Limited · humanPreprint
This large pharmacovigilance study analyzed 20.3 million FDA FAERS adverse event reports (2004–2024) to investigate impaired gastric emptying (IGE) as a potential class-wide adverse effect of GLP-1 receptor agonists (GLP-1 RAs). Researchers identified 6,868 IGE reports across nine GLP-1 RA agents and applied the proportional reporting ratio (PRR) method with sensitivity analyses, supplemented by cross-national validation using 29 reports from Brazil's pharmacovigilance database. The study found that all nine agents exceeded established Evans signal detection criteria, with PRRs ranging from 4.4 (exenatide) to 83.9 (injectable semaglutide). Notably, oral and injectable semaglutide showed comparable PRRs, suggesting a systemic rather than route-dependent mechanism. Tirzepatide prescribed for type 2 diabetes showed a substantially higher PRR than the same drug prescribed for obesity, which the authors interpret as a possible effect of diabetic autonomic neuropathy. A pre-litigation signal analysis was also conducted to account for potential notoriety bias. Key limitations include the inherent constraints of spontaneous pharmacovigilance data—including reporting bias, lack of denominator data, and inability to establish causation—as well as the small cross-national validation sample (n=29). The authors conclude that findings support pre-treatment risk stratification discussions for gastroparesis in GLP-1 RA candidates.
Unknown journal · May 2026DOI ↗ Limited · humanPreprint
This large pharmacovigilance study extracted 412,643 adverse event reports for five GLP-1 receptor agonists (semaglutide, tirzepatide, liraglutide, dulaglutide, and exenatide) from the FDA Adverse Event Reporting System (FAERS) spanning 2004–2024, comparing disproportionality signals using proportional reporting ratios (PRR) and reporting odds ratios (ROR). The study identified 154 drug-event signals overall. The most notable finding was a strong gastroparesis signal for semaglutide (PRR 88.9, 95% CI 85.4–92.6), which the authors describe as substantially higher than prior published estimates and as robust across three pre-specified sensitivity analyses using different comparator groups. All five agents showed statistically significant gastroparesis signals. Gastroparesis reports were consistently female-predominant across all agents (female-to-male ratio 2.7–3.6×). Tirzepatide's adverse event profile was notably dominated by device-usability reports rather than clinical events. Case-fatality rates varied across agents (0.6% to 3.7%). Key limitations include inherent FAERS biases (underreporting, stimulated reporting, lack of denominator data, and confounding by indication), which preclude causal inference or incidence estimation. The authors acknowledge the preprint status of this work.
Unknown journal · May 2026DOI ↗ Limited · human
This cross-sectional study investigated circulating levels of MOTS-c — a mitochondria-derived peptide involved in metabolic and immune regulation — in patients with Hashimoto's thyroiditis (HT) compared to healthy controls. A total of 180 participants (90 HT patients and 90 age- and sex-matched healthy controls) were enrolled. The study found that circulating MOTS-c levels were significantly lower in HT patients than in controls. Lower MOTS-c levels were independently associated with insulin resistance and markers of autoimmune burden (such as thyroid autoantibodies). The authors propose that impaired mitochondrial signaling, as reflected by reduced MOTS-c, may contribute to the pathophysiology of thyroid autoimmunity and metabolic dysregulation seen in HT. The study's cross-sectional design limits causal inference — it is unclear whether reduced MOTS-c is a cause or consequence of HT. Additional limitations include the single-timepoint measurement, potential confounders not fully addressed, and the absence of longitudinal follow-up. The findings position MOTS-c as a candidate biomarker linking metabolic dysfunction and immune dysregulation in thyroid autoimmunity, though further prospective and mechanistic research is needed to confirm this relationship.
Journal of clinical medicine · May 2026DOI ↗ Limited · human
This pharmacovigilance study investigated reports of dysesthesia (abnormal skin sensations, particularly burning sensations) associated with GLP-1 receptor agonists, including semaglutide, tirzepatide, exenatide, and others. The researchers conducted a disproportionality analysis using VigiBase — the WHO's global drug safety database — focusing on the High Level Term "Paraesthesia and dysesthesia," supplemented by a qualitative review of case narratives from the French Pharmacovigilance database and a broader literature review. The analysis found that exenatide was significantly associated with hypoesthesia and oral paraesthesia, while semaglutide and tirzepatide were associated with hyperaesthesia; semaglutide was also linked to dysesthesia and burning sensations specifically. The study suggests dysesthesia may be dose-dependent and more frequent with more potent agents used at higher doses. Many reported cases involved drug discontinuation followed by spontaneous resolution, and some rechallenge cases were documented. Key limitations include the inherent biases of spontaneous reporting systems (underreporting, confounding, notoriety bias), the inability to establish causality, and the absence of controlled comparison groups. The authors conclude that pharmacovigilance data reinforces signals already observed in clinical trials of semaglutide, tirzepatide, and retatrutide.
European journal of clinical pharmacology · May 2026DOI ↗ Limited · human
This observational cohort study measured serum levels of two circulating peptides — Nardilysin (NRDc) and MOTS-c — in 150 participants (118 kidney transplant recipients [KTRs] and 32 age-matched controls) to explore their potential roles as cardiometabolic biomarkers in this high-risk population. Using commercial ELISA kits, the researchers found that median serum NRDc and MOTS-c levels were significantly higher in KTRs compared to controls. Penalized logistic regression revealed an inverse association between elevated NRDc levels and prevalent cardiovascular (CV) disease in KTRs, suggesting that higher NRDc may be associated with lower odds of existing CV disease. KTRs were followed for a median of approximately 29 months, during which renal allograft loss and all-cause mortality were analyzed using Fine-Gray competing risk regression. The authors propose that elevated NRDc and MOTS-c in KTRs may reflect altered metabolic and inflammatory pathways unique to this population. Key limitations include the observational design, the relatively small and single-center cohort, the cross-sectional nature of the CV disease association, and the lack of incident CV event data. The authors acknowledge that longitudinal studies are needed to clarify causal relationships.
Kidney & blood pressure research · May 2026DOI ↗ Limited · human
This single-arm pragmatic trial examined psychosocial outcomes in 180 adults with obesity (mean age 44.1 years; 91% female; 81% white; mean weight 102.6 kg) enrolled in a telemedicine program (WeightWatchers Clinic) who received semaglutide or tirzepatide alongside an adjunctive virtual behavioral intervention tailored for patients on long-acting incretin therapy. Psychosocial measures—including depression (PHQ-8), perceived stress (Perceived Stress Scale), well-being (WHO-5), weight bias internalization (WBIS-2F), and weight-related quality of life (IWQOL-Lite)—were collected at baseline, 12 weeks, and 24 weeks. Wilcoxon signed-rank tests with False Discovery Rate correction were used; an intent-to-treat analysis using last observation carried forward (LOCF) was also performed. The study found statistically significant improvements from baseline to 24 weeks across all five psychosocial outcomes. Key limitations include the absence of a control group, a predominantly white and female sample limiting generalizability, and the inability to separate medication effects from behavioral intervention effects. The findings suggest an association between the combined telehealth and behavioral approach and improved psychosocial outcomes, but causality cannot be established.
Obesity science & practice · May 2026DOI ↗ Limited · human
This retrospective pharmacovigilance study analyzed the FDA Adverse Event Reporting System (FAERS) from Q1 2004 through Q2 2025 to identify risk factors for drug-related impaired gastric emptying (IGE), a recognized contributor to perioperative pulmonary aspiration risk. Researchers identified 731 drugs associated with IGE reports. Among the most frequently reported were antidiabetic agents, particularly five GLP-1 receptor agonists (GLP-1RAs): semaglutide, dulaglutide, tirzepatide, exenatide, and liraglutide. The study employed disproportionality analysis, logistic regression, LASSO regression, and time-to-onset analysis to characterize these associations. Multi-factor analysis identified female sex and younger age as patient-level risk factors for drug-related IGE. Key limitations include the inherent biases of spontaneous adverse event reporting (underreporting, confounding by indication, lack of denominator data), the inability to establish causality, and incomplete clinical information in FAERS records. The authors suggest findings may help clinicians identify patients at elevated risk for drug-related IGE and inform perioperative fasting and anesthetic planning, particularly given the growing clinical use of GLP-1RAs.
Frontiers in pharmacology · May 2026DOI ↗ Limited · human
This review evaluated the potential role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in managing lipedema, a chronic disorder marked by disproportionate subcutaneous fat accumulation, pain, inflammation, and fibrosis, for which liposuction remains the primary treatment. Authors searched PubMed through March 2026 using terms related to lipedema, GLP-1 RAs, tirzepatide, inflammation, and insulin resistance. Of 13 publications identified, only two specifically examined GLP-1 RAs in lipedema, and just one provided direct patient-level evidence: a small uncontrolled case series of 5 patients treated with exenatide that reported improvements in pain and limb volume. Additional translational evidence suggested GLP-1 RAs, particularly tirzepatide, may influence inflammatory and fibrotic pathways relevant to lipedema. The authors concluded that GLP-1 RAs have not been proven to directly affect lipedema progression, but may offer adjunctive benefit through weight reduction and metabolic improvement. Key limitations include the very small evidence base, absence of controlled trials in lipedema populations, and reliance on indirect evidence from obesity and fibroinflammatory research. The review highlights a significant gap in rigorous clinical data for this patient population.
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] · May 2026DOI ↗ Limited · human
This retrospective cohort study used the TriNetX Research Network — a large federated database — to examine whether GLP-1 receptor agonists (GLPs: semaglutide, tirzepatide, liraglutide, dulaglutide, exenatide, albiglutide, and lixisenatide) were associated with reduced postoperative inflammatory complications (IC) in patients undergoing dermatologic surgery. The study population included patients who underwent Mohs Micrographic Surgery or wide local excisions for melanoma or nonmelanoma skin cancer. Outcomes tracked over one month included wound disruption, hematoma, post-procedure infection, skin and subcutaneous tissue infection, and other procedural complications. After adjusting for demographics and proinflammatory comorbidities using hazard ratios and 95% confidence intervals, the study found that GLP use was associated with a statistically significant reduction in all measured IC categories compared with non-GLP users. Semaglutide and tirzepatide showed the largest individual reductions. Limitations include the retrospective, observational design — which cannot establish causation — along with potential residual confounding, database coding inaccuracies, and inability to control for medication adherence or surgical technique variability.
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] · May 2026DOI ↗ Limited · human
This case series describes four critically ill patients with type 2 diabetes mellitus who developed metformin-associated lactic acidosis (MALA) in the context of co-prescription of high-dose metformin with either a GLP-1 receptor agonist or a dual GIP/GLP-1 receptor agonist. In each case, MALA appeared to be precipitated by the introduction or dose escalation of the incretin-based therapy, or by an acute gastrointestinal illness occurring while the patient was on a maintenance GLP-1 receptor agonist dose. All four patients required acute renal replacement therapy. The authors propose that the shared gastrointestinal side-effect profile of these drug classes—including nausea, vomiting, decreased appetite, and abdominal pain—may contribute to dehydration and impaired renal metformin clearance, thereby elevating the risk of MALA. The study is limited by its small sample size (n=4), lack of a comparison group, and the inherent reporting biases of a case series design. The authors conclude that clinicians should exercise caution when co-prescribing these medication classes, with attention to kidney function monitoring and patient education on sick-day management rules.
Clinical nephrology. Case studies · May 2026DOI ↗ Limited · human
This retrospective observational study analyzed GLP-1 receptor agonist (GLP-1 RA) prescription records from the LUX MED private healthcare network in Poland between 2018 and 2025. Among 42,423 patients with more than one prescription, the study characterized how frequently patients switched between GLP-1 RA agents and identified factors associated with switching. The primary analysis used a discrete-time hazard model at the prescription-transition level, with subcutaneous semaglutide as the reference comparator. The study found that nearly 30% of patients switched agents at least once, and over 14% switched two or more times. After adjusting for switching opportunity and calendar time, liraglutide was associated with substantially lower odds of switching compared to subcutaneous semaglutide, while oral semaglutide and dulaglutide did not differ significantly. Temporal analyses revealed episodic peaks in switching and accelerating uptake of tirzepatide following its market entry. Key limitations include the retrospective, observational design; the lack of data on reasons for switching (e.g., tolerability, cost, availability); restriction to a single private-sector network; and the inability to establish causality. The authors characterize findings as hypothesis-generating.
Acta diabetologica · May 2026DOI ↗ Limited · human
This report examines the transfer of semaglutide into human breast milk in mothers using subcutaneous (injectable) semaglutide. The study found that semaglutide was undetectable in the breast milk of mothers receiving the drug via subcutaneous injection, and breastfed infants whose mothers used this route did not experience adverse effects. The report also highlights an important safety consideration regarding oral formulations of semaglutide (e.g., Rybelsus): these contain the absorption enhancer salcaprozate sodium (SNAC), which may be transferred into breast milk and potentially accumulate in nursing infants, raising concerns about the oral route during lactation. The report concludes that only injectable forms of semaglutide appear to be appropriate for use during breastfeeding based on currently available data. Limitations include the likely small number of mother-infant pairs studied and the observational nature of the data, which precludes definitive causal conclusions. Long-term infant outcomes were not assessed.
Unknown journal · May 2026Source ↗ Limited · human
This pilot observational study investigated the relationship between MOTS-c — a mitochondria-derived peptide — and cardiovascular risk markers in 32 stable peritoneal dialysis (PD) patients (mean age ~61 years, ~63% male). Researchers measured MOTS-c in three compartments: serum, urine, and peritoneal dialysate. Oxidative stress was assessed via plasma Advanced Oxidation Protein Products (AOPPs), and vascular stiffness was evaluated using carotid-femoral Pulse Wave Velocity (PWV), with echocardiography used to assess left ventricular systolic function. The study found that urinary MOTS-c was inversely correlated with AOPPs (suggesting a link to lower oxidative stress) and positively associated with PWV and left ventricular systolic function. Dialysate MOTS-c showed a strong inverse correlation with PWV and with both systolic and diastolic blood pressure, suggesting an association with a more favorable vascular profile. The authors propose a novel "Mitochondrial-Vascular Axis" in uremia and position MOTS-c as a potential biomarker. Key limitations include the very small sample size (n=32), pilot/cross-sectional design, single-center recruitment, and inability to establish causality from correlational data.
International urology and nephrology · May 2026DOI ↗ Limited · humanPreprint
This observational cohort analysis describes weight-loss outcomes and adverse event rates in 503 overweight adults who completed six months of the "Trimsulin Weight Loss Program," a nutraceutical regimen combining two proprietary products (a powdered drink mix and a capsule) with a structured diet and exercise protocol. The authors compare their results descriptively — without inferential statistics — to published real-world data for the prescription GLP-1 receptor agonist semaglutide and the dual GIP/GLP-1 agonist tirzepatide. The study reports that Trimsulin participants experienced mean weight reductions of 7.3% at 3 months and 14.1% at 6 months, numerically exceeding the comparator figures drawn from a separate published cohort. Adverse events were self-reported by 4.8% of Trimsulin participants versus much higher rates cited for the pharmacological comparators. Key limitations are substantial: there is no randomization, no placebo or active control arm, no blinding, no direct head-to-head comparison, reliance on self-reported adverse events, a highly selected completer-only analysis (503 of 1,000+ enrollees), differing baseline BMI profiles across cohorts, and the absence of any inferential statistical testing. The program's dietary and behavioral components cannot be disentangled from any supplement effect. The authors acknowledge the need for randomized controlled trials. The paper is identified as a preprint.
Unknown journal · May 2026DOI ↗ Limited · human
This case series describes two patients with severe obesity who developed moderate-to-severe cutaneous allodynia — a condition where normally non-painful stimuli such as touch or mild temperature change cause pain — while being treated with the dual GLP-1/GIP receptor agonist tirzepatide for weight management. In both cases, the onset of allodynia was temporally linked to dose escalation, occurring at higher doses, and resolved upon discontinuation of the drug. The allodynia varied between static and dynamic types across the two patients. The authors reviewed the tirzepatide U.S. prescribing information and found no prior documentation of skin pain or allodynia as an adverse event, though a prior FDA Adverse Event Reporting System (FAERS) pharmacovigilance analysis had identified rare allodynia signals across six GLP-1RAs. The authors assert this is the first case series specifically reporting allodynia with tirzepatide. Key limitations include the very small sample size (n=2), absence of a control group, and the inherent inability to establish causality from case reports alone. The temporal association and resolution upon drug withdrawal do, however, provide a suggestive signal warranting further investigation.
The American journal of case reports · May 2026DOI ↗ Limited · human
This study investigated the role of two mitochondrial-derived peptides (MDPs) — humanin (HN) and MOTS-c — in atrial fibrillation (AF), a common heart rhythm disorder. Researchers first examined human atrial tissue using public gene expression data, immunohistochemistry, and immunofluorescence, and measured plasma levels in a matched cohort of 39 AF patients and 39 sinus rhythm controls. They found that both peptides were significantly downregulated in AF tissue, with levels inversely correlated with fibrosis extent. Plasma MOTS-c was also reduced in AF patients and inversely correlated with NT-proBNP, a heart stress biomarker. Using an angiotensin II (AngII)-induced mouse AF model (n=36, male C57BL/6J), the study found that treatment with HNG (an HN analogue) or MOTS-c reduced AF inducibility and attenuated atrial fibrosis and hypertrophy. Peptide treatment was associated with improved mitochondrial structure, reduced fission proteins (Drp1, Fis1), and lower inflammatory cytokines. In vitro experiments in rat cardiomyocytes and fibroblasts showed reduced oxidative stress, fibroblast activation, proliferation, and migration. Exploratory RNA-sequencing suggested distinct mechanistic pathways. Key limitations include the small human cohort, the use of an animal model that may not fully replicate clinical AF, and the exploratory nature of mechanistic findings.
Biomedicines · May 2026DOI ↗ Limited · humanPreprint
This large-scale observational study used an EHR-linked body-composition "digital phenotyping" pipeline — incorporating large language model (LLM)-based data extraction — to compare lean body mass (LBM) changes in routine clinical care among adults initiating GLP-1 receptor agonists (GLP-1RAs). Of 670,422 first-episode GLP-1RA users (456,742 on semaglutide; 213,680 on tirzepatide), 7,965 had paired pre- and post-initiation body-composition measurements analyzable over 12 months. The study found that tirzepatide was associated with greater relative LBM loss than semaglutide at each time point assessed (3, 6, 9, and 12 months), with excess LBM losses ranging from approximately 1.1% to 2.0%. The authors also identified two GLP-1 "metabotypes": a "Depletive" metabotype (>20% total body weight loss with >5% LBM loss), which was more frequent with tirzepatide (10.3%) than semaglutide (6.7%), and a "Prime" metabotype (>10% total body weight loss with preserved LBM). Key limitations include the observational, real-world design; reliance on LLM-extracted EHR data; potential unmeasured confounding; and the relatively small subset with paired body-composition data relative to the overall cohort.
Unknown journal · May 2026DOI ↗ Limited · human
This study investigated whether the synthetic peptide BPC 157 (Body Protection Compound-157) could relax human arterial tissue and whether that effect depends on the endothelium and nitric oxide (NO) signaling. Researchers used residual segments of internal mammary artery (IMA) collected from 12 patients undergoing elective coronary artery bypass graft surgery. Arterial rings were prepared with the endothelium either intact or deliberately removed, then pre-contracted with phenylephrine. Cumulative doses of BPC 157 were applied, and separate experiments used the NOS inhibitor L-NAME to assess NO involvement. The study found that BPC 157 produced a concentration-dependent reduction in arterial contraction in both endothelium-intact and endothelium-denuded rings, but relaxation was significantly greater when the endothelium was present. L-NAME pre-treatment blunted the relaxation response, implicating the endothelial NO pathway as the primary mechanism. Residual relaxation in denuded rings suggested that additional, endothelium-independent mechanisms also contribute. The authors acknowledge limitations including the small sample size (n = 12), the ex vivo nature of the tissue model, and the absence of in vivo or molecular mechanistic data, calling for further research before clinical conclusions can be drawn.
Journal of clinical medicine · May 2026DOI ↗ Limited · human
This case report describes two adults living with well-controlled HIV-1 who presented with excess visceral abdominal fat (EVAF) under distinct clinical phenotypes. The first patient had a non-obese visceral adiposity phenotype (BMI 27 kg/m²) with increased waist circumference; treatment with tesamorelin, a growth hormone-releasing hormone analog, was associated with reductions in waist circumference, improved lipid levels, and enhanced functional well-being. The second patient had obesity (higher BMI) and received a GLP-1 receptor agonist; intermittent medication access led to fluctuating weight and persistent abdominal fat, after which the addition of tesamorelin was reported to provide more targeted visceral fat reduction. The authors argue that EVAF in people living with HIV can occur across BMI categories and may not be adequately captured by weight-based assessments alone. They conclude that individualized management informed by fat distribution patterns—rather than BMI or weight—is warranted. Key limitations include the single case-report design (n=2), absence of a control condition, lack of imaging-based visceral fat quantification reporting, and inability to draw generalizable conclusions about comparative efficacy.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · May 2026DOI ↗ Limited · human
This pharmacovigilance study used the U.S. FDA Adverse Event Reporting System (FAERS) database (Q2 2022–Q2 2025) to examine whether specific GLP-1 receptor agonists (GLP-1 RAs) — exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide — differ in their association with alopecia and reproductive or endocrine-related adverse events. Researchers identified 1,276 alopecia-related and 759 reproductive/endocrine-related cases, then applied disproportionality analyses using crude and adjusted reporting odds ratios (cROR/aROR) from logistic regression, controlling for potential confounders. Sensitivity analyses with positive and negative control drugs were used to validate signal robustness. The study found that semaglutide was significantly associated with disproportionate reporting of alopecia (aROR 1.23) and several hormonal conditions, including polycystic ovary syndrome (aROR 6.59) and menstrual abnormalities. By contrast, dulaglutide and tirzepatide showed negative or non-significant associations for several reproductive outcomes. Important limitations include the inherent biases of spontaneous reporting systems (e.g., underreporting, notoriety bias, inability to establish causation), lack of denominator data, and absence of clinical detail. The authors conclude that agent-specific differences in endocrine and dermatologic safety profiles may warrant personalised prescribing decisions and ongoing surveillance.
Diabetes/metabolism research and reviews · May 2026DOI ↗