Limited · human
This retrospective, claims-based observational study examined real-world persistence, adherence, and weight-loss effectiveness of GLP-1 receptor agonists (semaglutide/Wegovy) and the dual GLP-1/GIP agonist (tirzepatide/Zepbound) among 7,493 adults enrolled in Massachusetts Medicaid (MassHealth) who initiated treatment between July and December 2024. At 6 months, the study found moderate rates of persistence (60.8%, defined as no gap greater than 56 days between fills) and adherence (60.1%, defined as proportion of days covered ≥80%). Male sex and younger age were among the member-specific factors associated with lower persistence and adherence. In a subgroup of highly persistent and adherent members with prior authorization recertification data, both tirzepatide and semaglutide were associated with at least 5% body weight reduction at 6 months. Key limitations include the retrospective claims-based design, which cannot establish causality, the restriction to a Medicaid population limiting generalizability, and the weight-loss outcome being measured only in a select, highly adherent subgroup rather than the full cohort.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ Limited · human
This real-world pharmacovigilance study analyzed 40,253 adverse event reports submitted to the FDA Adverse Event Reporting System (FAERS) involving semaglutide, liraglutide, and tirzepatide used for weight loss. Researchers applied disproportionality analysis—using proportional reporting ratios (PRR) and reporting odds ratios (ROR)—to identify safety signals beyond the commonly studied gastrointestinal, renal, and pancreatic effects. The study population was predominantly female (68.6%), with median ages varying by drug. Key findings included that semaglutide showed the strongest disproportionality signals for psychiatric adverse events, including anxiety, depression, and suicidal ideation. Tirzepatide was associated with markedly elevated signals for injection-site reactions and indicators of misuse, such as incorrect dosing and off-label administration. Liraglutide showed a comparatively lower overall risk signal across these categories. Important limitations of this study include the inherent biases of spontaneous reporting systems (underreporting, confounding, lack of denominator data), the inability to establish causality, and the possibility that reporting patterns reflect prescribing trends or media attention rather than true pharmacological risk. The authors conclude that psychiatric monitoring and patient education warrant greater attention in clinical practice.
Pharmaceuticals (Basel, Switzerland) · Feb 2026DOI ↗ Limited · human
This case report describes a nasopharyngeal carcinoma patient who developed severe multisystem immune-related adverse events (irAEs) following combination treatment with sintilimab (a PD-1 immune checkpoint inhibitor) and thymosin alpha-1 (Tα1), an immunomodulatory peptide. The patient reportedly experienced high fever, skin rash, interstitial pulmonary edema, and multiple organ failure. The authors trace the clinical course from symptom onset through regression and use this case to discuss the potential risks of combining immune checkpoint inhibitors (ICIs) with immunomodulatory agents, suggesting that such combinations may trigger immune overactivation beyond what either agent causes alone. The paper reviews relevant literature to contextualize the case and proposes management strategies for clinicians encountering similar presentations. Key limitations include the inherent constraints of single-patient case reports: causality cannot be firmly established, findings are not generalizable, and confounding factors (e.g., underlying disease burden, other medications) cannot be fully excluded. The authors emphasize the need for heightened clinical vigilance when combining ICIs with immunomodulators like Tα1.
Clinical case reports · Feb 2026DOI ↗ Limited · human
This case report describes a single patient who self-administered Melanotan II (an unlicensed synthetic melanocortin peptide analog) over 64 days to achieve a tanning effect, with a three-month follow-up period after discontinuation. At the initial intraoral examination, clinicians observed brown pigmentation on the attached gingiva of both the maxillary and mandibular arches, distributed in a near-symmetrical pattern with greater intensity in the anterior mandibular region. Additional irregularly shaped, poorly defined pigmented lesions were noted on both left and right buccal mucosa. Following cessation of injections, the buccal mucosal pigmentation had nearly resolved by the one-month follow-up. However, gingival pigmentation persisted at three months, albeit with noticeably reduced intensity. The authors note that Melanotan II acts primarily via melanocortin 1 receptor activation on melanocytes, stimulating eumelanin production independently of UV exposure. The report highlights a gap in the published literature regarding the timeline for resolution of oral pigmentation associated with Melanotan II use, positioning this case as a contribution to a sparse evidence base. Key limitations include the single-patient design, absence of histological confirmation, and inability to control for confounding factors.
Life (Basel, Switzerland) · Feb 2026DOI ↗ Limited · human
This cross-sectional study analyzed publicly available FDA Adverse Event Reporting System (FAERS) data from January 2015 through December 2024 to characterize adverse events (AEs) associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs), using injectable insulin as a comparator. Across 112,532 reports where a GLP-1 RA was the primary suspect drug, the study found that administration-related reactions accounted for 63% of GLP-1 RA reports versus 39% for insulin. Reports of dosing issues and administration errors for GLP-1 RAs rose notably beginning in Q4 2022 and continued increasing through 2023 and 2024 — a pattern not observed for insulin — temporally coinciding with documented national GLP-1 supply shortages. The authors note several important limitations: FAERS data lack exposure denominators, making it impossible to calculate true incidence rates; reporting volume increases may reflect greater overall utilization rather than elevated per-patient risk; and FAERS is subject to underreporting and reporting biases. The study concludes that these patterns highlight the need for enhanced patient and provider education and continued post-marketing surveillance, particularly as compounded or alternative GLP-1 formulations may have contributed to administration errors during the shortage period.
Health affairs scholar · Feb 2026DOI ↗ Limited · human
This case report describes an 18-year-old woman with no prior medical history who developed euglycemic ketoacidosis (EKA) in association with self-administered semaglutide purchased online without medical supervision. After initiating the medication ten days prior and self-escalating doses, she presented with three days of nausea, intractable vomiting, and reduced oral intake. Laboratory findings revealed a high-anion gap metabolic acidosis (pH 7.24, bicarbonate 14 mmol/L, anion gap 24 mEq/L), markedly elevated β-hydroxybutyrate (5.9 mmol/L), and normal blood glucose (60 mg/dL), meeting criteria for EKA. She was treated with intravenous fluids, dextrose infusion, and supportive care, with clinical recovery and discharge within 36 hours. The authors propose that reduced oral intake combined with GLP-1 receptor agonist-induced gastrointestinal side effects may have triggered a starvation-like ketogenic state. Key limitations include the single-patient design, inability to verify the authenticity or exact composition of the online-purchased product, and lack of confirmed dosing history. The case raises awareness of EKA as a potential complication of GLP-1 receptor agonist use, particularly in unsupervised, non-diabetic individuals using unregulated sources.
Limited · human
This retrospective pharmacovigilance study analyzed FDA Adverse Event Reporting System (FAERS) data from Q1 2022 to Q3 2025 to compare gynecological hemorrhagic event reporting between tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a GLP-1 receptor agonist) in female patients. Researchers identified 103,607 female-specific reports—70,768 for tirzepatide and 32,839 for semaglutide—and calculated reporting odds ratios (RORs) using standardized MedDRA queries. The study found that gynecological hemorrhagic events were reported at nearly identical rates (0.60% for tirzepatide vs. 0.62% for semaglutide), with an ROR of 0.97 (95% CI: 0.82–1.14), indicating no statistically significant difference in reporting odds between the two agents. Notably, the authors flagged a substantial difference in reporter source composition: 94.6% of tirzepatide reports originated from consumers versus 53.4% for semaglutide, which may introduce bias and limits direct comparability. The authors concluded that no disproportionate safety signal was detected but emphasized that disproportionality analyses cannot establish causation, and that the consumer-reporting imbalance warrants cautious interpretation. Prospective, controlled studies were recommended to validate these findings.
Limited · human
This retrospective cohort study used the TriNetX Global Collaborative Network to investigate whether GLP-1 receptor agonist (GLP-1 RA) therapy is associated with an increased risk of nonarteritic anterior ischemic optic neuropathy (NAION) in adults with type 2 diabetes mellitus (T2DM). Researchers divided patients into two groups: those with T2DM receiving GLP-1 RA treatment and those with T2DM not receiving GLP-1 RAs. After one-to-one propensity-score matching on 20 covariates, each cohort contained 388,333 patients. Over a five-year follow-up period, the GLP-1 RA-treated cohort showed a statistically significant higher risk of NAION (risk ratio 1.339, 95% CI 1.137–1.577; risk difference 0.022%; p = 0.005). An E-value sensitivity analysis suggested the association was moderately robust to unmeasured confounding. The authors caution that the absolute risk difference is small and that GLP-1 RAs carry well-established cardiovascular and metabolic benefits. Key limitations include the retrospective, observational design using de-identified administrative data, potential residual confounding, and an inability to confirm causality. The authors call for prospective studies to clarify the mechanism and refine clinical guidelines.
Limited · human
This retrospective, multi-centre observational study used the TriNetX global healthcare research network to compare outcomes of oral semaglutide versus sitagliptin in patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D). From a pool of over 800,000 patients with both conditions, 3,470 initiated oral semaglutide and 22,840 initiated sitagliptin between October 2019 and December 2023. After propensity score matching (3,452 patients per group), the study found that the oral semaglutide group had a significantly lower 1-year all-cause mortality rate (4.3% vs. 7.0%, log-rank p < 0.001) and lower rates of hospitalisation compared with the sitagliptin group. Important limitations include the observational, non-randomised design, which introduces potential for residual confounding despite propensity score matching; the reliance on administrative/claims data from the TriNetX platform; and the inability to confirm medication adherence or establish causality. The authors note that prior evidence for semaglutide in HFpEF comes from injectable formulations, and these findings for the oral route remain hypothesis-generating pending randomised controlled trial confirmation.
Diabetes, obesity & metabolism · Jan 2026DOI ↗ Limited · human
This observational study investigated circulating levels of MOTS-c — a mitochondrial-derived peptide involved in metabolic regulation — in adults with and without obesity, and examined whether levels changed after bariatric surgery. Researchers compared 22 lean controls with 32 obese participants scheduled for bariatric surgery, measuring MOTS-c concentrations alongside metabolic and inflammatory markers. A subset of 10 obese patients was followed longitudinally before and 6 months after surgery. Adipose tissue MOTS-c expression was also assessed via immunofluorescence in lean (n=6) and obese (n=14) subjects. The study found that circulating MOTS-c was significantly higher in obese versus lean individuals (273 vs. 223 pg/mL), and positively correlated with BMI and HOMA-IR. A notable biphasic relationship emerged between MOTS-c and HOMA-IR, with a sharp rise above a threshold of ~6.6 mmol/L×µU/mL. Despite significant weight and BMI reductions following bariatric surgery, MOTS-c levels did not change significantly post-operatively. Adipose tissue expression did not differ between groups. The authors suggest MOTS-c may reflect a compensatory metabolic response in obesity and insulin resistance. Key limitations include the small sample size, particularly in the longitudinal substudy, and the lack of an independent validation cohort.
Journal of clinical & translational endocrinology · Dec 2025DOI ↗ Limited · human
This case report describes a 61-year-old woman with type 2 diabetes and morbid obesity who developed severe small bowel obstruction after more than a year of tirzepatide therapy. The patient experienced progressive constipation following initiation of tirzepatide, eventually presenting with acute diffuse abdominal pain and dry heaving. CT imaging revealed multiple dilated, fluid-filled small bowel loops with a transition point in the lower pelvis, moderate gastric distention, and free pelvic fluid. Initial conservative management with nasogastric decompression, bowel rest, intravenous fluids, and analgesia was insufficient, and the patient ultimately required laparoscopic adhesiolysis converted to exploratory laparotomy. Intraoperatively, a closed-loop obstruction caused by adhesive disease and an internal hernia was identified, necessitating resection of 25 cm of necrotic bowel. Pathology confirmed ischemic changes. Notably, tirzepatide had produced meaningful metabolic benefits, including hemoglobin A1c reduction and weight loss. The authors propose that tirzepatide's known effects on gastrointestinal motility may have worsened pre-existing constipation and contributed to the obstructive event in this predisposed patient. Key limitations include the single-patient design, the presence of confounding adhesive disease, and the inability to establish direct causation.
Limited · human
This study describes the development and validation of a urine-based liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for detecting semaglutide use in humans. Semaglutide is a GLP-1 receptor agonist originally approved for type 2 diabetes that has gained widespread use as a weight-loss aid. The authors note that semaglutide may confer a competitive advantage in weight-class sports (e.g., wrestling, boxing) by facilitating weight management, raising anti-doping concerns. The proposed method targets two unique urinary metabolites of semaglutide—designated U6 and U7—as biomarkers of exposure. Using only 2 mL of urine, the method achieved a reported limit of detection (LOD) of 50 pg/mL. The authors positioned this approach as a simpler alternative to existing blood-based testing regimens, given urine's relative ease of collection. Limitations include the absence of reported clinical validation data (e.g., pharmacokinetic profiling in dosed volunteers), no information on inter-individual variability, and no discussion of detection windows post-dose. The study is primarily an analytical methods paper rather than a clinical or pharmacological investigation.
Analytical and bioanalytical chemistry · Dec 2025DOI ↗ Limited · human
This case report describes a 65-year-old woman who developed pyoderma gangrenosum (PG) — a rare, rapidly progressing neutrophilic skin ulceration — at abdominal injection sites following use of the synthetic peptide melanotan. Four ulcerated wounds with erythematous borders were observed, clinically correlating with the injection sites. A diagnosis of PG was established based on wound appearance and progression, failure to respond to multiple antibiotic courses, and negative bacteriology (including negative Panton-Valentine leukocidin Staphylococcus aureus testing). The patient was treated with topical betamethasone, steroid occlusion tape, and oral prednisolone, with the prednisolone subsequently tapered and topical Dermovate initiated. The wounds healed over several months, leaving characteristic cribriform scarring. The authors acknowledge that while drug-induced PG has rarely been documented, this appears to be the first reported case of melanotan-induced PG in the literature. Key limitations include the inherent constraints of a single case report: no causal mechanism is established, there is no control or comparator, and generalizability is very limited. The report serves primarily to raise clinical awareness of a potentially serious and previously unreported adverse effect of melanotan use.
Limited · human
This retrospective observational study used the TriNetX electronic medical records database to examine cardiovascular outcomes and safety of semaglutide compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes (T2D) who had a body mass index (BMI) below 25 kg/m². From a large cohort of 340,721 patients identified between 2018 and 2020, the researchers compared all-cause mortality, cardiovascular outcomes, and adverse events between the two treatment groups. The study found that semaglutide was associated with a lower 3-year risk of all-cause mortality compared with DPP-4 inhibitors in this non-overweight population. These findings are notable because most landmark GLP-1 receptor agonist cardiovascular outcome trials have predominantly enrolled overweight or obese participants, leaving the effects in leaner individuals less well understood. Key limitations include the retrospective, non-randomized design, which introduces potential confounding by indication, residual confounding from unmeasured variables, and reliance on administrative/electronic health record data. Generalizability may also be limited by the database's geographic and demographic composition. The authors attribute differences in outcomes specifically to the semaglutide versus DPP-4 inhibitor comparison within this BMI subgroup.
European heart journal. Quality of care & clinical outcomes · Dec 2025DOI ↗ Limited · human
This retrospective, single-arm study evaluated the effects of a 7-day loading dose of thymosin α1 (Tα1) on peripheral blood lymphocyte counts, as well as the safety and efficacy of combining Tα1 with hypofractionated radiotherapy and PD-1 inhibitors in 48 patients with advanced or refractory cancers. Peripheral blood T cells, B cells, and natural killer cells were measured by flow cytometry before and after Tα1 administration. The study found that the 7-day Tα1 course was associated with statistically significant increases in total T cells, CD4+ T cells, and CD8+ T cells. Secondary outcomes including objective response rate, disease control rate, progression-free survival, and overall survival were also reported alongside adverse event data, with the authors characterizing the safety and efficacy profiles as satisfactory. Key limitations include the retrospective, non-randomized, single-arm design; the small and heterogeneous patient population spanning multiple tumor types; a median follow-up of only 13.7 months, which may be insufficient to assess long-term survival and late toxicities; and the absence of a control group, making it difficult to isolate Tα1's contribution. The authors acknowledge these findings are exploratory and call for larger, randomized, homogenous cohort studies to validate results.
Cancer management and research · Nov 2025DOI ↗ Limited · human
This multicenter retrospective observational study used the TriNetX database (2018–2021) to examine whether adding a GLP-1 receptor agonist (GLP-1 RA) to an SGLT2 inhibitor (SGLT2i) provides additional benefit over SGLT2i monotherapy in adults with both heart failure (HF) and type 2 diabetes (T2D). From nearly 929,000 eligible patients, 25,989 received combination therapy and 54,619 received SGLT2i monotherapy; after propensity score matching, each group contained 23,240 patients. Over one year, the study found that the combination group had a significantly lower rate of all-cause death (2.8% vs. 6.3%) and hospitalization compared with the monotherapy group. While propensity score matching was used to balance baseline characteristics, the retrospective and observational design limits causal inference, as unmeasured confounders (e.g., prescribing patterns, disease severity, medication adherence) may have influenced outcomes. The TriNetX database also relies on real-world electronic health records, which can have coding inaccuracies. The authors conclude that combination SGLT2i and GLP-1 RA therapy was associated with lower all-cause mortality and hospitalization risk in this HF and T2D population, but prospective randomized trials are needed to confirm these findings.
BMJ open diabetes research & care · Nov 2025DOI ↗ Limited · human
This study used synthetic target trial emulation and computational predictive modeling to compare amylin-pathway therapies — specifically CagriSema, cagrilintide, and amycretin formulations — for obesity and type 2 diabetes. Following PRISMA 2020 and TARGET framework guidelines, the researchers pooled data from seven randomized controlled trials (N = 5,786 participants) published through September 2025. Rather than analyzing real individual patient data, they reconstructed high-precision synthetic individual patient datasets and applied network meta-analysis, dose-response modeling, virtual head-to-head comparisons, and machine learning. The study reported that synthetic data reconstruction achieved greater than 99% fidelity to source trials, and virtual modeling suggested CagriSema outperformed subcutaneous amycretin at matched timepoints (posterior probability >0.95). Dose-response modeling identified an estimated ED80 for amycretin and benefit-risk analysis suggested a potential therapeutic window in the 10–20 mg subcutaneous range. Machine learning models predicted treatment response with 82–87% accuracy from baseline characteristics. Key limitations include reliance on reconstructed — not real — individual patient data, indirect comparisons rather than direct head-to-head trial evidence, and calibration metrics indicating moderate model uncertainty. The authors suggest these findings may inform future confirmatory trial design.
Metabolism open · Oct 2025DOI ↗ Limited · human
This experimental study investigated the potential of Growth Hormone Releasing Protein-6 (GHRP-6), a ghrelin hormone agonist, to improve in vitro maturation (IVM) of human oocytes. Researchers collected 240 human germinal vesicle (GV) oocytes and cultured them in varying concentrations of GHRP-6, comparing outcomes against a blastocyst single-step culture medium (control) and human tubal fluid (HTF) 10% (sham). Maturation rates were tracked over two days. A subset of 164 GV oocytes was then used to assess gene expression of CENP-E (associated with meiotic progression) and LINGO2 (a membrane protein gene) via real-time PCR after 24 hours of culture. The study found that a specific concentration of GHRP-6 produced the highest maturation rates on both day one and day two, outperforming both comparison media. However, real-time PCR analysis revealed that GHRP-6 did not significantly elevate expression of either CENP-E or LINGO2 in metaphase II oocytes, suggesting nuclear maturation was promoted without a corresponding improvement in cytoplasmic maturation markers. Key limitations include the absence of downstream developmental outcomes (e.g., fertilization or embryo quality data), a relatively small oocyte sample, and the lack of blinded assessment or patient-level randomization.
International journal of fertility & sterility · 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 ↗ 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 ↗