Limited · human
This study characterizes PG-102, a bispecific Fc fusion protein that co-activates both GLP-1 and GLP-2 receptors, combining preclinical animal work with a Phase I human trial. In db/db mice (a model of advanced type 2 diabetes with hyperglycemia and catabolic weight loss), PG-102 demonstrated superior and more sustained glycemic control compared to semaglutide or tirzepatide while preserving body weight — an effect attributed to β-cell preservation and enhanced glucose uptake rather than acute insulin stimulation. Mechanistic experiments suggested that dual receptor engagement was necessary for these benefits, with PG-102 also promoting coordinated, delayed receptor internalization compared to monospecific agents. The Phase I randomized, double-blind, placebo-controlled trial enrolled 24 adults with overweight (BMI 25–30 kg/m²) across three dose cohorts, with 18 receiving PG-102 and 6 receiving placebo. The primary endpoint was safety and tolerability. Treatment-emergent adverse events occurred in 83.3% of PG-102 participants and 66.7% of placebo participants; gastrointestinal events were mild to moderate. No serious adverse events or treatment discontinuations were reported. Limitations include the small sample size, single-center design, overweight-only population, and lack of efficacy endpoints in the human portion of the study.
Nature communications · Mar 2026DOI ↗ Review
This review synthesizes evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), with particular attention to the liver-heart connection. The authors draw on mechanistic studies, biopsy-based randomized trials, real-world data, and cardiovascular outcome trials. Key trial findings highlighted include: liraglutide (LEAN trial) achieving steatohepatitis resolution in 39% vs. 9% of placebo recipients; semaglutide showing dose-dependent histologic resolution (up to 59% vs. 17% in Phase 2) and meeting dual histologic endpoints in F2–F3 MASH at interim analysis; and tirzepatide (SYNERGY-NASH) demonstrating MASH resolution in 44–62% vs. 10% with fibrosis improvement signals. Cardiovascular outcome benefits were observed across LEADER, SUSTAIN-6, SELECT, and REWIND trials. Mechanistically, GLP-1RAs are described as reducing hepatic lipogenesis, inflammation, and insulin resistance while improving systemic cardiometabolic risk factors. The review concludes that semaglutide and tirzepatide may serve as foundational therapies for high-risk MASLD patients, while noting gaps in long-term durability data, optimal treatment duration, and evidence in cirrhosis.
Chronic diseases and translational medicine · Mar 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed ocular adverse event (AE) reports associated with five GLP-1 receptor agonists (exenatide, tirzepatide, dulaglutide, liraglutide, and semaglutide) using the FDA Adverse Event Reporting System (FAERS) from 2005 to 2024. Ocular AEs comprised 3.61% of all GLP-1 RA-related reports; the median patient age was 63 years, and 62.6% of reports involved female patients. Disproportionality analysis using reporting odds ratios (RORs) identified a statistically significant signal for ocular AEs associated with semaglutide, while exenatide showed a significant annual decline in proportional reporting (-5.15% per year). The authors note that semaglutide's signal may partly reflect its growing market dominance rather than a true differential risk. Key limitations acknowledged by the study include the absence of exposure denominators and comparator groups, vulnerability of FAERS to reporting bias (including under- and over-reporting), and inability to establish causality. The authors characterize the findings as hypothesis-generating and recommend clinician vigilance regarding ocular monitoring, particularly in populations already at elevated risk for diabetic eye disease, while calling for further prospective research to validate these associations and explore potential mechanisms.
Journal of clinical medicine · Mar 2026DOI ↗ Moderate · human
This retrospective cohort study used electronic health records from a large health system in Ohio and Florida (January 2021–June 2025) to examine real-world obesity treatment patterns and weight changes among adults who discontinued injectable semaglutide or tirzepatide within 3–12 months of initiation. A total of 7,938 patients (mean age ~56 years; ~64% female) were included. The study found that within one year of discontinuation, roughly 19.6% restarted the same medication and 35.2% received an alternative obesity treatment (most commonly another medication). Patients treated for obesity lost a mean of 8.4% of body weight before discontinuation, while those treated for type 2 diabetes lost 4.4%. In the year following discontinuation, the average weight change was modest (+0.5% for obesity indication; −1.3% for T2D indication), but with considerable individual-level variability—meaning some patients regained weight substantially while others did not. Key limitations include the retrospective, observational design (precluding causal inference), potential confounding by unmeasured factors, and restriction to a single health system in two U.S. states, which may limit generalizability.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Review
This narrative review compares two incretin-based therapies — semaglutide, a selective GLP-1 receptor agonist, and tirzepatide, a dual GIP/GLP-1 receptor agonist — across their mechanisms of action, clinical efficacy, therapeutic indications, and cardiovascular/renal evidence. The authors describe semaglutide as having a well-established clinical profile with demonstrated benefits in glycaemic control, body weight reduction, and cardiovascular and renal outcomes. Tirzepatide is presented as a newer agent offering superior weight loss and improvements in insulin sensitivity, with an expanding range of therapeutic indications, though the authors note its cardiovascular outcomes evidence is less mature than that of semaglutide. The review emphasizes that despite shared benefits in reducing HbA1c and body weight, the two molecules differ meaningfully in their pharmacological mechanisms and evidence bases, requiring individualized clinical decision-making. The authors frame both agents within a broader "incretin revolution" relevant to cardio-reno-metabolic prevention. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and therefore does not provide independent experimental evidence to confirm or quantify any specific clinical claims.
European heart journal supplements : journal of the European Society of Cardiology · Mar 2026DOI ↗ Limited · human
This qualitative, multi-method study explored how adults living with obesity make decisions about initiating pharmacotherapy. Researchers used three complementary methods — semi-structured interviews (n=15), a Photovoice study (n=12), and focus group discussions (n=12) — to purposively recruit adults aged 18–70 with a BMI ≥27 kg/m² and at least one obesity-related complication, all of whom were naïve to obesity medications. Through triangulation of findings across all three methods, the study identified five key factors shaping patient preferences: (1) anticipated treatment efficacy, (2) adequacy of information and community support, (3) safety and tolerability profile, (4) treatment burden and lifestyle integration, and (5) logistical and structural barriers. Tirzepatide was the most preferred agent across all methods, largely due to its perceived weight-reduction potential, while semaglutide ranked second, aided by its broader societal familiarity. Perceived efficacy and information trustworthiness emerged as the dominant drivers of preference, with safety concerns consistently moderating enthusiasm. The study is limited by its qualitative design, modest sample sizes, and the fact that all participants were medication-naïve, which may limit transferability to experienced patients. The authors recommend clinicians engage in shared decision-making tailored to individual information needs and social contexts.
Obesity pillars · Mar 2026DOI ↗ Moderate · human
This large retrospective cohort study examined real-world trends in 1-year treatment persistence and adherence among commercially insured adults without diabetes who newly initiated high-potency, weight loss-indicated GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Wegovy) and tirzepatide (Zepbound) — between January 2021 and June 2024. Using integrated medical and pharmacy claims data from approximately 17.9 million members, researchers identified 33,607 eligible new initiators. The study found that 1-year persistence nearly doubled over the observation period, rising from 33.2% in 2021 to 60.9% in the first half of 2024. Tirzepatide demonstrated notably higher persistence (approximately 64%) compared to semaglutide during overlapping availability years. The authors suggest that resolution of GLP-1RA product shortages, improved side effect and dose escalation management, and lifestyle support programs may have contributed to improving persistence trends. Key limitations include reliance on claims data (which cannot capture clinical nuance or patient-reported reasons for discontinuation), a commercially insured-only population limiting generalizability, and the inability to distinguish voluntary discontinuation from access-related gaps. The authors call for further research into discontinuation reasons and long-term cost-effectiveness.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ Limited · human
This retrospective, claims-based observational study examined real-world persistence, adherence, and weight-loss effectiveness of GLP-1 receptor agonists (semaglutide/Wegovy) and the dual GLP-1/GIP agonist (tirzepatide/Zepbound) among 7,493 adults enrolled in Massachusetts Medicaid (MassHealth) who initiated treatment between July and December 2024. At 6 months, the study found moderate rates of persistence (60.8%, defined as no gap greater than 56 days between fills) and adherence (60.1%, defined as proportion of days covered ≥80%). Male sex and younger age were among the member-specific factors associated with lower persistence and adherence. In a subgroup of highly persistent and adherent members with prior authorization recertification data, both tirzepatide and semaglutide were associated with at least 5% body weight reduction at 6 months. Key limitations include the retrospective claims-based design, which cannot establish causality, the restriction to a Medicaid population limiting generalizability, and the weight-loss outcome being measured only in a select, highly adherent subgroup rather than the full cohort.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ 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.
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 ↗ 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 ↗ 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 ↗ 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 ↗ Insufficient
This systematic review surveyed ClinicalTrials.gov (from inception through July 2025) to map the landscape of registered clinical trials investigating glucagon-like peptide-1 receptor agonists (GLP-1RAs) as potential treatments for substance use disorders (SUDs). Of 192 records identified, 33 trials met inclusion criteria. The most commonly studied SUD was alcohol use disorder (15 trials), followed by nicotine/tobacco (9), cocaine (4), opioid (4), and methamphetamine (1); no trials targeting cannabis use disorder were identified. Agents under investigation included semaglutide, exenatide, tirzepatide, liraglutide, dulaglutide, and pemvidutide. The review found that trial designs and outcome measures were highly heterogeneous, often blending self-reported measures (e.g., Timeline Follow-Back, craving scales) with objective indices (e.g., urine toxicology). The authors note that most registered trials rely on older-generation GLP-1RAs and that significant gaps exist for methamphetamine and cannabis use disorders. As a registry-based systematic review, it does not report clinical efficacy data from completed trials. The authors conclude that next-generation GLP-1RAs and trials using FDA-recommended endpoints are needed to establish efficacy and safety across the full spectrum of SUDs.
Addictive behaviors reports · 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 ↗