Strong · human
This living systematic review and network meta-analysis, commissioned by the American College of Physicians, synthesized evidence from 69 randomized controlled trials involving 112,511 adults with overweight or obesity (BMI ≥25 kg/m²) to compare pharmacologic weight-management treatments. Drugs examined included GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide), dual agonists (tirzepatide, retatrutide, semaglutide-cagrilintide), and other agents (naltrexone-bupropion, phentermine, phentermine-topiramate, orforglipron), with or without lifestyle intervention. The review found that nearly all studied interventions produced greater weight loss than placebo and/or lifestyle intervention alone. Semaglutide was found to probably reduce mortality and major adverse cardiovascular events (MACE). Semaglutide and tirzepatide demonstrated the greatest weight loss in both pairwise and network meta-analyses. However, nearly all active treatments were also associated with more treatment discontinuations due to adverse events compared with placebo. The authors noted that evidence for critical outcomes such as mortality, MACE, and serious adverse events remained limited, and direct head-to-head comparisons between treatments were scarce. Thirty-seven of the 69 included studies were rated at low risk of bias. The living review design allows for ongoing evidence updates as new trials emerge.
Annals of internal medicine · Jun 2026DOI ↗ Insufficient
This review examines the available information on dulaglutide, a GLP-1 receptor agonist used for type 2 diabetes management, in the context of breastfeeding safety. The authors note a complete absence of clinical data on dulaglutide use during lactation. They reason that, due to dulaglutide's large molecular weight of approximately 59,669 daltons as a protein molecule, transfer into breast milk is theorized to be minimal. Furthermore, even if trace amounts were present in milk, oral absorption by a nursing infant is considered unlikely because the compound would probably be degraded by proteolytic enzymes in the infant's gastrointestinal tract. Despite this theoretical reassurance, the authors conclude that caution is warranted when considering dulaglutide use during breastfeeding, with heightened concern for newborns and preterm infants, whose gastrointestinal systems may be less capable of fully degrading such compounds. The primary limitation of this review is the total lack of empirical human lactation data, meaning all conclusions are based on pharmacokinetic reasoning and extrapolation rather than direct measurement or clinical observation.
Unknown journal · May 2026Source ↗ Moderate · human
This systematic review and meta-analysis (PRISMA 2020, PROSPERO-registered) pooled three randomized controlled trials (N = 13,590 adults with type 2 diabetes) comparing once-weekly tirzepatide — a dual GIP/GLP-1 receptor agonist — against dulaglutide (a GLP-1 receptor agonist) over at least 26 weeks. The primary safety outcome was overall adverse event incidence, which the study found did not differ significantly between treatments (RR 1.04; moderate-certainty evidence). However, discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32; high-certainty evidence), suggesting a tolerability-persistence trade-off. Glycemic target achievement (HbA1c) was population-dependent: tirzepatide showed consistent benefit at the primary threshold in treatment-naïve patients receiving lower-dose dulaglutide, while the advantage narrowed in patients with established cardiovascular disease on higher-dose dulaglutide; heterogeneity was extreme at the strictest threshold. Weight-loss threshold achievement favored tirzepatide, though evidence certainty was very low due to substantial heterogeneity. Serious adverse events did not differ significantly. Key limitations include only three included trials, high heterogeneity for several outcomes, and restricted generalizability across patient subgroups. GRADE certainty ranged from very low to high across outcomes.
Healthcare (Basel, Switzerland) · Mar 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 ↗ 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 ↗ Moderate · human
This post hoc analysis of the AWARD-7 randomized controlled trial examined how dulaglutide (a GLP-1 receptor agonist) affects plasma concentrations of 21 Joslin Kidney Panel (JKP) proteins—biomarkers previously linked to end-stage kidney disease (ESKD) risk—in adults with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD). Researchers used the Joslin OLINK proteomic platform to compare changes in protein concentrations from baseline to 6 months between participants receiving once-weekly dulaglutide (n=124) and those receiving insulin glargine (n=125). The study found that 14 of the 21 JKP proteins increased in the insulin glargine group but decreased in the dulaglutide group, with statistically significant between-group differences. The most notable differences involved 8 TNF-receptor superfamily members, which play roles in inflammation and apoptosis. Additional proteins—including CD160, WFDC2, DLL1, LAYN, SYND1, and EPHA2—also differed significantly between groups. Effects were more pronounced in participants with lower kidney function, higher albuminuria, higher HbA1c, or higher BMI at baseline. The authors suggest these proteomic changes may help explain the kidney-protective effects observed with dulaglutide in AWARD-7. Key limitations include the post hoc, exploratory design, the 6-month follow-up window, and lack of adjustment for multiple comparisons.
Kidney international reports · Jan 2026DOI ↗ Moderate · human
This Phase III randomized controlled trial evaluated mazdutide, a novel once-weekly dual glucagon and GLP-1 receptor agonist, compared to dulaglutide in 731 Chinese adults with type 2 diabetes (T2D) on background oral anti-diabetic therapy. Participants were randomized 1:1:1 to one of two mazdutide doses or dulaglutide (1.5 mg) for 28 weeks. The study found that both mazdutide doses demonstrated non-inferiority and superiority to dulaglutide in reducing HbA1c from baseline, with least-squares mean treatment differences of -0.24% and -0.30% for the lower and higher doses, respectively. Mazdutide also produced significantly greater reductions in body weight than dulaglutide, with differences of -3.78% and -5.76% for the two doses. The safety profile was generally acceptable, though gastrointestinal adverse events occurred more frequently with mazdutide than dulaglutide. Limitations include the relatively short 28-week duration, restriction to a Chinese population, and the lack of a placebo arm, which may limit generalizability of findings.
In vitro
This study describes the development of a high-yield Chinese hamster ovary (CHO) cell manufacturing platform for a biosimilar of dulaglutide, a GLP-1/IgG4-Fc fusion protein approved for type 2 diabetes. Researchers used apoptosis-resistant CHO 4BGD cells and sequentially transfected two expression plasmids encoding dulaglutide, employing a two-step transgene amplification strategy using methotrexate (MTX) followed by methionine sulfoximine (MSX) selection. The dual-selection approach resulted in approximately 30% higher titers in polyclonal populations compared to MTX amplification alone. Through a clonal cell line selection pipeline, the top clone (4BGD/Dul #73) achieved a product titer of 1.05 g/L in a 3-week fed-batch process, with a specific productivity of up to 22 pg·cell⁻¹·day⁻¹ and stable expression over 69 days without selective pressure. Purity assessed by size-exclusion HPLC showed ≥95% monomer content. Biological activity testing in a GLP-1 receptor/CRE-luciferase reporter assay yielded an EC₅₀ of 52 pM for the biosimilar candidate versus 76 pM for the reference drug. Limitations include the absence of in vivo or clinical data, with all findings limited to cell culture and in vitro bioassay systems.
Pharmaceuticals (Basel, Switzerland) · Dec 2025DOI ↗ In vitro
This study developed a dual-mode semi-preparative anion-exchange chromatography (AEX) method to fractionate and characterize charge variants of dulaglutide, a GLP-1 receptor agonist used in type 2 diabetes management. Because dulaglutide is an acidic Fc-fusion protein with complex charge heterogeneity, standard characterization methods are technically challenging. The researchers isolated acidic, main, and basic charge variant fractions and subjected them to comprehensive downstream analyses, including assessments of sialic acid content, post-translational modifications (phosphorylation, sialylation, deamidation, oxidation), size heterogeneity, aggregation, truncation, and biological activity. A key finding was that aggregates in basic variants are primarily held together by non-covalent interactions, while acidic variants contain covalently linked aggregates—a structurally meaningful distinction. Charge variants showed only slight differences in biological activity, potentially linked to aggregate presence. A comparative analysis between the innovator product Trulicity® and a biosimilar candidate revealed minor differences in acidic variants, likely attributable to variations in phosphorylation and sialylation profiles. Limitations include the in vitro nature of the biological activity assessments and the absence of in vivo or clinical data. The study provides a detailed analytical framework for characterizing charge heterogeneity in complex biopharmaceuticals.
International journal of biological macromolecules · Sep 2025DOI ↗ Review
This evidence review examines the evolving landscape of incretin-based pharmacotherapy, focusing on GLP-1 receptor agonists (GLP-1RAs) and newer multi-receptor co-agonists for cardiometabolic disease management. The paper surveys established GLP-1RAs — including liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide — noting their reported benefits on glycated hemoglobin, body weight, lipid profiles, liver fat, and cardiovascular outcomes (reduction in major adverse cardiovascular events, or MACE). It also covers emerging agents: dual GIP/GLP-1 agonist tirzepatide (approved for diabetes and obesity), dual GLP-1/glucagon co-agonists (notable for synergistic weight loss), and triple GLP-1/GIP/glucagon receptor agonists such as retatrutide and efocipegtrutide, described as achieving the highest pharmacotherapy-associated weight loss observed to date. Additional novel classes reviewed include GLP-1/amylin agonists (CagriSema, Amycretin), non-semaglutide oral GLP-1 agents, and peptide YY/GLP-1 dual agonists. As a narrative review, the paper does not present original trial data, and its conclusions are based on synthesized existing literature, which may introduce selection bias. The authors anticipate that metabolic benefits will translate into cardiometabolic outcomes, though direct evidence for many newer agents remains limited.
World journal of cardiology · Aug 2025DOI ↗ Animal only
This preclinical study investigated whether mazdutide — a dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist — could improve cognition in a mouse model of type 2 diabetes mellitus (T2DM). Male db/db mice (a well-established T2DM model characterized by obesity and hyperglycemia) were treated with mazdutide and compared against dulaglutide, a GLP-1R-only agonist. Researchers assessed cognitive function via behavioral tests and examined brain pathology for neurodegenerative markers. They also applied transcriptomic, proteomic, and metabolomic (multi-omics) analyses to explore underlying molecular mechanisms. The study found that mazdutide-treated mice showed greater improvements in cognitive performance compared to dulaglutide-treated mice, along with better neuronal structure and brain tissue integrity. Multi-omics data implicated molecular pathways related to neuroprotection, energy metabolism, and synaptic plasticity as potential contributors to these effects. Key limitations include exclusive use of male mice, meaning results cannot be generalized to females, and the entirely preclinical nature of the study. No human data were collected, so whether these findings translate to people with T2DM remains unknown. The authors suggest mazdutide may warrant further investigation as a treatment for metabolic disorder-associated cognitive decline.
EBioMedicine · Jun 2025DOI ↗