Review
This review examines the expanding cardiovascular applications of glucagon-like peptide-1 (GLP-1) receptor agonists, a class of peptide-based agents originally developed for type 2 diabetes management. The authors synthesize molecular mechanistic data alongside clinical evidence from major cardiovascular outcome trials (CVOTs) to characterize how GLP-1 agonists may reduce risk across conditions including atherosclerosis, heart failure, stroke, and vascular dementia. Proposed mechanisms discussed include anti-inflammatory, anti-atherogenic, endothelial-protective, and direct cardioprotective effects. The review highlights findings from multiple CVOTs reporting reductions in major adverse cardiovascular events (MACEs), myocardial infarction, stroke, and cardiovascular mortality. Notably, the SELECT trial is cited as evidence extending potential benefit to non-diabetic individuals with obesity and established CVD. The review also addresses emerging dual GLP-1/GIP agonists such as tirzepatide and its own CVOT data. The authors acknowledge important limitations, including high drug costs, unresolved long-term safety questions, and real-world implementation barriers. As a narrative review, this paper does not generate primary data and is subject to the inherent risk of selective literature synthesis. It provides a useful conceptual overview but does not independently establish causality or efficacy.
Journal of clinical medicine · Sep 2025DOI ↗ Review
This scoping review examined the potential role of incretin mimetics — specifically GLP-1 receptor agonists (e.g., semaglutide), dual GLP-1/GIP receptor agonists (e.g., tirzepatide), and the investigational triple agonist retatrutide — as treatments for polycystic ovarian syndrome (PCOS). Following PRISMA guidelines and drawing on literature from EBSCO Medline and PubMed, the authors explored how these agents compare to traditional PCOS pharmacotherapy such as metformin and estradiol-progesterone combination pills. The review found that all three classes of incretin mimetics were associated with meaningful improvements in weight loss and insulin sensitivity relative to conventional treatments. Dual- and triple-acting agonists, which additionally target the GIP receptor, appeared to produce greater reductions in weight and improvements in insulin sensitivity than GLP-1-only agents. Some included studies also reported PCOS-specific symptom improvements, such as reductions in dysmenorrhea and changes in ovarian morphology. The authors note that the precise mechanisms by which incretin mimetics may address the hormonal dysregulation of PCOS remain unclear, and they call for further research to optimize the integration of these agents with existing standard-of-care therapies. Key limitations include the scoping review design, heterogeneity of included studies, and limited long-term human trial data.
Moderate · human
This meta-analysis systematically reviewed the evidence on GLP-1 receptor agonists (e.g., semaglutide, liraglutide) in patients undergoing spinal fusion surgery. Following Cochrane guidelines, the authors searched five major databases and included 11 studies encompassing 14,344 participants, assessing outcomes such as pseudoarthrosis, readmission, acute kidney injury (AKI), cerebrovascular accidents, and deep vein thrombosis. Quality assessment used the Newcastle-Ottawa Scale, and statistical analysis was performed with RevMan 5.4 using risk ratios for dichotomous outcomes. The study found that GLP-1 receptor agonist use was associated with a statistically significant reduction in pseudoarthrosis at both six months (RR = 0.63) and 12 months (RR = 0.64), but this benefit was not sustained at 24 months (RR = 1.03). GLP-1 receptor agonists were also associated with a significantly increased risk of AKI (RR = 1.30). No significant differences were observed for readmission, stroke, deep vein thrombosis, or reoperation rates. Subgroup analysis by diabetic status provided additional insights. Key limitations include the absence of randomized controlled trials among included studies, significant heterogeneity in several outcomes, variability in outcome definitions, and relatively short follow-up periods. The authors call for larger, well-designed RCTs to confirm these findings.
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 review paper examines survodutide, a dual glucagon and glucagon-like peptide-1 (GLP-1) receptor agonist, and its potential role in cardiometabolic disease management. The authors synthesize findings from Phase 2 clinical trials, which reported weight loss of up to 18.7% and HbA1c reductions of up to -1.71%, suggesting survodutide may outperform semaglutide on weight outcomes while achieving comparable glycemic control. The paper also discusses Phase 2 evidence showing improvements in liver fat content and fibrosis markers in patients with metabolic dysfunction-associated steatohepatitis (MASH), alongside proposed mechanisms for cardiovascular benefit, including reductions in visceral and epicardial adiposity, systemic inflammation, and fibrosis-related remodeling. Early signals of renal benefit are noted. Limitations acknowledged include higher rates of gastrointestinal adverse events and modest heart rate increases compared to some comparators, contributing to elevated discontinuation rates. The authors emphasize that definitive evidence from cardiovascular outcomes trials is still lacking, with the ongoing SYNCHRONIZE-CVOT trial expected to address this gap. As a narrative review relying primarily on Phase 2 data, the paper does not establish long-term cardiovascular efficacy or safety.
Cardiology in review · Sep 2025DOI ↗ Review
This review examines the current and emerging therapeutic landscape for celiac disease (CeD), an autoimmune enteropathy triggered by dietary gluten. The authors note that while a strict gluten-free diet (GFD) remains the only established treatment, its burdensome nature and incomplete efficacy in some patients have driven significant research into alternatives. The review systematically covers multiple therapeutic categories: gluten-degrading enzymes (e.g., AN-PEP, Latiglutenase, Zamaglutenase), gluten-sequestering agents (e.g., AGY-010, BL-7010), intestinal permeability modulators (e.g., Larazotide acetate, IMU-856), immune-modulating agents (e.g., ZED1227, AMG 714, EQ102), immune tolerization strategies (e.g., TAK-101, KAN-101, Nexvax2), probiotics, nutraceuticals, and food modification technologies. The authors conclude that despite encouraging preclinical and early clinical results across these approaches, no therapy has yet been conclusively proven as an effective GFD alternative. Key limitations of the review include its narrative rather than systematic design, potential selection bias in literature cited, and the absence of head-to-head comparisons between strategies. The authors emphasize the urgent need for further research to validate efficacy, optimize dosing, and establish safety in broader patient populations.
Nutrients · Sep 2025DOI ↗ Limited · human
This case report describes the use of Mazdutide, a dual glucagon-like peptide-1/glucagon receptor (GLP-1/GCGR) agonist, in a 15-year-old male presenting with obesity (BMI 30.64 kg/m²), type 2 diabetes (HbA1c 9.60%), and hyperuricemia (serum uric acid 511 µmol/L). The patient received a dose-escalation regimen of subcutaneous once-weekly Mazdutide alongside metformin and insulin over 36 weeks. The authors report substantial improvements across multiple metabolic parameters: body weight decreased by 16.8 kg (18.89% BMI reduction), HbA1c fell by 21.88%, and serum uric acid dropped by 37.00%. Lipid outcomes also improved, with triglycerides declining 69.02%, total cholesterol 13.65%, and LDL cholesterol 17.27%. Hepatic steatosis, confirmed by ultrasound, resolved by week 14. No hypoglycemic episodes or other adverse events were reported, and benefits were described as sustained after treatment ended. Key limitations include the single-patient design, the absence of a control condition, and the concurrent use of metformin and insulin, making it impossible to attribute outcomes specifically to Mazdutide. These preliminary observations may inform future controlled studies in adolescent populations.
Frontiers in endocrinology · Sep 2025DOI ↗ Preclinical
This study investigated how dysregulation of the NLRP3 inflammasome in melanocytes contributes to vitiligo pathogenesis. Using skin samples from vitiligo patients and a melanoma-Treg-induced vitiligo mouse model, the researchers found that NLRP3 expression is significantly elevated in vitiligo melanocytes. Mechanistically, they identified that decreased expression of the E3 ubiquitin ligase β-TrCP1 in vitiligo melanocytes reduces K27-linked ubiquitination of NLRP3, weakening its interaction with the autophagy receptor NDP52. This disrupts selective autophagic clearance of NLRP3, allowing it to hyperactivate inflammatory and pyroptotic pathways—including GSDMD pore formation and IL-1β release—ultimately destroying melanocytes. Genetic knockout of NLRP3 in mice alleviated vitiligo progression. As a potential therapeutic approach, the authors developed lysine-proline-valine (KPV)-modified deformable liposomes carrying Nlrp3 shRNA, which achieved melanocyte-targeted NLRP3 knockdown and reduced vitiligo development in mice. Key limitations include reliance primarily on a mouse model, limited human mechanistic validation, and the therapeutic intervention being tested only in animals, leaving clinical translation unestablished.
Cell death and differentiation · Sep 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (recruiting). The main purpose of the SYNERGY-OUTCOMES study is to find out whether retatrutide and tirzepatide can prevent major adverse liver outcomes (MALO) in people with high-risk metabolic dysfunction-associated steatotic liver disease (MASLD). The study will enroll adults who have MASLD based on non-invasive tests (NITs), which indicate they are more likely to develop MALO. Participants will be randomly assigned within a Master Protocol to receive either retatrutide (N1T-MC-RT01), tirzepatide (N1T-MC-TZ01) or placebo. The trial plans to enroll abo
ClinicalTrials.gov · Sep 2025View trial ↗ Moderate · human
This systematic review and meta-analysis pooled data from six randomized controlled trials (RCTs) involving 1,272 adults to evaluate the efficacy and safety of survodutide, a glucagon/GLP-1 receptor co-agonist peptide, for glycemic control and weight loss. Compared with placebo, the study found that survodutide was associated with statistically significant reductions in HbA1c, fasting glucagon levels, body weight, and waist circumference. Subgroup analyses suggested that higher total weekly doses and longer treatment durations (greater than 16 weeks) were associated with more pronounced effects on body weight and waist circumference, while greater HbA1c reductions were linked to higher doses. Secondary outcomes including BMI, total cholesterol, triglycerides, and blood pressure also showed modest reductions. On the safety side, survodutide was associated with a significantly higher risk of treatment discontinuation due to adverse events, with gastrointestinal events being the most frequently reported, though serious adverse events did not increase significantly. Limitations include the small number of included trials (six), limited participant diversity, and varying treatment durations across studies. The authors call for larger, longer, multicenter RCTs to confirm these findings across broader populations.
Diabetes, obesity & metabolism · Sep 2025DOI ↗ Animal only
This preclinical study developed a dual-crosslinked injectable hydrogel (HSMP-LA) designed to mimic natural gut mucus for treating colitis. The hydrogel combined thiol/maleimide-modified hyaluronic acid with two active agents: antimicrobial ε-polylysine (ε-PL) and larazotide acetate (LA), a tight junction–regulating peptide. In laboratory (in vitro) experiments using LPS-injured Caco-2 intestinal cells, sustained release of LA was reported to selectively inhibit zonulin-mediated tight junction disruption by targeting the MLCK/p-MLC signaling pathway, thereby restoring epithelial barrier integrity. The hydrogel also demonstrated broad-spectrum antimicrobial activity and strong mucoadhesive properties with prolonged retention. In a dextran sodium sulfate (DSS)-induced mouse model of colitis, HSMP-LA significantly reduced disease activity indices, suppressed pro-inflammatory cytokines, upregulated anti-inflammatory IL-10, repaired tight junction proteins (ZO-1, occludin, claudin-5), restored mucus production (MUC2), and rebalanced gut microbiota composition. The study's primary limitations are that all findings are confined to cell culture and animal models, with no human data reported. The dual-action strategy—simultaneously targeting barrier dysfunction and microbial imbalance—represents the authors' proposed innovation, though clinical translation remains undemonstrated.
Journal of controlled release : official journal of the Controlled Release Society · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy of thymosin α1 (Tα1), a synthetic immunomodulatory peptide, in treating sepsis. Researchers searched for prospective clinical studies measuring 28-day mortality in sepsis patients treated with Tα1 (excluding combination therapy studies), ultimately including 11 randomized controlled trials (RCTs) totaling 1,927 patients. The overall meta-analysis found a statistically significant reduction in 28-day mortality associated with Tα1 (OR 0.73, 95% CI: 0.59–0.90). However, when analysis was restricted to high-quality trials or multicenter trials — considered more rigorous subsets — the mortality benefit was no longer statistically significant (ORs 0.82 and 0.86, respectively). A heterogeneity of treatment effects analysis drawing on individual patient data from two large multicenter RCTs (representing ~75% of total patients) suggested potential benefits in subgroups with cancer (moderate credibility), diabetes, and coronary heart disease (both low credibility). Trial sequential analysis indicated the current evidence base is underpowered. The authors concluded that while Tα1 shows potential, its benefits appear to vary across patient subgroups, and personalized immunotherapy approaches warrant investigation in future, adequately powered trials.
Frontiers in cellular and infection microbiology · Sep 2025DOI ↗ Preclinical
This study investigated the role of Thymosin β4 (Tβ4) in breast cancer progression and its molecular mechanism. The researchers found that Tβ4 is significantly overexpressed in breast cancer tissues and cell lines, with high expression correlating with poorer clinical outcomes. Using functional experiments, the study showed that elevated Tβ4 promotes cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT), and angiogenesis, while inhibiting apoptosis. Mechanistically, the study identified that Tβ4 directly regulates SLC7A11, a cystine/glutamate antiporter, which in turn enhances glutathione biosynthesis and suppresses lipid peroxidation — effectively inhibiting ferroptosis (an iron-dependent form of programmed cell death). Rescue experiments, conducted both in cell cultures (in vitro) and animal models (in vivo), demonstrated that silencing SLC7A11 reversed the cancer-promoting effects of Tβ4. The study concludes that a novel Tβ4/SLC7A11 signaling axis modulates ferroptosis resistance and contributes to breast cancer malignancy. Limitations include reliance on preclinical models, and no human clinical trials were conducted, leaving the translational relevance to patients yet to be established.
Cellular signalling · Sep 2025DOI ↗ Limited · human
This IRB-approved pilot study investigated the safety of intravenous (IV) administration of BPC-157 (Body Protection Compound 157) in humans. Two participants — a 58-year-old Asian male and a 68-year-old Caucasian female, both with prior IV BPC-157 exposure — received escalating doses over two consecutive days at a private clinic in Florida. Baseline and follow-up fasting blood work and vital signs were collected across three days. The researchers measured biomarkers related to heart, liver, kidney, and thyroid function, as well as blood glucose. Both participants reportedly tolerated the infusions without any adverse side effects, and no clinically meaningful changes in the monitored biomarkers were observed. The authors conclude that IV BPC-157 appeared safe and well-tolerated in these two individuals and call for larger studies to confirm these findings. Key limitations are substantial: the study included only two participants with prior BPC-157 exposure, lacked a control group, had no blinding, involved a very short observation window (three days), and was conducted at a single private clinic. These factors severely restrict the generalizability of the findings and preclude any broad conclusions about safety or efficacy.
Alternative therapies in health and medicine · Sep 2025Source ↗ Review
This review paper examines the challenge of preserving muscle mass during weight loss induced by GLP-1–based pharmacotherapies, including GLP-1 receptor agonists (e.g., semaglutide), dual GLP-1/GIP agonists (e.g., tirzepatide), and triple GLP-1/GIP/glucagon agonists (e.g., retatrutide). The authors note that while these agents can produce clinically meaningful weight loss (5–10% or more of body weight), a portion of that loss comes from lean mass, including skeletal muscle, which may contribute to long-term weight regain and increase the risk of sarcopenia. The paper discusses the biology of myokines—over 600 signaling proteins released during muscle contraction identified in human myocyte research—as potentially important targets for protecting or expanding muscle mass. The authors explore emerging anti-obesity agents and their potential combinations with incretin-based therapies to preferentially reduce fat mass while sparing or building muscle. The paper calls for further research to clarify the functional consequences of lean mass changes during weight loss and maintenance. As a narrative review, it synthesizes existing literature without conducting original trials, and no new clinical data are presented. Generalizability is limited by the review format and the evolving evidence base for newer agents.
World journal of diabetes · Sep 2025DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from 25 randomized controlled trials (RCTs) involving approximately 2,600 patients to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) — including liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide, and retatrutide — on metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Across a median treatment period of 24 weeks, the authors reported that GLP-1RAs were associated with a statistically significant mean reduction in liver fat content of 5.21%, with retatrutide showing the largest effect. Histological analyses suggested significant improvements in steatosis, hepatocellular ballooning, and lobular inflammation, though improvements in fibrosis did not reach statistical significance. Liver enzymes (ALT, AST, γ-GT) and liver stiffness also improved significantly, with semaglutide showing the most pronounced effect on stiffness. No liver-related adverse drug effects were identified. Limitations include heterogeneity across trials, variable treatment durations, and the relatively short median follow-up, which may be insufficient to capture fibrosis outcomes. The evidence base is derived entirely from RCTs in human populations.
The Journal of clinical endocrinology and metabolism · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis examined the risk of pancreatitis and pancreatic cancer associated with GLP-1 receptor agonists (GLP-1 RAs), including dulaglutide, exenatide, liraglutide, semaglutide, beinaglutide, retatrutide, and tirzepatide. Following PRISMA guidelines, the authors searched PubMed, Embase, and the Cochrane Library, ultimately including 62 randomised controlled trials encompassing 66,232 patients with a mean age of 58.3 years and a mean follow-up of approximately 43.5 weeks. The pooled analysis found a statistically significant increase in pancreatitis risk overall (RR: 1.44, 95% CI 1.09–1.89); however, this significance disappeared when results were stratified by background medication use, suggesting that concomitant medications may be a confounding factor. For pancreatic cancer, no significant overall association was identified (RR: 1.30, 95% CI 0.86–1.97), though a significant signal emerged in the subgroup taking background medications (RR: 1.85, 95% CI 1.05–3.26). The authors note this subgroup finding may be an artifact, as many excluded trials had zero events in both arms. Key limitations include variable follow-up durations, heterogeneous patient populations, and the influence of concomitant therapies, which complicate causal attribution to GLP-1 RAs alone.
Endocrinology, diabetes & metabolism · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis pooled data from 33 randomized controlled trials (n = 12,028 adults with overweight or obesity) to evaluate whether combining lifestyle modifications with GLP-1 receptor agonists (GLP-1RAs) produces greater improvements in body weight and cardiometabolic markers than lifestyle modification plus placebo. Searches covered PubMed, Embase, and the Cochrane Library through May 2025, and the protocol was pre-registered on PROSPERO. The study found that the combination therapy was associated with a statistically significant mean weight reduction of 7.13 kg, along with improvements in waist circumference, fat mass, systolic blood pressure, fasting blood glucose, glycated hemoglobin, total cholesterol, triglycerides, and LDL cholesterol. HDL cholesterol did not show a significant change. Subgroup analyses suggested that longer treatment duration, use of semaglutide or tirzepatide, weekly dosing, and trials conducted in North America were associated with larger weight loss effects. No included trials were rated high risk of bias. GRADE certainty ranged from low to high across outcomes, with heterogeneity and potential publication bias limiting confidence in several findings. The authors conclude that results should be interpreted cautiously given this variability in evidence certainty.
EClinicalMedicine · Aug 2025DOI ↗ Limited · human
This study investigated the detection of ibutamoren (MK-677), a growth hormone secretagogue, in human hair samples to aid forensic interpretation of anti-doping hair test results. Two scenarios were examined: (1) a single 10 mg oral dose administered to a male volunteer, with hair collected 4 weeks later; and (2) hair collected from an individual who had consumed 60 capsules of 10 mg ibutamoren over 90 days, also sampled 4 weeks after discontinuation. Researchers developed a liquid/liquid extraction method using bicalutamide-D4 as an internal standard, with a validated linear range of 0.5–250 pg/mg and a limit of detection of 0.1 pg/mg. The study found that a single 10 mg dose produced a positive hair result at 1.3 pg/mg in the 0–1 cm segment, while the prolonged-use scenario yielded 224 pg/mg in the 0–4 cm segment. The authors conclude that these findings establish, for the first time, ibutamoren's incorporation into human hair and provide reference concentration ranges to support interpretation of hair test results in anti-doping proceedings. Key limitations include the very small sample size (essentially two subjects) and the non-controlled nature of the second case.
Clinica chimica acta; international journal of clinical chemistry · Aug 2025DOI ↗ Review
This review examines the evolving pharmacological landscape for obesity management, with a focus on gut-brain axis hormones and their therapeutic potential. The authors describe how nutrient-stimulated gastroenteropancreatic hormones — including GLP-1, GIP, glucagon, and amylin — have become central targets in obesity drug development. The review covers both marketed agents and those in ongoing clinical trials. GLP-1 receptor agonists (e.g., weekly injectable or daily oral semaglutide) are reported to achieve roughly 15–17% weight loss with a favorable safety profile. The dual GLP-1/GIP agonist tirzepatide is described as achieving up to approximately 22.5% weight loss at higher doses. Combination therapies under investigation — such as cagrilintide plus semaglutide (Cagrisema), GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GLP-1/GIP/glucagon) — are noted as potentially reaching weight loss comparable to bariatric surgery. The review also discusses cardiometabolic benefits and challenges around long-term treatment adherence for both patients and clinicians. As a narrative review, it synthesizes existing trial data rather than generating new primary evidence, and conclusions depend on the quality of the underlying studies cited.
Medicina clinica · Aug 2025DOI ↗