Animal only
This animal study investigated whether Growth Hormone-Releasing Peptide-6 (GHRP-6), a GH secretagogue hexapeptide, could reduce cardiac damage following myocardial infarction. Using a permanent left coronary artery ligation model in rats (a non-reperfusion model), researchers divided animals into three groups: sham-operated controls, infarcted rats treated with saline, and infarcted rats treated with GHRP-6. Treatment began post-surgery and continued for seven days. Outcomes were assessed via echocardiography and histology on day seven. A separate cohort of twelve healthy rats was used for mitochondrial proteomic analysis six hours after compound administration. The study found that, compared to the saline-treated infarcted group, GHRP-6-treated rats showed reduced myocardial tissue loss, less interstitial fibrosis and scarring, and improved left ventricular function. Proteomic data suggested that potential mechanisms may include upregulation of fatty acid beta-oxidation, apoptosis-prevention pathways, antioxidant defenses, and mitochondrial metabolic reprogramming. Key limitations include the exclusive use of an animal model, a short seven-day observation window, a small sample size, and the mechanistic proteomic findings being derived from healthy rather than infarcted animals. No human data were generated.
Pharmaceuticals (Basel, Switzerland) · Mar 2026DOI ↗ Moderate · human
This retrospective cohort study used electronic health records from a large health system in Ohio and Florida (January 2021–June 2025) to examine real-world obesity treatment patterns and weight changes among adults who discontinued injectable semaglutide or tirzepatide within 3–12 months of initiation. A total of 7,938 patients (mean age ~56 years; ~64% female) were included. The study found that within one year of discontinuation, roughly 19.6% restarted the same medication and 35.2% received an alternative obesity treatment (most commonly another medication). Patients treated for obesity lost a mean of 8.4% of body weight before discontinuation, while those treated for type 2 diabetes lost 4.4%. In the year following discontinuation, the average weight change was modest (+0.5% for obesity indication; −1.3% for T2D indication), but with considerable individual-level variability—meaning some patients regained weight substantially while others did not. Key limitations include the retrospective, observational design (precluding causal inference), potential confounding by unmeasured factors, and restriction to a single health system in two U.S. states, which may limit generalizability.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Animal only
This animal study investigated whether MOTS-c, a 16-amino acid mitochondrial-derived peptide, influences adrenal gland physiology in adult male Wistar rats. Sixteen rats received either continuous subcutaneous MOTS-c or saline for 24 hours via micro-osmotic pumps. The researchers used qRT-PCR, immunohistochemistry, ELISA, and RNA sequencing to assess adrenal tissue responses. The study first confirmed that endogenous MOTS-c expression was higher in the zona fasciculata/reticularis compared to the zona glomerulosa. MOTS-c treatment did not alter classical steroidogenic gene expression or circulating corticosterone and aldosterone levels. However, RNA sequencing identified 39 differentially expressed genes, most notably a 4.3-fold upregulation of the purinergic receptor P2ry4. The authors interpreted these findings as evidence that MOTS-c "primes" adrenocortical cells for steroidogenic responsiveness—via calcium signaling, lipid metabolism modulation, stress-response protein downregulation, and mitophagy inhibition—without directly stimulating basal hormone synthesis. Key limitations include the exclusive use of male rats, the short 24-hour treatment window, small sample size (n=16), and the absence of functional stimulation challenges (e.g., ACTH) to test the proposed "readiness" hypothesis.
Folia histochemica et cytobiologica · Mar 2026DOI ↗ Review
This narrative review compares two incretin-based therapies — semaglutide, a selective GLP-1 receptor agonist, and tirzepatide, a dual GIP/GLP-1 receptor agonist — across their mechanisms of action, clinical efficacy, therapeutic indications, and cardiovascular/renal evidence. The authors describe semaglutide as having a well-established clinical profile with demonstrated benefits in glycaemic control, body weight reduction, and cardiovascular and renal outcomes. Tirzepatide is presented as a newer agent offering superior weight loss and improvements in insulin sensitivity, with an expanding range of therapeutic indications, though the authors note its cardiovascular outcomes evidence is less mature than that of semaglutide. The review emphasizes that despite shared benefits in reducing HbA1c and body weight, the two molecules differ meaningfully in their pharmacological mechanisms and evidence bases, requiring individualized clinical decision-making. The authors frame both agents within a broader "incretin revolution" relevant to cardio-reno-metabolic prevention. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and therefore does not provide independent experimental evidence to confirm or quantify any specific clinical claims.
European heart journal supplements : journal of the European Society of Cardiology · Mar 2026DOI ↗ Animal only
This study examined the effects of graviola (Annona muricata L.) oil extract (GOE) supplemented at three doses (200, 400, and 600 mg/kg feed) on growth performance and circadian rhythm profiles of several biomarkers in 48 male Anatolian Merino lambs over a 60-day feeding trial. Blood samples were collected at four time points across the day (07:00, 13:00, 19:00, and 01:00) on multiple study days to capture circadian variation. Measured biomarkers included Apelin (an adipokine), cardiac troponin I (cTnI), the circadian clock protein BMAL1, the mitochondria-derived peptide MOTS-c, and brown adipose mitochondrial carrier protein 1 (BMCP1), all assessed via ELISA. The 400 mg/kg dose was associated with the greatest linear improvement in live weight gain and with modulation of BMAL1, MOTS-c, and BMCP1 peaking at 19:00. The 600 mg/kg dose showed the most favorable results for Apelin and cTnI at certain time points. Limitations include the exclusive use of a single animal species, a relatively small sample size, lack of human relevance, and the observational nature of biomarker interpretation within a non-randomized animal production context.
BMC veterinary research · Mar 2026DOI ↗ Moderate · human
This meta-analysis pooled data from five randomised controlled trials to evaluate the efficacy and safety of mazdutide — a dual GLP-1 and glucagon receptor agonist — for weight management in non-diabetic adults with overweight or obesity. Searches were conducted across Cochrane Library, PubMed, Google Scholar, and ClinicalTrials.gov, and analyses were performed using random-effects models in RevMan 5.4. The pooled results reported by the study authors indicate that mazdutide was associated with significant reductions in percentage body weight (mean difference –12.42%), absolute body weight (–9.76 kg), and waist circumference (–7.98 cm) compared with control conditions. Secondary cardiometabolic outcomes — including systolic blood pressure (–7.68 mmHg), total cholesterol (–0.57 mmol/L), and LDL cholesterol (–0.37 mmol/L) — also showed reductions. Adverse events were slightly more frequent in the mazdutide groups (RR = 1.12), described as mild to moderate. A dose-wise meta-regression suggested a significant dose-dependent relationship. The authors acknowledge that findings are constrained by the small number of included trials (n = 5), which limits the robustness and generalisability of conclusions.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Review
This paper is a narrative review examining the clinical evidence on retatrutide (LY3437943), a novel triple receptor agonist targeting the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). The authors conducted an electronic literature search across Scopus, PubMed/MEDLINE, and Google Scholar to synthesize available findings. According to the review, studies in people with type 2 diabetes mellitus (T2DM) reported reductions in HbA1c of up to 2.16% and fasting glucose reductions of up to 69.1 mg/dL, alongside weight loss of up to 16.94%. In individuals with overweight or obesity (without T2DM), weight loss reached up to 26.56% (approximately 24.15 kg). Additional findings included reductions in BMI, waist circumference, and systolic blood pressure in those with T2DM and overweight/obesity, as well as a relative liver fat reduction of up to 86% in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). The most commonly reported adverse events were mild-to-moderate gastrointestinal symptoms, particularly at higher doses. The authors conclude that retatrutide's effects on glycemic control, weight, and potential pleiotropic benefits warrant further investigation through larger, longer-duration trials.
Expert review of clinical pharmacology · Mar 2026DOI ↗ Insufficient
This paper describes a pre-registered protocol for a systematic review and network meta-analysis (NMA) examining the comparative efficacy and safety of GLP-1 receptor agonists (GLP-1 RAs) and novel co-agonists (e.g., dual/triple agonists) for weight loss in adults with overweight or obesity who do not have diabetes. The authors plan to search PubMed, Ovid, and Cochrane CENTRAL for randomized controlled trials (RCTs) comparing these agents against placebo or each other. Trials involving participants with diabetes, specific comorbidities, or prior bariatric surgery will be excluded. The primary outcome is relative change in body weight from baseline at approximately 6 months and 1–1.5 years. Secondary outcomes include absolute weight change, total adverse events, gastrointestinal adverse events, serious adverse events, and death. Frequentist random-effects pairwise and network meta-analyses will be conducted, with treatment rankings generated via the surface under the cumulative ranking curve (SUCRA). Risk of bias will be assessed using the Cochrane RoB 2 tool and the RoB-NMA tool. Importantly, this is a protocol paper only — no data have been collected or analyzed yet — so no results or conclusions about the efficacy or safety of any specific agent are available at this stage.
Systematic reviews · Mar 2026DOI ↗ Limited · human
This Brazilian retrospective regulatory surveillance study examined patterns of GLP-1 receptor agonist (GLP-1 RA) consumption, pharmacovigilance reports, and product falsification alerts between 2020 and 2024. Researchers triangulated data from three official sources: national pharmaceutical sales records classified by the Anatomical Therapeutic Chemical (ATC) system, adverse event reports submitted to Vigimed (Brazil's national pharmacovigilance platform linked to the global VigiBase), and official counterfeit product alerts. The study found that semaglutide was the dominant GLP-1 RA in the Brazilian market. Consumption was heavily concentrated in higher-GDP regions, revealing a geographic and economic disparity that did not align with regional diabetes prevalence rates. Pharmacovigilance data revealed a notable proportion of reports associated with off-label use, suggesting potential gaps in clinical practice and regulatory oversight. Additionally, documented cases of counterfeit GLP-1 RA products highlighted supply chain vulnerabilities. The authors concluded that rising demand, widespread off-label use, and product falsification collectively require a coordinated regulatory response. Limitations include the retrospective and observational nature of the data, reliance on administrative and surveillance databases, and the potential for underreporting in pharmacovigilance systems.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Limited · human
This Austrian real-world study examined afamelanotide treatment outcomes in 20 patients with erythropoietic protoporphyria (EPP), a rare genetic disorder causing severe phototoxic reactions upon light exposure. Researchers compared pre- and post-treatment data on quality of life (QoL), phototoxic burn tolerance time (PBTT), UV index, and the incidence and severity of phototoxic reactions for the year 2023. The study found that the EPP-specific QoL score increased markedly, with the median rising from 11.11 to 79.17 under therapy. PBTT also improved substantially, increasing from a median of 15 minutes before treatment to 250 minutes during treatment. The proportion of patients experiencing phototoxic reactions fell from 88% at baseline to 33% on therapy. Reported side effects were described as only mild and transient. The authors concluded that these findings support the effectiveness and safety of afamelanotide in EPP. Limitations include the small sample size (n=20), the non-randomized, uncontrolled observational design, and the potential for recall or reporting bias inherent to real-world cohort studies.
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG · Mar 2026DOI ↗ Review
This review examines the role of intestinal barrier dysfunction in coeliac disease (CD), a condition in which genetically predisposed individuals mount an immune-mediated response to dietary gluten that damages the small intestine. The authors explore the evidence that increased intestinal permeability is a central feature of CD pathophysiology, detailing the contributing mechanisms: dysregulation of the protein zonulin, pro-inflammatory cytokines, alterations in gut microbiota, and immune responses to gliadin peptides. The review then comprehensively surveys therapeutic strategies aimed at restoring barrier integrity, including dietary interventions, nutritional supplements, and investigational pharmacological agents such as larazotide acetate (a tight-junction regulator) and IMU-856 (a SIRT6 activator targeting mucosal regeneration). The authors also highlight a key limitation in the field: the absence of validated, reliable biomarkers for accurately measuring intestinal permeability in CD. They advocate for further research into barrier-restoring therapies, particularly as adjuncts to a gluten-free diet for maintaining disease remission. As a narrative review, the paper synthesises existing literature but does not generate new primary data, and conclusions are subject to the quality and heterogeneity of the underlying studies.
Limited · human
This retrospective observational study analyzed data from the National Poison Data System (NPDS) to characterize and compare glucagon-like peptide-1 receptor agonist (GLP-1 RA) exposures reported to U.S. poison centers between 2017 and 2024, focusing on differences between children (ages 6–17) and adults. Across 13,924 single-substance GLP-1 RA exposures, the authors found a dramatic overall increase of 1,830.8% in exposure rates over the study period, with an even steeper 4,805.0% rise among children 6–17 years old, most of which occurred after 2021. The majority of exposures (91.7%) resulted in no or mild effects; however, moderate effects were seen in 8.0% of cases and major effects in 42 exposures, with two deaths recorded. Children aged 6–17 were significantly more likely to be hospitalized than adults (RR: 2.66), and adolescents aged 12–17 were more likely to experience a serious medical outcome (RR: 1.68). Vomiting was the most common clinical effect in children (88.2%) versus adults (61.3%). Notably, exposures among children were far more likely to be classified as intentional misuse compared to adults (RR: 8.12). Limitations include reliance on voluntarily reported poison center data, potential underreporting, and inability to establish causation.
Journal of medical toxicology : official journal of the American College of Medical Toxicology · Mar 2026DOI ↗ Moderate · human
This systematic review and nonlinear meta-regression examined how body weight changes after people stop taking GLP-1 receptor agonists (GLP-1RAs), a class of medications widely used for obesity management. Researchers searched five major databases through August 2025 and identified 48 eligible studies. The core quantitative analysis focused on six randomised controlled trials (n = 3,236 participants) and applied a mixed-effects exponential recovery model to characterise the trajectory of weight regain over time. The study found that weight regain after GLP-1RA discontinuation follows a predictable, decelerating pattern: approximately 60% of treatment-related weight loss was regained within one year of stopping. The modelled plateau of regain was estimated at 75.3% (95% CI 68.9–81.6%) of lost weight, suggesting a residual but substantially attenuated long-term benefit. The rate constant of 0.0302 per week corresponded to a regain half-life of roughly 23 weeks. Secondary outcomes (HbA1c, systolic blood pressure) were explored but not the primary focus. Limitations include that most included studies carried moderate risk of bias, weight trajectories beyond 52 weeks were extrapolated rather than directly observed, and heterogeneity across study populations, GLP-1RA agents, and treatment durations may affect generalisability.
EClinicalMedicine · Mar 2026DOI ↗ Limited · human
This qualitative, multi-method study explored how adults living with obesity make decisions about initiating pharmacotherapy. Researchers used three complementary methods — semi-structured interviews (n=15), a Photovoice study (n=12), and focus group discussions (n=12) — to purposively recruit adults aged 18–70 with a BMI ≥27 kg/m² and at least one obesity-related complication, all of whom were naïve to obesity medications. Through triangulation of findings across all three methods, the study identified five key factors shaping patient preferences: (1) anticipated treatment efficacy, (2) adequacy of information and community support, (3) safety and tolerability profile, (4) treatment burden and lifestyle integration, and (5) logistical and structural barriers. Tirzepatide was the most preferred agent across all methods, largely due to its perceived weight-reduction potential, while semaglutide ranked second, aided by its broader societal familiarity. Perceived efficacy and information trustworthiness emerged as the dominant drivers of preference, with safety concerns consistently moderating enthusiasm. The study is limited by its qualitative design, modest sample sizes, and the fact that all participants were medication-naïve, which may limit transferability to experienced patients. The authors recommend clinicians engage in shared decision-making tailored to individual information needs and social contexts.
Obesity pillars · Mar 2026DOI ↗ Animal only
This animal study investigated the neuroprotective effects of hexarelin, a growth hormone secretagogue receptor type 1a (GHS-R1a) agonist, on retinal ganglion cell (RGC) survival following optic nerve transection (ONT) in golden hamsters. Researchers administered hexarelin at varying doses either once or twice daily for five days post-ONT and quantified RGC survival at seven days using Tuj1 immunostaining on retinal whole mounts. Single daily doses (25, 50, and 100 µg/kg) produced a dose-dependent increase in RGC survival compared to saline controls (62.4%, 68.5%, and 74.6% vs. 51.2%, respectively). Twice-daily dosing yielded further improvements, with the highest tested regimen (150 µg/kg twice daily) associated with a survival rate exceeding baseline (109.2% vs. 72.9% for twice-daily saline). The study suggests hexarelin may exert anti-apoptotic neuroprotective effects in the retina, attributed to its GHS-R1a agonism. Key limitations include the use of a single animal species (golden hamster), absence of mechanistic pathway data, and no translation to human subjects or disease models such as glaucoma.
Indian journal of pharmacology · Mar 2026DOI ↗ Review
This narrative review examines the current and investigational pharmacological treatments for erythropoietic protoporphyrias (EPP), a group of ultra-rare inherited disorders of heme biosynthesis causing severe, painful phototoxic reactions triggered by visible light exposure. The authors searched PubMed and clinical trial databases to synthesize available evidence on two investigational agents—dersimelagon (a melanocortin-1 receptor agonist) and bitopertin (a glycine transport inhibitor)—alongside the only currently approved therapy, afamelanotide. The review notes that afamelanotide effectively reduces pain and extends tolerable sun exposure time but does not address the underlying disease mechanism and is approved only for adults, leaving pediatric patients without a treatment option. The authors report that available trial data for both dersimelagon and bitopertin suggest treatment effects versus placebo, though they emphasize that the safety and efficacy profiles of both agents require further characterization. A key limitation highlighted is the absence of head-to-head comparison data against afamelanotide, which the authors argue is necessary to inform regulatory decisions and ensure meaningful patient access. The review concludes that both agents hold promise but that additional robust clinical evidence is needed before their roles in EPP management can be fully established.
Expert opinion on pharmacotherapy · Mar 2026DOI ↗ Moderate · human
This network meta-analysis systematically evaluated the comparative efficacy and safety of four investigational glucagon receptor agonist (GRA)-based agents — retatrutide, cotadutide, mazdutide, and survodutide — in adults with type 2 diabetes, overweight, or obesity. Researchers searched PubMed, Cochrane, Embase, and Scopus, ultimately including 14 randomised controlled trials analyzed using frequentist network meta-analysis with random-effects models. Key outcomes included absolute and percent body weight change, HbA1c reduction, adverse events, and treatment discontinuation due to adverse events. The study found that retatrutide produced the greatest absolute weight reduction versus placebo (MD −13.44 kg), followed by survodutide (MD −10.74 kg) and mazdutide (MD −6.47 kg); cotadutide's effect did not reach statistical significance. Retatrutide also showed the largest HbA1c reduction, though only its effect was statistically significant among the agents. Regarding tolerability, mazdutide demonstrated the most favorable safety profile, while retatrutide and cotadutide were associated with comparatively lower tolerability. The authors acknowledge limitations inherent to network meta-analysis, including reliance on early- and mid-phase trial data and the absence of direct head-to-head comparisons between agents.
Endocrinology, diabetes & metabolism · Mar 2026DOI ↗ Preclinical
This study investigated whether GLP-1 receptor agonist medicines cause disproportionate loss of lean body mass (LBM) or skeletal muscle in the context of obesity-related weight loss. Researchers conducted four pre-clinical studies in obese mice and a proof-of-concept clinical trial in humans (registered as NCT05606471). In obese mice, GLP-1 medicines primarily reduced body fat, with a small but statistically significant decrease in LBM. Notably, liver mass loss exceeded muscle mass loss among lean tissues. Although absolute muscle mass and strength declined, relative muscle mass and strength improved, leading to better running performance. The study also found that muscle atrophy during immobilization was similar regardless of treatment, but GLP-1 medicines produced a distinct muscle proteome signature compared to calorie restriction alone. In the human trial, patients with obesity treated with GLP-1 medicines showed improved body composition without negative effects on strength. The authors conclude that, in middle-aged mice and humans, GLP-1 medicines slightly reduce absolute muscle values but positively affect overall body composition and mobility. Limitations include the proof-of-concept (small-scale) nature of the clinical component and the use of animal models as a primary evidence base.
Cell reports. Medicine · Mar 2026DOI ↗ Moderate · human
This large retrospective cohort study examined real-world trends in 1-year treatment persistence and adherence among commercially insured adults without diabetes who newly initiated high-potency, weight loss-indicated GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Wegovy) and tirzepatide (Zepbound) — between January 2021 and June 2024. Using integrated medical and pharmacy claims data from approximately 17.9 million members, researchers identified 33,607 eligible new initiators. The study found that 1-year persistence nearly doubled over the observation period, rising from 33.2% in 2021 to 60.9% in the first half of 2024. Tirzepatide demonstrated notably higher persistence (approximately 64%) compared to semaglutide during overlapping availability years. The authors suggest that resolution of GLP-1RA product shortages, improved side effect and dose escalation management, and lifestyle support programs may have contributed to improving persistence trends. Key limitations include reliance on claims data (which cannot capture clinical nuance or patient-reported reasons for discontinuation), a commercially insured-only population limiting generalizability, and the inability to distinguish voluntary discontinuation from access-related gaps. The authors call for further research into discontinuation reasons and long-term cost-effectiveness.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ 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 ↗