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 ↗ Animal only
This preclinical study examined how survodutide — a dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist in clinical development for obesity and MASH — acts in the brain to reduce body weight. Researchers first mapped GCGR and GLP-1R expression in human and mouse circumventricular organs (CVOs), finding that GCGR is barely detectable in the area postrema (AP) and arcuate nucleus of the hypothalamus (ARH), whereas GLP-1R is expressed in both regions. Using a fluorophore-labeled version of survodutide in mice, the study found that the compound accesses CVOs and nearby hypothalamic and hindbrain nuclei directly, without evidence of broadly crossing the blood-brain barrier. C-Fos activation mapping showed that survodutide activated multiple brain nuclei associated with food intake control. A long-acting GCGR-selective agonist, by contrast, did not activate satiety-related brain regions or reduce food intake, though it did reduce body weight, suggesting the appetite-suppressing effects of survodutide are primarily GLP-1R dependent. Limitations include the exclusively preclinical (mouse) design and the use of a labeled surrogate compound. The authors conclude the findings support a dual mechanism for survodutide's weight-lowering effects.
Molecular metabolism · Feb 2026DOI ↗ Review
This systematic review, conducted following PRISMA guidelines, synthesizes findings from 68 peer-reviewed studies examining the mechanisms, clinical applications, formulations, and adverse effects of four major sunless tanning agents: dihydroxyacetone (DHA), melanotan (I and II), forskolin, and carotenoids. The authors found that DHA produces skin pigmentation through the Maillard reaction (a non-enzymatic browning of amino acids in the stratum corneum) and has shown additional dermatologic utility in vitiligo and erythropoietic protoporphyria, as well as potential antifungal properties—though concerns about cytotoxicity, genotoxicity, and systemic absorption were noted. Melanotan I and II, which act on melanocortin receptors, were associated with serious adverse effects in unregulated use, including rhabdomyolysis, renal infarction, and priapism. Forskolin was reported to stimulate melanin production independently of melanocortin receptors, with efficacy demonstrated primarily in animal models. Orally ingested carotenoids were found to accumulate in skin and subcutaneous fat, producing a yellow-orange hue. The review acknowledges significant limitations: lack of standardized reporting, heterogeneous outcomes across studies, and insufficient long-term human safety data, particularly for forskolin and carotenoids. The authors conclude that further rigorous clinical research and updated regulatory guidance are needed.
The Journal of clinical and aesthetic dermatology · Feb 2026Source ↗ Moderate · human
This secondary analysis pooled data from two randomized, double-blind, placebo-controlled crossover trials to examine whether the GLP-1 receptor agonist (RA) dulaglutide affects copeptin — a stable surrogate marker for vasopressin (antidiuretic hormone) — in euvolemic individuals. A total of 54 participants were included: 34 with primary polydipsia and 20 healthy volunteers. Participants received three weeks of either subcutaneous dulaglutide or saline placebo once weekly before crossing over. Fasting blood samples for copeptin were collected after each treatment phase. The study found that dulaglutide was associated with a statistically significant suppression of copeptin levels, with a median within-subject difference of −0.7 pmol/L (p = .047), representing approximately a 12% reduction relative to placebo. This effect was not significantly correlated with dulaglutide-related changes in blood pressure, BMI, or nausea frequency. The authors suggest this finding may help explain GLP-1's known role in fluid and sodium homeostasis. Key limitations include the secondary-analysis design (not pre-specified as the primary outcome), modest sample size, a mixed population (healthy and polydipsic participants), and the reliance on copeptin as a proxy rather than directly measured vasopressin.
European journal of endocrinology · Feb 2026DOI ↗ Animal only
This systematic review examines the preclinical evidence for pharmacological activation of estrogen-related receptors (ERRα/β/γ) as a strategy to mimic the beneficial effects of exercise. The authors focused on synthetic pan-ERR agonists, particularly SLU-PP-332 and SLU-PP-915, reviewing experimental literature published between 2020 and 2024 from animal and cell-based models. The review found that these compounds appear to induce a gene expression program resembling that of acute aerobic exercise, dependent on ERRα, including activation of genes such as Ddit4 and Slc25a25. In preclinical obesity models, pan-ERR agonists were associated with enhanced fatty acid oxidation, increased oxidative-glycolytic (type IIa) muscle fiber composition, improved endurance capacity, reduced adiposity, better glycemic control, and increased basal energy expenditure, all without apparent toxicity signals. The compounds also showed potential to restore mitochondrial function and reduce inflammation in aging kidney models. The authors conclude that ERR activation is a promising exercise-mimetic strategy but explicitly acknowledge that no human clinical trials have been conducted, making translation to clinical practice premature. This represents a major limitation of the current evidence base.
Revista medica de Chile · Feb 2026DOI ↗ In vitro
This study investigated whether Thymosin α1 (Tα1), an endogenous thymic peptide known to modulate immune function, could enhance CD8+ T cell-mediated killing of breast cancer cells. Researchers isolated CD8+ T cells from peripheral blood of ten healthy donors and tested them under four conditions: unstimulated, CD3/CD28-stimulated, Tα1-treated, or exhaustion-rescue. Cytotoxic activity was assessed against MDA-MB-231 breast cancer cells and CD44+ cancer stem-like cells. The study reported that Tα1 treatment significantly increased cancer cell apoptosis, suppressed tumor cell proliferation, and boosted granzyme B secretion compared to CD3/CD28 stimulation alone. In artificially exhausted T cells, Tα1 partially restored effector function and reduced expression of exhaustion markers PD-1, TIM-3, and LAG-3. Complementary bioinformatic analysis of TCGA-BRCA data (n=1,112) using a four-gene Tα1 Response Index correlated with antigen presentation and cytotoxic gene programs. Key limitations include the small donor sample (n=10), use of healthy donor rather than patient-derived T cells, an in vitro experimental design, and the exploratory nature of the transcriptomic index. Results may not directly translate to in vivo or clinical settings.
Human immunology · Jan 2026DOI ↗ Insufficient
This systematic review surveyed ClinicalTrials.gov (from inception through July 2025) to map the landscape of registered clinical trials investigating glucagon-like peptide-1 receptor agonists (GLP-1RAs) as potential treatments for substance use disorders (SUDs). Of 192 records identified, 33 trials met inclusion criteria. The most commonly studied SUD was alcohol use disorder (15 trials), followed by nicotine/tobacco (9), cocaine (4), opioid (4), and methamphetamine (1); no trials targeting cannabis use disorder were identified. Agents under investigation included semaglutide, exenatide, tirzepatide, liraglutide, dulaglutide, and pemvidutide. The review found that trial designs and outcome measures were highly heterogeneous, often blending self-reported measures (e.g., Timeline Follow-Back, craving scales) with objective indices (e.g., urine toxicology). The authors note that most registered trials rely on older-generation GLP-1RAs and that significant gaps exist for methamphetamine and cannabis use disorders. As a registry-based systematic review, it does not report clinical efficacy data from completed trials. The authors conclude that next-generation GLP-1RAs and trials using FDA-recommended endpoints are needed to establish efficacy and safety across the full spectrum of SUDs.
Addictive behaviors reports · Jan 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.
Animal only
This review paper proposes "cytoprotection" as a conceptual framework for evaluating antiarrhythmic drugs — defined as the ability to suppress arrhythmias while avoiding adverse electrophysiological or systemic effects. The authors systematically compare conventional antiarrhythmics (Classes I–IV) and newer agents (late INa inhibitors, IKs enhancers, RyR2 stabilizers, gap junction modulators, and atrial-selective antiarrhythmics), characterizing them as offering only partial cytoprotection over a narrow-to-moderate range. By contrast, the stable gastric pentadecapeptide BPC 157 is hypothesized to offer broader, "full-range" cytoprotective-antiarrhythmic effects. The authors cite preclinical rodent studies showing BPC 157 restoring sinus rhythm, normalizing ECG intervals, preventing AV block, suppressing ventricular tachycardia, and attenuating ST-segment changes across diverse arrhythmia models (hypo-/hyperkalemia, ischemia-reperfusion, drug-induced). In vitro HEK293 cell data reportedly show direct membrane-stabilizing actions. The authors acknowledge that human clinical data on BPC 157 remain limited and non-cardiac in nature, and explicitly call for translational clinical investigation. The paper's central claims about BPC 157 in arrhythmias rest almost entirely on preclinical and in vitro evidence, with no controlled human cardiac trials reported.
Pharmaceuticals (Basel, Switzerland) · Jan 2026DOI ↗ Review
This narrative review examines complementary biological strategies for managing celiac disease (CeD) beyond a strict gluten-free diet (GFD). The authors synthesize evidence on several therapeutic approaches: (1) enzymatic degradation of immunogenic gluten peptides using bacterial and fungal prolyl endopeptidases (PEPs) and engineered enzyme combinations such as latiglutenase; (2) restoration of intestinal barrier integrity via the zonulin antagonist larazotide acetate; (3) gut microbiota modulation using probiotic strains including Lactobacillus and Bifidobacterium to reduce inflammation and support gliadin breakdown; and (4) plant-derived cysteine proteases from sprouting cereals as gluten detoxification agents. The review also considers enzymatic processing in food production to improve safety and accessibility of gluten-free products. The authors frame these strategies as a multidimensional complement to the GFD, particularly for patients with persistent symptoms or incomplete mucosal recovery following accidental gluten exposure. Limitations inherent to this study type include the absence of a systematic search protocol, potential selection bias in source inclusion, and the inability to draw causal conclusions. Primary clinical trial data across the reviewed interventions vary considerably in quality and scale.
Review
This review paper examines the benefits and harms of GLP-1 receptor agonists (GLP-1 RAs) and dual GLP-1/GIP agonists in the management of obesity. The authors summarize evidence indicating that these drug classes can facilitate significant short-term weight loss and associated improvements in obesity-related conditions, including type 2 diabetes mellitus, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. The paper also catalogues a range of adverse effects: common gastrointestinal issues (nausea, vomiting, acute pancreatitis, dehydration, and malnutrition), reduced efficacy of oral contraceptives, allergic reactions, and rarer events such as thyroid cell tumours and non-arteritic anterior ischaemic optic neuropathy. The authors highlight that up to one-third of weight lost may be lean tissue (muscle and bone), discontinuation rates may reach 80% at two years, and subsequent weight regain can account for up to two-thirds of prior loss—often disproportionately as fatty tissue. The paper recommends that GLP-1 RA therapy be initiated alongside supervised exercise and individualised dietary guidance, with ongoing monitoring for cessation, malnutrition, and inappropriate fat regain. A key limitation is that this is a narrative review and does not present original trial data.
Drug and therapeutics bulletin · Jan 2026DOI ↗ Review
This narrative review examines three incretin-based therapies — liraglutide, semaglutide, and tirzepatide — approved for weight management in non-diabetic individuals with obesity. The authors provide background on the physiological roles of the incretin hormones GIP and GLP-1 in the gastrointestinal tract, explaining how pharmacological analogues of these hormones, initially developed for type 2 diabetes, were subsequently found to produce clinically meaningful weight reduction. The review compares the three agents across efficacy, safety, cost-effectiveness, and real-world clinical trends. Lifestyle interventions (dietary modification, physical activity, sleep, and stress management) are discussed as foundational components of obesity management. The authors highlight that all three agents are now regulatory-approved for obesity in non-diabetic patients. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and is therefore subject to selection bias in the studies chosen. It does not conduct a formal systematic search or meta-analysis, limiting the objectivity of comparisons. No new clinical trial data are presented, and conclusions about relative efficacy and cost-effectiveness are drawn from the authors' interpretation of the existing evidence base.
Rambam Maimonides medical journal · Jan 2026DOI ↗ In vitro
This study developed and validated a stability-indicating High-Performance Liquid Chromatography (HPLC) method for the simultaneous quantification of two GLP-1 receptor agonists — Semaglutide (SEM) and Tirzepatide (TIR) — used in the treatment of type 2 diabetes and obesity. The method employed a C18 column with an isocratic mobile phase of 0.1% formic acid and acetonitrile (30:70), achieving rapid separation with retention times of 1.42 min for SEM and 1.68 min for TIR. The method was validated per ICH guidelines, demonstrating strong linearity (1–500 µg/mL, r > 0.9999), sensitivity (LOD: 10 ng/mL for TIR; 16 ng/mL for SEM), accuracy, and precision. The method successfully resolved both compounds from degradation products generated under acidic, basic, oxidative, and photolytic stress conditions. It was also applied to bulk drug, pharmaceutical dosage forms, and spiked rat plasma. A comprehensive six-pronged sustainability assessment was performed using nine analytical greenness, whiteness, blueness, and violet innovation tools. A key limitation is that the plasma work used spiked rat samples rather than real patient samples, meaning no clinical or pharmacokinetic conclusions about humans can be drawn.
BMC chemistry · Jan 2026DOI ↗ Moderate · human
This systematic review and meta-analysis examined the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and heart rate (HR) changes in people with overweight or obesity who do not have diabetes. Researchers searched four major databases (PubMed, Web of Science, Embase, and Cochrane Library) and ultimately included 12 randomized controlled trials. Using both pairwise and network meta-analysis methods, the study calculated mean differences (MDs) in HR compared to placebo. Pairwise meta-analysis found that all analyzed GLP-1RAs — including liraglutide, semaglutide, orforglipron, oral semaglutide, tirzepatide, retatrutide, and the drug class overall — were associated with statistically significant increases in heart rate versus placebo. Network meta-analysis, which allows indirect comparisons across agents, suggested that orforglipron 36 mg was associated with the most pronounced HR increase, while tirzepatide 5 mg showed the least increase (and its result was not statistically significant). Key limitations include the indirect nature of network comparisons, variability in trial designs and follow-up durations, and the restriction to a non-diabetic population, which limits generalizability. The clinical significance of the observed HR increases was not fully addressed.
European journal of medical research · Jan 2026DOI ↗ Animal only
This rat study used Fourier Transform Infrared (FTIR) spectroscopy to investigate how the stable gastric pentadecapeptide BPC 157 affects aortic wall composition following unilateral adrenalectomy. Abdominal aortas were collected from rats at three time points (15 minutes, 5 hours, and 24 hours) after surgery. BPC 157 was administered intragastrically immediately following the procedure. Spectral data were analyzed using principal component analysis (PCA) and support vector machine discriminant analysis (SVMDA). The study found that BPC 157-treated animals showed clear and reproducible spectral separation from controls at all time points, with the most notable differences in amide I and amide II bands (associated with protein secondary structure, including collagen and elastin) and lipid C-H stretching bands (associated with membrane integrity). The authors interpreted these signatures as consistent with early extracellular matrix reinforcement and membrane preservation in the vascular wall. Limitations include the exclusive use of an animal model, a small number of time points, and the indirect, spectroscopic nature of the outcome measures, which do not constitute direct functional or histological endpoints. No human data were reported.
Pharmaceuticals (Basel, Switzerland) · Jan 2026DOI ↗ Review
This review examines the expanding therapeutic applications of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) beyond their original indication of glycemic control in type 2 diabetes. The authors survey clinical trial evidence supporting the use of GLP-1 RAs across several cardiometabolic conditions, including obesity, heart failure with preserved ejection fraction, chronic kidney disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). The review highlights that robust clinical trial data exist for weight loss, cardiovascular outcome improvements, and renal function preservation. The authors also note that additional trials are ongoing to further broaden and strengthen the evidence base. Practical challenges are discussed, including high costs, limited patient access, adherence difficulties, and implementation barriers—especially for indications outside of diabetes. The review identifies emerging innovations, such as oral GLP-1 RA formulations and combination therapies, as potential avenues to improve accessibility and long-term use. The authors conclude that as clinical guidelines continue to evolve, targeted integration of GLP-1 RAs into care pathways may reshape prevention and treatment strategies for complex chronic diseases. As a narrative review, this paper synthesizes existing literature but does not generate new primary data, which limits the directness of its evidence.
Reviews in cardiovascular medicine · Jan 2026DOI ↗ Animal only
This study investigated a novel hydrogel-based therapy for intrauterine adhesions (IUA), a condition where uterine scarring causes infertility. The researchers engineered a hydrogel combining two components: a bioactive extracellular matrix derived from decidualized endometrium (DEndo-UdECM) and the anti-fibrotic peptide Thymosin β4 (Tβ4), designed for sustained local release. Using a mouse model of IUA, the study reported that a single administration of the hydrogel restored normal endometrial tissue architecture, reduced fibrosis, and resulted in near-complete fertility recovery in treated animals. Mechanistic investigations suggested the hydrogel worked by shifting macrophage polarization toward an anti-inflammatory M2 phenotype, suppressing pyroptosis-driven inflammation, and inhibiting the TGF-β/Smad3 signaling pathway, which drives fibrotic scarring. The study's primary limitation is that all experimental work was conducted in a murine model, meaning the findings have not yet been validated in humans or large-animal models. Whether the regenerative and anti-fibrotic effects, as well as the fertility outcomes, would translate to human patients remains unknown. Nonetheless, the study provides a mechanistically detailed preclinical proof-of-concept for a biomaterial strategy targeting the root pathology of IUA.
Nature communications · Jan 2026DOI ↗ Moderate · human
This post hoc analysis of the AWARD-7 randomized controlled trial examined how dulaglutide (a GLP-1 receptor agonist) affects plasma concentrations of 21 Joslin Kidney Panel (JKP) proteins—biomarkers previously linked to end-stage kidney disease (ESKD) risk—in adults with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD). Researchers used the Joslin OLINK proteomic platform to compare changes in protein concentrations from baseline to 6 months between participants receiving once-weekly dulaglutide (n=124) and those receiving insulin glargine (n=125). The study found that 14 of the 21 JKP proteins increased in the insulin glargine group but decreased in the dulaglutide group, with statistically significant between-group differences. The most notable differences involved 8 TNF-receptor superfamily members, which play roles in inflammation and apoptosis. Additional proteins—including CD160, WFDC2, DLL1, LAYN, SYND1, and EPHA2—also differed significantly between groups. Effects were more pronounced in participants with lower kidney function, higher albuminuria, higher HbA1c, or higher BMI at baseline. The authors suggest these proteomic changes may help explain the kidney-protective effects observed with dulaglutide in AWARD-7. Key limitations include the post hoc, exploratory design, the 6-month follow-up window, and lack of adjustment for multiple comparisons.
Kidney international reports · Jan 2026DOI ↗ Review
This review examines the potential role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in managing diabetic foot ulcers (DFUs), a serious chronic complication of diabetes associated with high rates of disability, recurrence, and mortality. The authors note that DFU-related mortality is strongly tied to cardiovascular events, suggesting that treatment should extend beyond local wound care to include cardiovascular risk reduction. The review systematically describes personalized application strategies for GLP-1 RAs based on DFU clinical staging, and compares mono-, dual-, and triple-target GLP-1 RA agents in terms of their clinical translational potential and adverse effect profiles specific to DFU patients. Notably, the authors highlight a key tension: while GLP-1 RAs have demonstrated cardiovascular protective effects in outcome trials, their appetite-suppressing and gastric-emptying-delaying properties may worsen malnutrition in DFU patients during acute infection phases. The review synthesizes existing evidence to propose more rational, stage-specific treatment frameworks. As a narrative review, it does not generate new primary data, and its conclusions are limited by the quality and scope of the underlying studies it synthesizes.
Frontiers in endocrinology · Jan 2026DOI ↗