Limited · human
This Phase 1 randomized, double-blind, placebo-controlled trial examined the safety and efficacy of mazdutide — a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist — at doses up to 16 mg in adults with overweight or obesity but without diabetes. Thirty-two participants received once-weekly subcutaneous injections of mazdutide (n=24, split across two dose-escalation cohorts) or placebo (n=8) for 20 weeks. The study found that both mazdutide cohorts experienced substantially greater mean percent reductions in body weight from baseline (approximately -20% and -21%, respectively) compared to the placebo group (approximately -0.1%), with statistically significant differences. The authors also reported improvements in metabolic markers and concluded that the 16 mg dose was well tolerated. Key limitations include the small sample size (particularly the placebo group of only 8 participants), the short 20-week duration, the Phase 1 design which is primarily safety-focused, and the absence of participants with diabetes, limiting generalizability. These findings suggest a dose-response relationship at higher doses than previously studied, but larger and longer trials are needed to confirm these results.
Diabetes, obesity & metabolism · Aug 2025DOI ↗ Preclinical
This study investigated whether thymosin beta 4 (Tβ4), encoded by the gene TMSB4X, plays a role in Alzheimer's disease (AD) pathology and could serve as a potential intervention target. Researchers generated cerebral organoids ("mini-brains") from induced pluripotent stem cells (iPSCs) carrying familial AD (fAD)-associated mutations in the amyloid precursor protein (APP) gene. Using these organoids, they characterized dynamic changes in cellular states and found that mature neuron formation was markedly reduced in fAD organoids compared to healthy controls, alongside increased cellular senescence and beta-amyloid (Aβ) production. Notably, TMSB4X/Tβ4 expression was significantly decreased both in fAD organoid neurons and in excitatory neurons from post-mortem AD patient brain data. Treatment with Tβ4 protein appeared to rescue neurodevelopmental deficits and reduce Aβ formation in the fAD organoids. Corroborating findings were also reported in 5xFAD transgenic mice. The study concludes that Tβ4 may act as a neuroprotective factor capable of mitigating altered neurogenesis and AD pathology. Key limitations include the use of organoid and animal models rather than human clinical data, and the inherent complexity of translating organoid findings to human disease.
Stem cell reports · Aug 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 2 interventional trial (recruiting). This study will explore the use of glucagon-like peptide 1 receptor agonist (GLP-1RA) used concurrently with levonorgestrel intrauterine device in patients with poor surgical candidacy for a hysterectomy or patients who are pursuing fertility sparing. GLP-1RA are a class of medications that mimic the natural hormone glucagon-like peptide-1. These medications trigger the pancreas to release insulin which can help lower blood sugar levels and delay gastric emptying. The recent FDA approval of GLP-1RAs has changed the landscape for pharmacothe
ClinicalTrials.gov · Aug 2025View trial ↗ Animal only
This study developed a biodegradable buccal suction patch designed to improve the systemic delivery of peptide therapeutics by bypassing gastrointestinal degradation. Researchers replaced previously used non-degradable silicone materials with thermally crosslinked, synthesized copolyesters, fabricated via a scalable mold-casting process. Mechanical testing across multiple polymer formulations and patch shapes identified the best-performing biodegradable candidate, and degradation was confirmed in both aqueous media and simulated waste environments. An ex vivo model using porcine buccal tissue demonstrated that the biodegradable patch, when combined with a chemical permeation enhancer, improved permeation of a poorly permeable dye compared to controls. In an in vivo study conducted in beagle dogs, the patch substantially improved the bioavailability of semaglutide (4.11 kDa) relative to a commercially available oral tablet over a 10-minute application window. Additionally, the patch achieved a relative bioavailability of approximately 26% for bremelanotide (1.03 kDa) compared to subcutaneous injection. Limitations include the use of an animal model (beagle dogs) rather than human subjects, a small experimental scale, and the need for further clinical translation studies. The work highlights a potential sustainable alternative to silicone-based buccal delivery devices.
Journal of Controlled Release · Aug 2025
Review
This editorial provides a narrative overview of the rapidly escalating global obesity crisis and the evolving landscape of pharmacological treatments, with a focus on GLP-1 receptor agonists such as oral semaglutide. Drawing on the World Obesity Atlas 2025, the authors highlight that the number of adults living with obesity is projected to more than double—from 524 million in 2010 to 1.13 billion by 2030. The editorial notes that the global market for weight-loss medications has been revised upward to $150 billion by 2035, reflecting explosive growth in demand. The authors discuss the FDA's acceptance of a new drug application for oral semaglutide, potentially the first oral agent approved for long-term weight management. Key concerns raised include the limited long-term and real-world safety and efficacy data for GLP-1 receptor agonists, challenges with treatment adherence, and the proliferation of unregulated compounded ("copycat") versions of these drugs that lack quality and safety evaluation. As an editorial, this piece synthesizes publicly available data and regulatory updates rather than presenting original research, and it does not conduct systematic literature searches or meta-analyses. Its conclusions are opinion-based and should be interpreted accordingly.
Medical science monitor : international medical journal of experimental and clinical research · Aug 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 ↗ Limited · human
This systematic review examined the existing literature on BPC-157 (Body Protection Compound-157), a naturally occurring gastric pentadecapeptide, specifically through the lens of orthopedic sports medicine. Researchers searched PubMed, Cochrane, and Embase for English-language studies published from database inception through June 2024. Of 544 identified articles, 36 met inclusion criteria — 35 preclinical studies and only 1 clinical study. Preclinical findings suggested BPC-157 may enhance growth hormone receptor expression, promote angiogenesis, stimulate cell growth pathways, and reduce inflammatory cytokines, with improved functional, structural, and biomechanical outcomes reported across muscle, tendon, ligament, and bone injury models. The sole clinical study was a retrospective case series in which 7 of 12 patients reported musculoskeletal pain relief lasting more than 6 months following intraarticular injection for chronic knee pain. The compound was found to be hepatically metabolized with a half-life under 30 minutes and renally cleared. Preclinical safety data showed no adverse effects across multiple organ systems; no clinical safety data were identified. The authors note that BPC-157 lacks FDA approval and is banned in professional sports, and caution about risks from unregulated manufacturing. The review is limited almost entirely to preclinical evidence, leaving significant gaps in human safety and efficacy data.
HSS journal : the musculoskeletal journal of Hospital for Special Surgery · Jul 2025DOI ↗ Review
This review examines the rationale and emerging clinical evidence for triple receptor agonist therapies targeting GLP-1, GIP, and glucagon receptors as next-generation treatments for obesity and type 2 diabetes (T2D). The authors focus primarily on retatrutide, the most clinically advanced triple agonist, which has completed Phase 2 trials. In people with obesity, retatrutide achieved up to 24.2% mean weight loss over 48 weeks; in people with T2D, it produced 16.9% mean weight loss over 36 weeks, alongside a 2.2% reduction in HbA1c and 82% of participants reaching HbA1c ≤ 6.5%. The review also highlights improvements in blood pressure, lipid profiles, waist circumference, and liver fat (82% reduction in hepatic steatosis). Gastrointestinal side effects were the most commonly reported adverse events, with no major safety signals identified in Phase 2. The authors also briefly discuss other unimolecular triple agonists and combination regimens in development. Key limitations include that this is a narrative review of Phase 2 data; Phase 3 confirmatory trials are still ongoing. Conclusions about long-term efficacy, safety, and cardiovascular/renal outcomes remain premature pending those results.
Current cardiovascular risk reports · Jul 2025DOI ↗ Preclinical
This study developed a novel injectable soft tissue filler by loading the GHK-Cu tripeptide (glycyl-L-histidyl-L-lysine copper complex) onto hydroxyapatite microspheres (HAPs), which were then combined with carboxymethyl cellulose, glycerol, and water to form a gel formulation called GHK-Cu@CMHA. The researchers report this is the first combination of HAPs and GHK-Cu designed to address implant-induced inflammation. The formulation demonstrated sustained GHK-Cu release over 7 days in laboratory testing, along with good flowability and injectability. Using a lipopolysaccharide (LPS)-induced inflammation model tested both in cell culture (in vitro) and in animals (in vivo), the study found that GHK-Cu@CMHA reduced levels of inflammatory cytokines and reactive oxygen species (ROS), while increasing superoxide dismutase (SOD) activity, suggesting antioxidant effects. Histological staining (H&E and Masson) indicated collagen deposition at treatment sites. Key limitations include the absence of human data, reliance on an LPS-induced inflammation model that may not fully replicate clinical filler complications, and no long-term safety or efficacy follow-up. These findings are preliminary and require further clinical validation before any conclusions about human benefit can be drawn.
Colloids and surfaces. B, Biointerfaces · Jul 2025DOI ↗ Animal only
This study investigated whether dietary supplementation with GHRP-6, a synthetic ghrelin analog peptide, could modulate endocrine and immune responses in gilthead seabream (Sparus aurata), a commercially important aquaculture species. Fish were fed diets containing GHRP-6 for 97 days and then challenged with Incomplete Freund's Adjuvant (IFA), an immune stimulant, via intraperitoneal injection. Samples were collected 72 hours post-injection. The study found that GHRP-6-fed fish maintained more stable plasma levels of lactate, triglycerides, and cortisol following IFA challenge compared to control fish, suggesting reduced metabolic stress. Circulating immunoglobulin levels were significantly elevated in the GHRP-6/IFA group, indicating enhanced humoral immunity. Transcriptomic analysis showed the anterior intestine was the most responsive tissue, with upregulation of immune-related genes including il10, il15, il34, and mx1. Spleen tissue showed increased expression of il8, il10, and ighm, suggesting a balanced inflammatory response. No histological damage was observed in the intestine or spleen. Limitations include the exclusive use of a single fish species, no mammalian or human data, a single GHRP-6 dietary concentration tested, and the authors themselves characterize results as "preliminary."
Review
This review article, published as part of a special issue on GLP-1 receptor agonists, examines the emerging class of glucagon receptor (GCGR)-based multi-agonist drugs as pharmacological treatments for obesity. The authors discuss several investigational agents — mazdutide, pemvidutide, survodutide, and retatrutide — all of which are in advanced stages of clinical development. According to the review, early-phase trial data for these agents suggest they can produce significant weight loss, potentially exceeding that seen with currently available therapies. The article also highlights their potential to address obesity-related comorbidities such as type 2 diabetes and cardiovascular disease, and notes that some agents are being evaluated in cardiovascular outcomes trials. The authors position GCGR-based multi-agonists as potentially important additions to future obesity treatment guidelines, particularly for patients who have not responded adequately to existing medications or lifestyle interventions. Key limitations and considerations noted include cost, access, and the need for long-term safety data as these drugs progress toward regulatory approval. As a narrative review, this article synthesizes existing trial data but does not generate new primary evidence.
Drugs in context · Jul 2025DOI ↗ In vitroPreprint
This study investigated whether Tβ4-17, a small bioactive peptide derived from thymosin β4 and identified via iTRAQ technology, could enhance the sensitivity of cisplatin (DDP)-resistant ovarian cancer cells to chemotherapy. Using in vitro models of DDP-resistant ovarian cancer cell lines, the researchers examined the effects of Tβ4-17 alone and in combination with DDP on cell proliferation, migration, and apoptosis. Multiple assays were employed, including CCK8 viability assays, EDU fluorescence proliferation assays, cell scratch (wound healing) assays, qRT-PCR, and Western blot. The study found that Tβ4-17 combined with DDP significantly inhibited proliferation and migration of resistant cells and promoted apoptosis compared to either agent alone. Mechanistically, the researchers reported that NF-κB p65 was highly expressed in DDP-resistant cells, and that Tβ4-17 down-regulated NF-κB p65 protein expression. Use of NF-κB inhibitors and activators further supported this proposed pathway. Key limitations include the exclusive use of cell-line models with no animal or human data, the preprint status of the work, and the absence of in vivo validation. Findings are preliminary and require further study.
Unknown journal · Jul 2025DOI ↗ Animal only
This preclinical study investigated whether three GLP-1-based receptor agonists — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP receptor agonist), and retatrutide (triple GIP/GLP-1/glucagon receptor agonist) — could alter the interoceptive (subjective-like) effects of alcohol in rats. Using an operant drug discrimination paradigm in both male and female rats, researchers trained animals to distinguish alcohol from vehicle, then tested whether these compounds disrupted that learned discrimination. The study found that acute administration of all three agents attenuated alcohol's discriminative stimulus effects, suggesting modulation of how alcohol "feels" internally. Repeated semaglutide treatment maintained this effect over a 15-day period, and the effect reversed within three days of cessation. The authors suggest these findings may help explain clinically observed reductions in alcohol craving and drinking in humans receiving GLP-1 receptor agonists. Limitations include the exclusive use of animal models, meaning direct translation to human subjective alcohol experience remains uncertain, and the study does not assess long-term outcomes or dependence-related endpoints.
Psychopharmacology · Jul 2025DOI ↗ Strong · human
This Bayesian network meta-analysis (NMA) synthesized evidence from 19 randomized controlled trials (RCTs) enrolling 29,506 adults with overweight or obesity (BMI ≥ 25 kg/m²) to compare the weight-loss efficacy and safety of GLP-1 receptor agonists (liraglutide, semaglutide), dual agonists (tirzepatide, survodutide), and the triple agonist retatrutide against placebo over at least 36 weeks. The study found that retatrutide and dual agonists achieved equivalent mean weight loss (approximately −11.0 kg), both outperforming GLP-1 receptor agonists (approximately −9.0 kg). Retatrutide showed the highest odds of achieving ≥15% weight loss (OR 54.6), followed by dual agonists (OR 16.4) and GLP-1 receptor agonists (OR 9.0). However, retatrutide was also associated with the highest adverse event risk. Meta-regression analyses indicated that type 2 diabetes mellitus attenuated weight loss across all drug classes, while female-dominant and higher-BMI cohorts showed enhanced outcomes. Limitations include indirect comparisons inherent to NMA methodology, heterogeneity across trials in baseline characteristics, and the fact that retatrutide data remain from earlier-phase trials. The authors recommend individualized treatment selection based on patient-specific factors.
Obesity (Silver Spring, Md.) · Jul 2025DOI ↗ Animal only
This controlled animal trial investigated the comparative effects of three butyrate-based dietary supplements — tributyrin with copper and essential oils (TB-500), di- and tri-butyrin (TB-300), and coated sodium butyrate (SB-500) — versus a control diet in 1,000 Arbor Acres broiler chicks across four treatment groups (250 birds each, six replicates). Over 35 days, researchers measured growth performance, carcass traits, serum biochemistry, immune markers, gene expression (mTOR, TLR4, NBN), intestinal histomorphometry, caecal microbiota, and litter hygiene. The study found that TB-300 was associated with improved body weight (+4.6%), feed conversion ratio (–5.2%), and European Production Efficiency Factor (+14.9%). SB-500 was linked to reduced litter Clostridia and aerobic bacterial counts. All butyrate treatments were associated with improved intestinal villus morphology, elevated serum total proteins and digestive enzymes (lipase and protease), and upregulated TLR4 gene expression. TB-300 and SB-500 were associated with reduced serum lipids, urea, and AST, alongside enhanced mTOR and NBN gene expression. Limitations include that the study was conducted exclusively in broiler chickens, findings are not directly translatable to humans, and it did not include a blinded assessment of outcomes.
Scientific reports · Jul 2025DOI ↗ Review
This narrative review examines how rapidly advancing obesity pharmacotherapies — particularly GLP-1 receptor agonists, dual and triple incretin agonists, and amylin-based combination therapies — are challenging the longstanding criteria used to determine eligibility for bariatric surgery. The authors note that current surgical guidelines were established when effective medical alternatives were limited, and argue that newer agents achieving 15–25% body weight reduction now approach outcomes historically associated only with surgery. The review compares surgical and pharmacologic interventions across dimensions of efficacy, safety, metabolic benefit, and cost-effectiveness, and considers whether a stepwise, pharmacotherapy-first approach may be appropriate — particularly for individuals with a BMI of 30–40 kg/m². The authors also discuss potential roles for pharmacotherapy in perioperative care and long-term obesity management, and call for personalized treatment strategies. As a narrative review, the paper does not conduct a systematic search or meta-analysis, which limits its ability to make definitive comparative claims. It reflects the authors' interpretive synthesis of existing literature rather than new primary data, and is subject to selection bias inherent to the narrative format.
Medicina (Kaunas, Lithuania) · Jul 2025DOI ↗ Limited · human
This paper presents a case report of a man in his early 30s who developed transaminitis (elevated liver enzymes) after taking MK-677, an oral growth hormone secretagogue, for approximately two months. MK-677 has been growing in popularity as a performance-enhancing supplement. The patient was otherwise healthy, with no other apparent causes for liver injury identified. Following discontinuation of the supplement, liver function tests gradually returned to normal levels, suggesting a causal relationship between MK-677 use and the hepatotoxic event. The authors highlight that while known side effects of MK-677 include oedema, increased appetite, and muscle pain, reports of hepatotoxicity associated with its use are rare. This case adds to the limited literature on potential adverse hepatic effects of MK-677. Key limitations include the single-patient design, lack of a liver biopsy or formal causality assessment score (e.g., RUCAM), inability to fully exclude confounders such as contaminants in the supplement, and the inherent difficulty in establishing definitive causality from a single case report.
BMJ case reports · Jul 2025DOI ↗ 🧪 TrialInsufficient
Registered observational trial (enrolling by invitation). This observational study will explore how Wegovy® (Semaglutide) is used in everyday situations, how it might affect things like weight, body mass index (BMI) and waist circumference, and what kind of impact it could have on overall quality of life. The overall purpose of this study is to understand how Wegovy impacts weight when used as part of regular medical care. Participants will be treated with Wegovy as prescribed to the participant by their doctor, in accordance with normal clinical practice. The study will last for about two yea
ClinicalTrials.gov · Jul 2025View trial ↗ Animal only
This study investigated the mechanisms underlying weight loss produced by CagriSema — a combination of cagrilintide (an amylin analogue) and semaglutide (a GLP-1 analogue) — in a rat model. Researchers quantified the contributions of reduced energy intake versus preserved energy expenditure to overall weight loss. Rats treated with CagriSema achieved approximately 12% body weight loss alongside a 39% reduction in food intake. To isolate the role of energy intake, the authors used two comparison conditions: pair-feeding (matching food intake to CagriSema-treated animals) and weight matching (determining how much food restriction alone would be needed to achieve equivalent weight loss, which required a 51% reduction in intake). The gap between these conditions suggested that roughly one-third of CagriSema's weight loss effect was attributable to blunting of metabolic adaptation — the phenomenon where the body typically reduces energy expenditure in response to caloric restriction. Limitations include that findings are from an animal model and may not directly translate to humans, and the study does not address long-term outcomes. The authors conclude that CagriSema's dual action on both energy intake and expenditure may contribute to its potential effectiveness as an obesity treatment.
Nature metabolism · Jul 2025DOI ↗ Moderate · human
This multicentre retrospective observational study used TriNetX, a global healthcare data platform, to examine real-world associations between semaglutide use and survival outcomes in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD). Researchers identified over 1.1 million eligible patients, of whom 14,511 initiated semaglutide and 69,700 initiated sitagliptin between 2018 and 2020. After propensity score matching to balance baseline characteristics, 13,703 patients were included in each group. The study found that the semaglutide group had a significantly lower 3-year incidence of all-cause death (7.2% vs. 9.5%) compared with the sitagliptin group. Secondary outcomes including acute heart failure, acute myocardial infarction, and stroke also favored semaglutide. The authors note these findings are consistent with the randomized FLOW trial. Key limitations include the retrospective, non-randomized design, potential for residual confounding despite propensity score matching, reliance on administrative coding data, and the inability to account for medication adherence or dosing details. Findings should be interpreted as associative, not causal.
Open heart · Jul 2025DOI ↗