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 ↗ 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 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 ↗ 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 ↗ 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 ↗ Limited · human
This cross-sectional study analyzed publicly available FDA Adverse Event Reporting System (FAERS) data from January 2015 through December 2024 to characterize adverse events (AEs) associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs), using injectable insulin as a comparator. Across 112,532 reports where a GLP-1 RA was the primary suspect drug, the study found that administration-related reactions accounted for 63% of GLP-1 RA reports versus 39% for insulin. Reports of dosing issues and administration errors for GLP-1 RAs rose notably beginning in Q4 2022 and continued increasing through 2023 and 2024 — a pattern not observed for insulin — temporally coinciding with documented national GLP-1 supply shortages. The authors note several important limitations: FAERS data lack exposure denominators, making it impossible to calculate true incidence rates; reporting volume increases may reflect greater overall utilization rather than elevated per-patient risk; and FAERS is subject to underreporting and reporting biases. The study concludes that these patterns highlight the need for enhanced patient and provider education and continued post-marketing surveillance, particularly as compounded or alternative GLP-1 formulations may have contributed to administration errors during the shortage period.
Health affairs scholar · Feb 2026DOI ↗ Animal only
This preclinical study examined how survodutide — a dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist in clinical development for obesity and MASH — acts in the brain to reduce body weight. Researchers first mapped GCGR and GLP-1R expression in human and mouse circumventricular organs (CVOs), finding that GCGR is barely detectable in the area postrema (AP) and arcuate nucleus of the hypothalamus (ARH), whereas GLP-1R is expressed in both regions. Using a fluorophore-labeled version of survodutide in mice, the study found that the compound accesses CVOs and nearby hypothalamic and hindbrain nuclei directly, without evidence of broadly crossing the blood-brain barrier. C-Fos activation mapping showed that survodutide activated multiple brain nuclei associated with food intake control. A long-acting GCGR-selective agonist, by contrast, did not activate satiety-related brain regions or reduce food intake, though it did reduce body weight, suggesting the appetite-suppressing effects of survodutide are primarily GLP-1R dependent. Limitations include the exclusively preclinical (mouse) design and the use of a labeled surrogate compound. The authors conclude the findings support a dual mechanism for survodutide's weight-lowering effects.
Molecular metabolism · Feb 2026DOI ↗ Moderate · human
This secondary analysis pooled data from two randomized, double-blind, placebo-controlled crossover trials to examine whether the GLP-1 receptor agonist (RA) dulaglutide affects copeptin — a stable surrogate marker for vasopressin (antidiuretic hormone) — in euvolemic individuals. A total of 54 participants were included: 34 with primary polydipsia and 20 healthy volunteers. Participants received three weeks of either subcutaneous dulaglutide or saline placebo once weekly before crossing over. Fasting blood samples for copeptin were collected after each treatment phase. The study found that dulaglutide was associated with a statistically significant suppression of copeptin levels, with a median within-subject difference of −0.7 pmol/L (p = .047), representing approximately a 12% reduction relative to placebo. This effect was not significantly correlated with dulaglutide-related changes in blood pressure, BMI, or nausea frequency. The authors suggest this finding may help explain GLP-1's known role in fluid and sodium homeostasis. Key limitations include the secondary-analysis design (not pre-specified as the primary outcome), modest sample size, a mixed population (healthy and polydipsic participants), and the reliance on copeptin as a proxy rather than directly measured vasopressin.
European journal of endocrinology · Feb 2026DOI ↗ Limited · human
This case report describes an 18-year-old woman with no prior medical history who developed euglycemic ketoacidosis (EKA) in association with self-administered semaglutide purchased online without medical supervision. After initiating the medication ten days prior and self-escalating doses, she presented with three days of nausea, intractable vomiting, and reduced oral intake. Laboratory findings revealed a high-anion gap metabolic acidosis (pH 7.24, bicarbonate 14 mmol/L, anion gap 24 mEq/L), markedly elevated β-hydroxybutyrate (5.9 mmol/L), and normal blood glucose (60 mg/dL), meeting criteria for EKA. She was treated with intravenous fluids, dextrose infusion, and supportive care, with clinical recovery and discharge within 36 hours. The authors propose that reduced oral intake combined with GLP-1 receptor agonist-induced gastrointestinal side effects may have triggered a starvation-like ketogenic state. Key limitations include the single-patient design, inability to verify the authenticity or exact composition of the online-purchased product, and lack of confirmed dosing history. The case raises awareness of EKA as a potential complication of GLP-1 receptor agonist use, particularly in unsupervised, non-diabetic individuals using unregulated sources.
Review
This review paper examines the benefits and harms of GLP-1 receptor agonists (GLP-1 RAs) and dual GLP-1/GIP agonists in the management of obesity. The authors summarize evidence indicating that these drug classes can facilitate significant short-term weight loss and associated improvements in obesity-related conditions, including type 2 diabetes mellitus, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. The paper also catalogues a range of adverse effects: common gastrointestinal issues (nausea, vomiting, acute pancreatitis, dehydration, and malnutrition), reduced efficacy of oral contraceptives, allergic reactions, and rarer events such as thyroid cell tumours and non-arteritic anterior ischaemic optic neuropathy. The authors highlight that up to one-third of weight lost may be lean tissue (muscle and bone), discontinuation rates may reach 80% at two years, and subsequent weight regain can account for up to two-thirds of prior loss—often disproportionately as fatty tissue. The paper recommends that GLP-1 RA therapy be initiated alongside supervised exercise and individualised dietary guidance, with ongoing monitoring for cessation, malnutrition, and inappropriate fat regain. A key limitation is that this is a narrative review and does not present original trial data.
Drug and therapeutics bulletin · Jan 2026DOI ↗ Review
This narrative review examines three incretin-based therapies — liraglutide, semaglutide, and tirzepatide — approved for weight management in non-diabetic individuals with obesity. The authors provide background on the physiological roles of the incretin hormones GIP and GLP-1 in the gastrointestinal tract, explaining how pharmacological analogues of these hormones, initially developed for type 2 diabetes, were subsequently found to produce clinically meaningful weight reduction. The review compares the three agents across efficacy, safety, cost-effectiveness, and real-world clinical trends. Lifestyle interventions (dietary modification, physical activity, sleep, and stress management) are discussed as foundational components of obesity management. The authors highlight that all three agents are now regulatory-approved for obesity in non-diabetic patients. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and is therefore subject to selection bias in the studies chosen. It does not conduct a formal systematic search or meta-analysis, limiting the objectivity of comparisons. No new clinical trial data are presented, and conclusions about relative efficacy and cost-effectiveness are drawn from the authors' interpretation of the existing evidence base.
Rambam Maimonides medical journal · Jan 2026DOI ↗ 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 ↗ Review
This review examines the expanding therapeutic applications of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) beyond their original indication of glycemic control in type 2 diabetes. The authors survey clinical trial evidence supporting the use of GLP-1 RAs across several cardiometabolic conditions, including obesity, heart failure with preserved ejection fraction, chronic kidney disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). The review highlights that robust clinical trial data exist for weight loss, cardiovascular outcome improvements, and renal function preservation. The authors also note that additional trials are ongoing to further broaden and strengthen the evidence base. Practical challenges are discussed, including high costs, limited patient access, adherence difficulties, and implementation barriers—especially for indications outside of diabetes. The review identifies emerging innovations, such as oral GLP-1 RA formulations and combination therapies, as potential avenues to improve accessibility and long-term use. The authors conclude that as clinical guidelines continue to evolve, targeted integration of GLP-1 RAs into care pathways may reshape prevention and treatment strategies for complex chronic diseases. As a narrative review, this paper synthesizes existing literature but does not generate new primary data, which limits the directness of its evidence.
Reviews in cardiovascular medicine · Jan 2026DOI ↗ Review
This review examines the potential role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in managing diabetic foot ulcers (DFUs), a serious chronic complication of diabetes associated with high rates of disability, recurrence, and mortality. The authors note that DFU-related mortality is strongly tied to cardiovascular events, suggesting that treatment should extend beyond local wound care to include cardiovascular risk reduction. The review systematically describes personalized application strategies for GLP-1 RAs based on DFU clinical staging, and compares mono-, dual-, and triple-target GLP-1 RA agents in terms of their clinical translational potential and adverse effect profiles specific to DFU patients. Notably, the authors highlight a key tension: while GLP-1 RAs have demonstrated cardiovascular protective effects in outcome trials, their appetite-suppressing and gastric-emptying-delaying properties may worsen malnutrition in DFU patients during acute infection phases. The review synthesizes existing evidence to propose more rational, stage-specific treatment frameworks. As a narrative review, it does not generate new primary data, and its conclusions are limited by the quality and scope of the underlying studies it synthesizes.
Frontiers in endocrinology · Jan 2026DOI ↗ Review
This review examines the evolving therapeutic role of amylin, a pancreatic peptide hormone, in managing "diabesity" — the coexistence of diabetes and obesity — over the past five years. The authors describe amylin's physiological mechanisms, including postprandial glucose regulation through delayed gastric emptying and glucagon suppression, as well as appetite control via central nervous system pathways. The review covers preclinical development of long-acting amylin analogs with improved pharmacokinetics and reduced aggregation, which demonstrated significant metabolic benefits in animal models. Clinically, the review highlights pramlintide, a synthetic amylin analog shown to modestly improve glycemic control and promote weight loss in diabetic patients. It also discusses cagrilintide, a newer long-acting analog, which the authors report has produced substantial weight reduction in individuals with obesity. Notably, the review emphasizes that combining amylin analogs with GLP-1 receptor agonists may achieve synergistic weight loss exceeding 15%. Limitations include the inherent constraints of a review design — it does not present new primary data, and the breadth of evidence cited spans preclinical to early clinical stages, meaning conclusions about long-term efficacy and safety remain preliminary.
Journal of obesity & metabolic syndrome · 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 ↗