Limited · human
This real-world observational study examined weight trajectories in 4,182 patients during the 6 months following their last documented semaglutide or tirzepatide prescription, drawn from a federated health network. The study found that approximately two-thirds of the full cohort showed stable weight or continued weight loss after their final prescription. In a representative subset of 300 patients whose clinical notes were analyzed using a large language model (LLM), treatment discontinuation was confirmed in 119 patients (40%), and of those, 72% did not demonstrate weight regain. The study also noted that exercise counseling was documented more frequently among patients who maintained weight loss compared to those who experienced weight regain (26.2% vs. 14.7%; P = .04). Key limitations include the observational and retrospective design, reliance on documented prescriptions rather than confirmed medication use, potential incompleteness of clinical records, use of an LLM for data curation introducing possible inaccuracies, and the inability to establish causation. The authors acknowledge that further studies are needed to understand the mechanisms behind these real-world patterns of weight maintenance after GLP-1 receptor agonist discontinuation.
Biology methods & protocols · Apr 2026DOI ↗ Limited · human
This cross-sectional study investigated the relationship between serum levels of MOTS-c — a mitochondria-derived peptide encoded in the 12S rRNA — and myocardial ischemia-reperfusion injury (MIRI) in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). Seventy-two AMI patients were divided into MIRI (n=34) and non-MIRI (n=38) groups. The study measured MOTS-c concentrations in both peripheral serum and intracoronary blood, alongside clinical variables. The MIRI group displayed lower systolic blood pressure, lower pre-operative TIMI grade, and lower HDL-C, while showing higher total ischemic time, door-to-balloon time, culprit vessel stenosis severity, Killip grade, and adverse event rates. Multivariate logistic regression identified postoperative peripheral serum MOTS-c as an independent protective factor against MIRI, and ROC analysis suggested potential predictive value for MIRI. Limitations include the small sample size, single-center cross-sectional design, lack of causal inference, and the absence of dynamic longitudinal monitoring of MOTS-c. The authors conclude that MOTS-c warrants further investigation as a novel biomarker and potential therapeutic target for MIRI, pending validation in larger prospective studies.
Biomedicines · Apr 2026DOI ↗ Animal only
This study examined how combination antiretroviral therapy (cART) interacts with calorie-dense diets to affect heart function in a rat model. One hundred and twenty weanling Sprague Dawley rats were assigned to one of three diets (normal chow, calorie-dense low-protein, or calorie-dense normal-protein) for 15 weeks, then subdivided into four treatment groups for an additional 9 weeks: saline control, dolutegravir (DTG) plus tesamorelin, DTG alone, or a classical cART regimen. At week 24, electrocardiographic (ECG) recordings and myocardial tissue analysis were performed. The study found statistically significant differences across groups in multiple ECG parameters, including Q, R, S, and T wave amplitudes, PR interval, QRS duration, ST height, and corrected QT interval. Myocardial fibrosis was notably observed in animals receiving DTG alone or classical cART while on calorie-dense diets. The authors suggest these structural changes may disrupt electrical conduction and predispose to arrhythmias. Notably, tesamorelin appeared to attenuate these cardiac effects, leading the authors to implicate growth hormone pathway dysfunction in the pathology. Key limitations include the exclusive use of an animal model, meaning findings may not directly translate to humans.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas · Apr 2026DOI ↗ Review
This systematic review (PRISMA-compliant, PROSPERO-registered) examined the association between GLP-1 receptor agonists (GLP-1 RAs) and hair loss by searching four major databases (PubMed, Embase, Scopus, Web of Science). Of 133 studies identified, 24 met inclusion criteria as primary articles. The review found that semaglutide and tirzepatide showed the highest reported incidence of hair loss and the strongest pharmacovigilance signals among GLP-1 RAs. The predominant subtypes reported were androgenetic alopecia and telogen effluvium, with telogen effluvium most frequently linked to tirzepatide—the agent associated with the greatest magnitude of weight loss. The authors noted that hair loss with semaglutide appeared dose-dependent, and that females were disproportionately affected. Rapid weight loss was identified as a potential contributing mechanism, especially for telogen effluvium. Other agents—liraglutide, dulaglutide, lixisenatide, and exenatide—had fewer studies and generally lower reported risk. Key limitations include the reliance on pharmacovigilance data and heterogeneous study designs, which preclude definitive causal conclusions. The authors call for large, prospective randomized trials to establish causality and temporal relationships.
Science progress · Apr 2026DOI ↗ In vitro
This computational study introduces the concept of "carbonless" biomolecular design, in which all carbon atoms in amino acids and peptides are systematically replaced by boron and nitrogen atoms under an isoelectronicity constraint. Using glycine, histidine, lysine, and the copper-binding tripeptide Gly-His-Lys (GHK) as model systems, the researchers applied density functional theory (DFT) calculations with aqueous solvation modeling and conformer sampling to identify the most stable carbonless analogues (cGly, cHis, cLys, and cGHK) among all possible boron-nitrogen constitutional isomers. The study predicted that cGHK displays a broader conformational landscape than native GHK under physiological aqueous conditions, suggesting enhanced structural flexibility. Copper(II) binding was modeled using an experimentally informed coordination motif, and thermodynamic calculations indicated that cGHK binds Cu(II) more favorably than GHK by approximately 6.24 kcal/mol. The work is entirely theoretical; no synthesis, cell-based, animal, or human experiments were conducted. Limitations include the absence of experimental validation of the proposed carbonless structures, reliance on computational approximations for solvation and conformational sampling, and uncertainty about whether these novel BN-substituted molecules could be synthesized or would exhibit biological stability.
Physical chemistry chemical physics : PCCP · Apr 2026DOI ↗ InsufficientPreprint
This narrative review examines the pharmacogenomics of GLP-1 receptor agonists — principally semaglutide (Ozempic®/Wegovy®) and the dual GIP/GLP-1 agonist tirzepatide (Mounjaro®/Zepbound®) — with a focus on explaining the wide inter-individual variability in efficacy and tolerability observed in clinical practice. The authors synthesise evidence around key genetic loci, including GLP1R, GIPR, ARRB1, TCF7L2, and MC4R, and highlight a purported April 2026 genome-wide association study (GWAS) conducted by 23andMe (n=27,885) as the largest pharmacogenomic study of GLP-1 therapies to date. The review also surveys the competitive landscape among Novo Nordisk, Eli Lilly, 23andMe Research Institute, and PGxAI, and dedicates substantial attention to South Asian and Indian populations, arguing that their large diabetes burden and undercharacterised pharmacogenomic profiles represent a critical gap. The authors conclude that GLP-1 pharmacogenomics has advanced from exploratory science toward actionable clinical discovery. Limitations include the narrative (non-systematic) design, reliance on a preprint-stage GWAS of uncertain peer-review status, and the absence of prospective clinical validation data for genotype-guided prescribing.
Unknown journal · Apr 2026DOI ↗ Review
This review examines the current clinical development pipeline for metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, MASH (metabolic dysfunction-associated steatohepatitis), with a particular focus on cardiovascular comorbidities. The authors highlight the strong bidirectional relationship between MASLD and cardiometabolic risk, arguing that effective treatments should address both hepatic and cardiovascular outcomes simultaneously. The review surveys a broad range of drug candidates and mechanisms, including incretin mimetics (e.g., semaglutide), thyroid hormone receptor-beta agonists (e.g., resmetirom), farnesoid X receptor agonists, PPAR agonists, de novo lipogenesis inhibitors, and fibroblast growth factor analogues. The authors note that the two FDA-approved therapies — resmetirom and semaglutide — have demonstrated reductions in major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality in MASH patients, with semaglutide also showing benefit in heart failure with preserved ejection fraction. However, the review emphasizes that cardiovascular outcome data for most other pipeline agents remain limited or absent. A key limitation is that this is a narrative review and does not involve primary data collection or meta-analytic methods.
Biomedicines · Apr 2026DOI ↗ Animal only
This study investigated the anti-inflammatory and antioxidant properties of the bioactive tripeptide complex GHK-Cu (Glycyl-L-histidyl-L-lysine-Cu²⁺) using zebrafish larvae as an in vivo model. Researchers induced acute inflammation in larvae using either copper sulfate (CuSO₄) or lipopolysaccharide (LPS) and then assessed the effects of GHK-Cu treatment. According to the study, GHK-Cu notably reduced the migration of neutrophils and macrophages to sites of inflammation. It also suppressed the gene expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) while upregulating the anti-inflammatory cytokine IL-10. The compound was further reported to reduce markers of oxidative stress, including nitric oxide (NO) and reactive oxygen species (ROS), and to improve superoxide dismutase (SOD) activity. Pathway analysis suggested that GHK-Cu's effects may be mediated in part through downregulation of the JAK1 signaling pathway. The authors propose that these findings provide a theoretical basis for the use of GHK-Cu as a functional cosmetic ingredient. Key limitations include the use of a non-mammalian animal model and the absence of human or cell-culture mechanistic data, meaning clinical translation remains unestablished.
European journal of pharmacology · Apr 2026DOI ↗ Limited · human
This review-style report examines the transfer of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, into human breastmilk following subcutaneous administration. The paper notes that tirzepatide is generally undetectable in breastmilk at doses up to 5 mg, suggesting minimal maternal-to-infant transfer via lactation. The authors further reason that even if trace amounts were present, oral absorption by a nursing infant would likely be negligible, as the peptide is expected to undergo partial degradation in the infant's gastrointestinal tract and exhibits poor oral bioavailability. Based on these considerations, the paper concludes that maternal use of tirzepatide need not be an automatic reason to discontinue breastfeeding, while still recommending caution — particularly in the context of newborns or preterm infants, whose gastrointestinal and metabolic systems may differ from those of older infants. The report acknowledges that available data remain limited and calls for additional research before stronger conclusions can be drawn. Key limitations include the small body of evidence underpinning these conclusions and the absence of robust clinical trial data in lactating populations.
Unknown journal · Apr 2026Source ↗ Review
This systematic review, conducted according to PRISMA 2020 guidelines, synthesized evidence from 15 studies evaluating GLP-1 receptor agonist and dual incretin-based pharmacotherapies for obesity management, including semaglutide, liraglutide, tirzepatide, dulaglutide, and dual GIP/GLP-1 receptor agonists. Study participants were predominantly female (up to 79.3%), ranging in mean age from 22.4 to 59.8 years, with BMIs between 29.3 and 43.0 kg/m², and frequent comorbidities such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease. The review found that weight loss was dose-dependent across agents, with dual GIP/GLP-1 therapy showing the greatest reductions. Cardiometabolic outcomes included reductions in HbA1c, systolic blood pressure, and LDL cholesterol across therapies. Gastrointestinal adverse events — particularly nausea, vomiting, and diarrhea — were commonly reported but generally mild, while serious events such as pancreatitis and gallbladder complications were rare. Treatment discontinuation rates were described as generally low. Limitations include the heterogeneity of included studies, variability in populations, and the review's reliance on previously published trial data rather than original participant-level analysis.
Disease-a-month : DM · Apr 2026DOI ↗ Review
This review paper examines the emerging evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) — specifically liraglutide, semaglutide, and tirzepatide — as potential interventions in prediabetes. The authors synthesize findings showing that GLP-1RAs were associated with reduced progression to type 2 diabetes mellitus (T2DM), with normoglycaemia achieved in a notable proportion of subjects (up to 66%, 81%, and 93.3% for liraglutide, semaglutide, and tirzepatide, respectively). However, these glycaemic benefits were only partially maintained after drug discontinuation. The review also highlights modest reductions in HbA1c, fasting glucose, body weight, and fat mass, alongside improvements in insulin sensitivity and β-cell function. Potential cardiovascular benefits — including reduced risk of atherosclerotic cardiovascular disease and heart failure — were noted, particularly with tirzepatide. Experimental data suggested possible benefits for metabolic dysfunction-associated steatotic liver disease (MASLD). The safety profile was described as acceptable, with mild-to-moderate gastrointestinal effects being the most commonly reported adverse events. The authors acknowledge that the current evidence base is limited and call for large, well-designed randomised controlled trials to define the precise role of GLP-1RAs in prediabetes management.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Apr 2026DOI ↗ Animal only
This preclinical study investigated whether obesity could be reversed without activating the GLP-1 receptor (GLP-1R), which is commonly associated with adverse gastrointestinal side effects in current therapies. Using diet-induced obese (DIO) mice and rats, as well as GLP-1R knock-out (KO) mice, researchers tested selective, dual, and triple agonists targeting the GIP receptor (GIPR), glucagon receptor (GCGR), and GLP-1R in various combinations. Three independent experimental approaches — (1) administering the triagonist retatrutide to GLP-1R KO mice, (2) physically combining separate selective GIPR and GCGR agonists, and (3) testing a novel unimolecular GIPR:GCGR co-agonist called BWB3054 — all demonstrated meaningful reductions in body weight and improvements in blood glucose without meaningful GLP-1R engagement. BWB3054 showed potency at the mouse GIPR comparable to retatrutide, 4-fold reduced potency at the mouse GCGR, and more than 100-fold reduced potency at the mouse GLP-1R. Indirect calorimetry and pair-feeding studies were used to characterize mechanisms of weight loss. A key limitation is that all experiments were conducted in rodents, leaving the translatability of these findings to humans uncertain. The study raises the possibility that GLP-1R-independent obesity treatment strategies could avoid the GI tolerability issues seen with current agents.
Molecular metabolism · Apr 2026DOI ↗ Animal onlyPreprint
This mouse study investigated whether the endogenous copper-binding peptide GHK-Cu could improve age-related cognitive decline, and whether outcomes differed based on how the compound was delivered. Aged C57BL/6J mice (20–21 months old) received GHK-Cu either intraperitoneally (IP) for 5 days or intranasally (IN) for 8 weeks. Researchers assessed hippocampal-dependent spatial learning, along with hippocampal tissue markers and bulk RNA sequencing. Both delivery routes were associated with improvements in escape learning, though IN administration showed broader and more sustained benefits across both sexes, while IP dosing produced a more limited effect, primarily in males. Immunohistochemistry revealed route-dependent changes in markers of synaptic density (synaptophysin), neuroinflammation (GFAP, MCP-1, TGF-β), and cellular senescence (p21). Transcriptomic analysis showed striking divergence: IN treatment was associated with suppression of oxidative phosphorylation and MYC target pathways, while IP treatment activated stress-response, DNA repair, and mitochondrial metabolic pathways. The authors conclude that GHK-Cu can improve cognitive outcomes through mechanistically distinct biological programs depending on the route and duration of administration. Key limitations include use of a single rodent strain, lack of human data, and preprint status (not yet peer-reviewed).
Unknown journal · Apr 2026DOI ↗ In vitro
This study investigated the catalytic properties of GHK-Cu (a copper-bound tripeptide composed of glycine, histidine, and lysine) as a mimic of the enzyme laccase, which is naturally used in the detection and degradation of phenolic compounds. Researchers characterized GHK-Cu's enzyme-like kinetics, finding a maximum reaction velocity (Vmax) of 1.735 × 10⁻⁴ mM·s⁻¹ and a Michaelis constant (Km) of 0.061 mM, suggesting strong substrate affinity and catalytic efficiency compared to natural laccase. Building on this, the team developed colorimetric assays to detect two phenolic compounds—epinephrine (EP) and 2-aminophenol (2-AP)—across defined concentration ranges in ultrapure water and seawater. Additionally, a portable cotton-based sensor paired with a smartphone platform was constructed to enable field-ready detection of 2-AP in seawater. The study is conducted entirely in vitro and focuses on analytical chemistry applications rather than biological or therapeutic effects of GHK-Cu. Key limitations include the absence of any cell-based, animal, or human testing; findings are restricted to a controlled laboratory sensing context. The work proposes GHK-Cu's copper-coordination structure as a template for designing novel synthetic laccase mimetics.
Biosensors · Apr 2026DOI ↗ Review
This narrative review examines the pharmacological mechanisms, safety profiles, and regulatory status of twelve peptides commonly marketed in sports medicine contexts, spanning both FDA-approved compounds (e.g., tesamorelin/Egrifta) and unapproved "gray market" substances (e.g., BPC-157, CJC-1295, TB-500, ipamorelin, and others). The authors note that while many unapproved peptides show promising tissue repair and metabolic effects in animal models, rigorous human safety and efficacy data are largely absent. The review highlights a growing direct-to-consumer gray market operating outside regulatory oversight and discusses the potential for serious patient harm. Notably, the authors address the placebo effect as a possible mediator of perceived peptide efficacy and examine how social media may amplify this effect. A clinician-oriented framework is proposed to guide evidence-based patient discussions about peptide use for musculoskeletal healing and athletic performance, including consideration of alternative treatments. Key limitations include the narrative (non-systematic) review methodology and the inherently limited and heterogeneous evidence base for most compounds discussed, particularly in human populations.
Sports medicine (Auckland, N.Z.) · Apr 2026DOI ↗ Limited · human
This multicenter retrospective cohort study used the TriNetX database to examine whether preoperative exposure to GLP-1 receptor agonists (GLP-1 RAs) was associated with postoperative GLP-1 RA use following metabolic bariatric surgery (MBS). Researchers identified adults who underwent MBS and applied 1:1 propensity score matching to compare those with and without preoperative GLP-1 RA exposure (n = 2,811 per group). The study found that patients with prior GLP-1 RA exposure had more than twice the rate of postoperative GLP-1 RA initiation (15.3% vs. 7.6%; HR: 2.14, 95% CI: 1.81–2.52). The exposure group also showed a modestly higher prevalence of suboptimal weight control post-surgery (HR: 1.18), though rates of suboptimal glycemic control, hospitalization, and emergency department visits did not differ significantly between groups. These patterns were consistent across surgical subtypes and age groups. The authors interpret the findings as identifying a distinct patient phenotype with greater treatment complexity rather than a direct causal relationship. Key limitations include the retrospective design, reliance on a claims-based database, and potential residual confounding despite propensity score matching.
Obesity surgery · Apr 2026DOI ↗ Limited · human
This systematic review examined the effects of GLP-1 receptor agonists (GLP-1 RAs) on patients with hidradenitis suppurativa (HS), a chronic, painful inflammatory skin condition often associated with obesity and metabolic syndrome. Researchers searched Embase and PubMed, screening 300 papers and ultimately including 10 studies in the final analysis. The review found that HS patients using GLP-1 RAs tended to experience improvements in clinical course, including reductions in pain and suppuration, as well as improvements in quality of life and mental health. Cardiovascular risk markers also appeared to improve. Notably, inflammatory laboratory parameters did not show statistically significant changes. Higher drug doses were more frequently associated with clinical improvement, while reductions in weight or BMI did not consistently correlate with improvements in Hurley staging, pain, or depression scores. The authors suggest this raises the possibility that GLP-1 RAs may act through direct anti-inflammatory mechanisms beyond weight loss alone, though they acknowledge this remains unresolved. Key limitations include the small number of included studies (10), likely heterogeneous study designs across the included papers, and the inability to establish causality or rule out confounding. The authors call for further dedicated studies to clarify the mechanism of benefit.
Journal of clinical medicine · Apr 2026DOI ↗ Strong · human
This network meta-analysis pooled data from 11 randomized controlled trials (n = 83,215) to compare the cardiovascular (CV) efficacy and safety of GLP-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes and established cardiovascular disease or high CV risk. Trials were identified through a systematic search of five major databases up to December 2025. Using a frequentist random-effects framework, the authors found that several GLP-1RAs — including subcutaneous semaglutide, efpeglenatide, albiglutide, tirzepatide, oral semaglutide, liraglutide, and dulaglutide — significantly reduced three-point major adverse cardiovascular events (MACE) compared with placebo, with no detected heterogeneity or inconsistency. Subcutaneous semaglutide, efpeglenatide, and albiglutide ranked highest by P-score. No agent significantly reduced all-cause or CV mortality versus placebo. Tirzepatide and dulaglutide were associated with reduced stroke risk. Tolerability signals showed higher rates of discontinuation due to gastrointestinal adverse events with subcutaneous semaglutide, oral semaglutide, lixisenatide, and ITCA 650. The authors concluded that MACE reduction is the most consistent efficacy signal across GLP-1RAs in this population. Limitations include the indirect nature of network comparisons and differing trial designs and populations across included studies.
Canadian journal of diabetes · Apr 2026DOI ↗ 🧪 TrialInsufficient
Registered N/A interventional trial (recruiting). This pilot study will evaluate the feasibility, acceptability, and perceived usefulness of the SWITCH mobile nutrition behavioral intervention among adults receiving GLP-1 receptor agonist therapy for obesity and/or type 2 diabetes. Participants will complete baseline assessments, receive a 6-week app-based nutrition intervention consisting of daily dietary self-monitoring and weekly learning modules, and complete follow-up assessments and a structured interview.
ClinicalTrials.gov · Apr 2026View trial ↗ Moderate · human
This large genome-wide association study (GWAS) investigated whether genetic variants explain why people respond differently to GLP-1 receptor agonists (GLP-1 RAs) such as semaglutide and tirzepatide. Researchers analyzed self-reported weight loss and side effects in 27,885 individuals on GLP-1 RA therapy. The study identified a missense variant in the GLP1R gene significantly associated with greater weight loss efficacy, with carriers of the effect allele losing an additional estimated 0.76 kg per copy. Separate genetic associations were found linking variants in both GLP1R and GIPR to nausea or vomiting during GLP-1 RA treatment; notably, the GIPR association appeared specific to tirzepatide users, consistent with tirzepatide's dual GLP-1/GIP receptor mechanism. The authors built a broader predictive model incorporating these findings, suggesting the potential to stratify patients by expected efficacy and side effect risk—a step toward precision medicine for obesity. Key limitations include reliance on self-reported outcomes, which may introduce recall and reporting bias, and the observational nature of the design, which limits causal inference beyond the genetic associations themselves.