approximately 19.7%). All three agents reduced both fat and lean mass, improved plasma insulin levels and insulin resistance (HOMA-IR), lowered cholesterol, and reduced markers of liver damage (AST and ALT) as well as liver hypertrophy. Gene expression analysis showed suppression of fatty acid synthesis genes, but no significant effect on inflammatory gene expression. Energy expenditure was reduced by all agents; only tirzepatide significantly decreased the respiratory quotient. A key limitation is that this is a mouse model study, and findings may not directly translate to humans. The authors suggest MC4R KO mice are a valid model for studying obesity-related drug efficacy.
International journal of obesity (2005) · Feb 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from 10 randomized controlled trials (3,236 participants) to evaluate the efficacy and safety of incretin-based dual and triple receptor agonists — specifically tirzepatide, retatrutide, and mazdutide — in overweight or obese adults. The authors searched PubMed, the Cochrane Library, and Google Scholar through June 2025 and applied a random-effects model to pool outcomes. The study found that these agents were associated with statistically significant reductions in body weight (mean difference: −11.47 kg), waist circumference (−9.40 cm), glycated hemoglobin (−0.96%), and fasting plasma glucose (−26.89 mg/dL) compared to placebo. On the safety side, treatment was associated with a higher risk of any adverse event (RR 1.13), gastrointestinal adverse events (nausea, vomiting, diarrhea, constipation), treatment discontinuation due to adverse events (RR 1.96), and hypoglycemic episodes (RR 3.08). No significant difference in serious adverse events was observed. Limitations include the relatively small number of pooled trials, heterogeneity inherent across different agents and doses, and the restriction to placebo-controlled comparisons, which limits conclusions about comparative effectiveness between agents.
Cardiology in review · Feb 2026DOI ↗ Insufficient
This study investigated compounded semaglutide and tirzepatide products being sold by compounding pharmacies following the resolution of the innovator drug shortage. Researchers conducted a Google-based search of compounding pharmacy websites between February and March 2025, identifying 33 unique compounded GLP-1 products. Two-thirds contained semaglutide and one-third contained tirzepatide. Nearly half of the products combined the active GLP-1 ingredient with additional agents such as cyanocobalamin, glycine, niacinamide, docusate, or ondansetron. Single-ingredient products were predominantly offered in sublingual (82%) or oral disintegrating tablet (ODT) (18%) formulations. The study found that the vast majority of products lacked transparency around beyond-use dating and storage conditions. The authors concluded there was little scientific justification for adding nutrients or docusate sodium to these formulations; while ondansetron co-formulation had a theoretical rationale, evidence for subcutaneous delivery was absent. Sublingual and ODT formats also lacked comparative evidence against FDA-approved oral tablets. A key limitation is that this was an observational web survey, not a clinical study, so no safety or efficacy data on patients were collected or analyzed.
The Annals of pharmacotherapy · Feb 2026DOI ↗ In vitro
This study investigated how different photoaffinity crosslinkers influence the biological activity, labeling efficiency, and target protein preference of quinazolinone-based active molecules—specifically QDAU5, a compound previously shown to promote vascular normalization. The researchers constructed a library of photocrosslinkers and multifunctional photoaffinity probes using structures such as thiophene-substituted α-ketoamide, tetrazole, isoxazole, and 2-nitrobenzyl alcohol, then applied Photoaffinity Labeling–Affinity-Based Protein Profiling (PAL-AfBPP) combined with proteomic analysis to assess probe performance. Prior work had identified EphrinB2 as an intracellular target of QDAU5; this study further validated Thymosin β4 (Tβ4) as an additional potential target and began characterizing how QDAU5 interacts with Tβ4 at a molecular level. The findings suggest that the choice of photocrosslinker meaningfully affects both the retained bioactivity of the parent compound and which proteins are captured, offering practical guidance for PAL-AfBPP probe design. Limitations include that this is primarily a chemical biology and proteomics study conducted at the in vitro/biochemical level, with no human clinical data. The mechanistic link between QDAU5–Tβ4 interaction and angiogenesis regulation requires further validation in vivo.
Bioorganic chemistry · Feb 2026DOI ↗ In vitro
This study investigated the metabolic profiles of three amylin receptor agonists — pramlintide, cagrilintide, and KBP-066 — in the context of sports anti-doping research. Motivated by growing concerns about misuse of weight-loss peptide hormones in athletic disciplines where weight management is performance-relevant, researchers used comprehensive in vitro models (human skin and kidney S9 fractions, biological fluids) to characterize how these compounds are broken down. High-resolution tandem mass spectrometry (HRMS/MS) was used to identify metabolites, and authentic post-administration rat plasma samples were analyzed for cagrilintide to assess in vivo relevance. The study found that all three peptides underwent N-terminal and C-terminal degradation, producing multiple stable metabolites considered suitable as analytical detection targets. Metabolites predicted from in vitro experiments for cagrilintide were confirmed in rat plasma samples. The researchers developed and validated an LC-MS/MS-based detection method applicable to anti-doping screening. Limitations include the primary reliance on in vitro models; the only in vivo data came from rat samples, not humans. This represents the first systematic metabolic characterization of these three compounds in an anti-doping context and lays groundwork for future human monitoring programs.
Journal of pharmaceutical and biomedical analysis · Feb 2026DOI ↗ In vitro
This study investigated the in vitro metabolic profile of SLU-PP-332, a synthetic agonist of estrogen-related receptors alpha, beta, and gamma (ERRα/β/γ), developed as an "exercise mimetic" — a compound designed to replicate some physiological benefits of physical exercise, such as increased fatty acid oxidation, oxidative muscle fiber development, and improved exercise endurance. Because the World Anti-Doping Agency (WADA) prohibits metabolic modulators in competitive sports, identifying the metabolites of SLU-PP-332 is an important step for anti-doping surveillance. The researchers incubated SLU-PP-332 with pooled human liver S9 fractions to simulate Phase I and Phase II hepatic metabolism, then analyzed the resulting products using liquid chromatography-high-resolution mass spectrometry (LC-MS/HRMS). They identified 22 metabolites in total: five monohydroxylated, three dihydroxylated, four reduced dihydroxylated, and several glucuronidated and sulfated conjugates. Eight metabolites (M1, M7, M9, M10, M13, M14, M19, and M20) were identified as the most abundant and were flagged as priority targets for doping-control testing. The authors note that full structural elucidation of all metabolites requires further investigation. No human or animal subjects were involved; all findings are limited to an in vitro cell-free system.
Drug testing and analysis · Feb 2026DOI ↗ Animal only
This systematic review examines the use of platelet-rich plasma (PRP), growth factors (PDGF, TGF-β1, IGF-1, FGF, VEGF, BMPs), and the stable gastric pentadecapeptide BPC 157 in the treatment of tendon, ligament, and muscle injuries, as well as osteotendinous, myotendinous, and muscle-to-bone junction injuries. The authors frame these interventions under the concept of "cytoprotection," emphasizing restoration of tissue integrity. The review concludes that while growth factors delivered locally via carriers show improvements in tendon, ligament, and muscle healing, some (PDGF, TGF-β1, IGF-1) appear to have limited benefit in muscle lesions, and all show limited or no efficacy at junctional healing sites. By contrast, the authors argue that BPC 157 — proposed as a cytoprotection mediator — demonstrated consistent efficacy across tendon, ligament, muscle, and junctional injuries in rat studies, via both systemic (intraperitoneal, intragastric, drinking water) and local (topical cream) administration, without requiring carriers or scaffolds. The authors suggest translational potential for clinical use and call for further clinical trials. Key limitations include that the supporting evidence for BPC 157 is derived almost exclusively from preclinical (rat) studies, with no human clinical trial data presented.
Pharmaceuticals (Basel, Switzerland) · Feb 2026DOI ↗ In vitro
This study investigated, for the first time, how the small peptide Thymosin β4 (Tβ4) interacts with zinc ions (Zn²⁺) at physiological pH. Using a panel of biophysical techniques — including zeta potential analysis, dynamic light scattering (DLS), electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy with elemental mapping (SEM/EDS) — the researchers characterized the structural and chemical consequences of Zn²⁺ binding to this intrinsically disordered 43-amino-acid peptide. The study found that Zn²⁺ progressively neutralizes Tβ4's negative surface charge, triggering a sharp aggregation transition. ESI-MS identified peptide-to-zinc complexes at a 1:3 molar ratio, while DLS and SEM confirmed formation of compact, low-solubility supramolecular assemblies. NMR data indicated that Zn²⁺ binding does not induce folding of the peptide. Importantly, the study compared the experimentally determined critical aggregation concentration with known physiological extracellular Zn²⁺ levels, concluding that aggregation is unlikely under normal plasma or interstitial conditions but could occur in Zn-rich microenvironments such as the synaptic cleft. The authors propose that Zn²⁺-mediated Tβ4 assembly may be relevant in neurological or inflammatory contexts. This is a foundational biochemical characterization study with no direct in vivo or clinical component.
International journal of molecular sciences · Feb 2026DOI ↗ Review
This Chinese clinical comprehensive evaluation systematically compared five long-acting GLP-1 receptor agonists (dulaglutide, semaglutide, polyethylene glycol loxenatide, tirzepatide, and mazdutide) for the management of type 2 diabetes within China's healthcare context. The researchers constructed a quantitative, six-dimensional scoring framework—covering efficacy, safety, economy, innovation, suitability, and accessibility—with indicator weights derived through a Delphi expert consultation process. Evidence sources included drug labels, systematic literature reviews, and real-world data. Semaglutide scored highest (76.6/100) followed by dulaglutide (72.6), polyethylene glycol loxenatide (64.8), tirzepatide (62.9), and mazdutide (55.1). Semaglutide and dulaglutide were classified as "Strong Recommendations," largely due to superior cardio-renal outcome evidence. Tirzepatide and polyethylene glycol loxenatide received "Conditional Recommendations," while mazdutide was "Not Recommended" owing to insufficient evidence, lack of national reimbursement listing, and high cost. Key limitations include the inherent subjectivity of the Delphi weighting process, the China-specific formulary and reimbursement context limiting global generalizability, and the composite nature of the scoring system potentially obscuring individual domain differences.
Diabetes, metabolic syndrome and obesity : targets and therapy · Feb 2026DOI ↗ Limited · human
This case report describes a nasopharyngeal carcinoma patient who developed severe multisystem immune-related adverse events (irAEs) following combination treatment with sintilimab (a PD-1 immune checkpoint inhibitor) and thymosin alpha-1 (Tα1), an immunomodulatory peptide. The patient reportedly experienced high fever, skin rash, interstitial pulmonary edema, and multiple organ failure. The authors trace the clinical course from symptom onset through regression and use this case to discuss the potential risks of combining immune checkpoint inhibitors (ICIs) with immunomodulatory agents, suggesting that such combinations may trigger immune overactivation beyond what either agent causes alone. The paper reviews relevant literature to contextualize the case and proposes management strategies for clinicians encountering similar presentations. Key limitations include the inherent constraints of single-patient case reports: causality cannot be firmly established, findings are not generalizable, and confounding factors (e.g., underlying disease burden, other medications) cannot be fully excluded. The authors emphasize the need for heightened clinical vigilance when combining ICIs with immunomodulators like Tα1.
Clinical case reports · Feb 2026DOI ↗ Review
This commentary argues that the rising popularity of GLP-1 receptor agonists and dual GIP/GLP-1 agonists (such as tirzepatide) for obesity treatment risks overshadowing the need for structural, population-level interventions targeting the food environment. The authors highlight several limitations of a pharmacotherapy-centered approach: high and rising costs (citing recent tirzepatide price increases in the United Kingdom), unequal access across health systems, and the well-documented tendency for weight regain following cessation of these medications. The paper contends that obesity is fundamentally driven by structural factors — including the pervasive availability, marketing, and placement of ultra-processed and high-fat, salt, or sugar (HFSS) foods, alongside limited access to nutritious options. The authors call for complementary population-level policies such as mandatory food reformulation, restrictions on HFSS food marketing, and improved affordability and access to minimally processed foods. The paper acknowledges that medications may provide individual-level benefit but concludes that only comprehensive food-system reform can achieve sustainable reductions in obesity and diet-related disease. As a commentary, it presents no original empirical data, and its conclusions rest on cited evidence rather than new research.
Public health nutrition · Feb 2026DOI ↗