Review
This narrative review synthesized evidence on injectable semaglutide for weight management specifically in non-diabetic adults, drawing on 27 studies (including RCTs, observational studies, and qualitative reports) identified through PubMed, Scopus, and Web of Science (2019–2025) using the SANRA framework. The authors found that, according to the included literature, semaglutide (2.4 mg) was associated with mean body weight reductions of approximately 14.9% in non-diabetic adults, compared to roughly 9.6% in diabetic populations. Beyond weight loss, the review reported improvements in cardiometabolic markers and quality-of-life measures. Gastrointestinal adverse effects were identified as the primary driver of treatment discontinuation. The review also highlighted practical barriers to real-world use, including high out-of-pocket costs, global supply constraints, and evidence of weight regain following cessation. Tirzepatide was used as a comparative benchmark. The authors conclude that semaglutide represents a meaningful advance in obesity pharmacotherapy but emphasize that its utility depends on integration into multimodal treatment strategies and resolution of structural access issues. Limitations include the narrative (non-systematic) design, potential for selection bias in study inclusion, and inability to pool effect sizes statistically.
Health science reports · Mar 2026DOI ↗ Animal only
This preclinical study investigated whether combining interleukin-15 (IL-15) with thymosin alpha 1 (Tα1) could reverse CD8+ T cell immunosenescence and enhance antitumor immunity in hepatocellular carcinoma (HCC). Using an orthotopic HCC model in aged C57BL/6 mice (22–26 months old), animals were randomized to saline, IL-15 alone, Tα1 alone, or combination therapy. The study found that the combination treatment significantly suppressed tumor growth and prolonged survival compared to either agent alone or control. Mechanistically, combination therapy reduced the proportion of senescent CD8+ T cells, expanded activated effector populations, and upregulated cytotoxic markers such as granzyme B, perforin, and interferon-gamma. Transcriptomic and Western blot analyses indicated that the combination suppressed chronically overactivated PI3K/AKT signaling in hepatic CD8+ T cells — an effect confirmed by in vitro experiments using primary human CD8+ T cells co-cultured with Huh7 hepatoma cells, where the AKT agonist SC79 reversed the therapeutic benefit. Key limitations include the exclusively preclinical design (no human clinical data), use of a single mouse HCC model, and the need for further validation of the proposed mechanism in clinical settings.
Journal of gastroenterology and hepatology · Mar 2026DOI ↗ Moderate · human
This open-label randomized controlled trial (NCT03082885) enrolled 73 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), randomizing them to standard medical therapy (SMT, n=38) or SMT plus Thymosin α1 (Tα1, n=35), with a primary endpoint of 90-day transplant-free survival. Using flow cytometry and ELISA, researchers characterized peripheral immune cell subsets and serum cytokines at baseline and over follow-up. The study found that 90-day survivors had higher baseline effector T (TE) cell proportions, lower regulatory T cells (Tregs), and higher pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) compared to non-survivors. Non-survivors developed a progressive hyperinflammatory trajectory over time. Tα1 treatment was associated with improved 90-day transplant-free survival, reduced Treg frequencies (including CD226 low/- Treg subsets) at weeks 4–8, and moderation of late-stage hyperinflammation without suppressing early immune activation. The authors conclude Tα1 may rebalance immune responses in ACLF. Key limitations include the open-label design, relatively small sample size, and a single-center context, which may limit generalizability.
Immunopharmacology and immunotoxicology · Mar 2026DOI ↗ Limited · human
This pharmacovigilance study compared post-marketing adverse event reporting patterns for tirzepatide (a dual GIP/GLP-1 receptor agonist) against semaglutide and liraglutide (GLP-1 receptor agonists) using aggregated Individual Case Safety Reports (ICSRs) from the EudraVigilance database. Researchers applied pairwise disproportionality analyses using reporting odds ratios (RORs) at the System Organ Class (SOC) level, with false discovery rate correction and sensitivity analyses limited to serious and healthcare professional-reported cases. The study found that, compared with semaglutide, tirzepatide was associated with higher relative reporting for immune system disorders (ROR 1.97) and hepatobiliary disorders (ROR 1.71). Compared with liraglutide, tirzepatide showed higher reporting for musculoskeletal (ROR 2.02) and psychiatric disorders (ROR 2.14), but lower reporting for neoplasms (ROR 0.28). Eight SOCs remained significant across all analytical conditions. The authors emphasize that these findings are hypothesis-generating only, as disproportionality analyses cannot establish causality, do not adjust for exposure levels, and are subject to reporting biases inherent in spontaneous pharmacovigilance databases. Confirmation in exposure-adjusted studies is recommended.
International journal of molecular sciences · Mar 2026DOI ↗ Review
This critical review examines the emerging use of peptides and peptide analogues as performance-enhancing drugs in both competitive sport and recreational bodybuilding. The authors survey a range of compounds — including growth hormone secretagogues (e.g., Ipamorelin), growth hormone-releasing hormone analogues (e.g., CJC-1295, Sermorelin), and synthetic peptide fragments (e.g., Frag 176-191, KPV) — which are promoted in bodybuilding communities for purported benefits in muscle growth, fat loss, recovery, and anti-inflammation. The review notes that these compounds are attractive partly due to their enhanced receptor selectivity and stability compared to older anabolic agents. However, the authors conclude that clinical evidence supporting their use in sport contexts is limited; most existing research addresses therapeutic applications under controlled medical settings, not the high-dose or stacked protocols typical in bodybuilding. The review identifies potential risks including cardiovascular strain, insulin resistance, dyslipidemia, and psychiatric instability. It also highlights the dangers posed by an unregulated supply chain prone to mislabeling and contamination. Anti-doping detection remains challenging due to peptides' structural similarity to endogenous hormones and short half-lives. A key gap identified is the near-complete absence of population-level prevalence data, particularly for recreational users. The authors characterize peptide use in sport as high-risk and ethically problematic pending longitudinal safety evidence.
The Journal of sports medicine and physical fitness · Mar 2026DOI ↗ Limited · human
This study characterizes PG-102, a bispecific Fc fusion protein that co-activates both GLP-1 and GLP-2 receptors, combining preclinical animal work with a Phase I human trial. In db/db mice (a model of advanced type 2 diabetes with hyperglycemia and catabolic weight loss), PG-102 demonstrated superior and more sustained glycemic control compared to semaglutide or tirzepatide while preserving body weight — an effect attributed to β-cell preservation and enhanced glucose uptake rather than acute insulin stimulation. Mechanistic experiments suggested that dual receptor engagement was necessary for these benefits, with PG-102 also promoting coordinated, delayed receptor internalization compared to monospecific agents. The Phase I randomized, double-blind, placebo-controlled trial enrolled 24 adults with overweight (BMI 25–30 kg/m²) across three dose cohorts, with 18 receiving PG-102 and 6 receiving placebo. The primary endpoint was safety and tolerability. Treatment-emergent adverse events occurred in 83.3% of PG-102 participants and 66.7% of placebo participants; gastrointestinal events were mild to moderate. No serious adverse events or treatment discontinuations were reported. Limitations include the small sample size, single-center design, overweight-only population, and lack of efficacy endpoints in the human portion of the study.
Nature communications · Mar 2026DOI ↗ Review
This review synthesizes evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), with particular attention to the liver-heart connection. The authors draw on mechanistic studies, biopsy-based randomized trials, real-world data, and cardiovascular outcome trials. Key trial findings highlighted include: liraglutide (LEAN trial) achieving steatohepatitis resolution in 39% vs. 9% of placebo recipients; semaglutide showing dose-dependent histologic resolution (up to 59% vs. 17% in Phase 2) and meeting dual histologic endpoints in F2–F3 MASH at interim analysis; and tirzepatide (SYNERGY-NASH) demonstrating MASH resolution in 44–62% vs. 10% with fibrosis improvement signals. Cardiovascular outcome benefits were observed across LEADER, SUSTAIN-6, SELECT, and REWIND trials. Mechanistically, GLP-1RAs are described as reducing hepatic lipogenesis, inflammation, and insulin resistance while improving systemic cardiometabolic risk factors. The review concludes that semaglutide and tirzepatide may serve as foundational therapies for high-risk MASLD patients, while noting gaps in long-term durability data, optimal treatment duration, and evidence in cirrhosis.
Chronic diseases and translational medicine · Mar 2026DOI ↗ In vitro
This in vitro study investigated how Thymosin α1 (Tα1) may help reduce the HIV-1 viral reservoir by acting on immune cells. Researchers differentiated THP-1 cells into monocyte-derived dendritic cells (MoDCs) and co-cultured them with peripheral blood mononuclear cells (PBMCs) obtained from people living with HIV-1 (PLWH). The study found that Tα1 stimulation of MoDCs triggered secretion of the IL-15/IL-15 receptor alpha (IL-15/RA) complex, which was associated with enhanced CD8+ T cell and NK cell functionality — including increased secretion of IFN-γ, TNF-α, and granzyme B (GZMB) — along with reductions in intracellular HIV-1 p24 levels and integrated HIV-1 DNA. Notably, these effects were only observed in PBMCs from immunological responders (CD4+ T cell count >350 cells/µL) and not in non-responders. Key limitations include reliance on an in vitro cell line model (THP-1) rather than primary human dendritic cells, lack of an in vivo component, and the correlational nature of many associations. The authors suggest that Tα1's IL-15 pathway activation in dendritic cells could be a candidate mechanism for functional HIV cure strategies, warranting future clinical investigation.
Virulence · Mar 2026DOI ↗ Moderate · human
This phase 2 randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of mazdutide 9 mg — a once-weekly dual glucagon and glucagon-like peptide-1 (GLP-1) receptor agonist — in Chinese adults with obesity (BMI ≥30 kg/m²) without diabetes over 24 weeks. Eighty participants were randomized 3:1 to receive mazdutide 9 mg (n=60) or placebo (n=20). The primary endpoint was percentage change in body weight from baseline to week 24. The study found that participants receiving mazdutide 9 mg experienced a mean body weight reduction of approximately 12.78%, compared to a gain of 1.80% in the placebo group, representing a treatment difference of approximately −14.58% (95% CI: −18.00 to −11.16). The authors concluded that mazdutide 9 mg was safe and produced substantial weight reductions in this population. Key limitations include the relatively small sample size, the short 24-week duration, the single-country (China) population limiting generalizability, the phase 2 (exploratory) design, and industry sponsorship by Innovent Biologics. The findings are described as supportive of further clinical development.
Med (New York, N.Y.) · Mar 2026DOI ↗ Review
This narrative review examines the evolving role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in managing chronic kidney disease (CKD), particularly in patients with type 2 diabetes, obesity, and established cardiovascular disease. The authors summarize evidence from cardiovascular outcomes trials showing that GLP-1RAs are associated with reduced albuminuria and slower estimated glomerular filtration rate (eGFR) decline, with effects that appear additive to those of SGLT2 inhibitors. They highlight dedicated kidney trials—notably with semaglutide—suggesting slowed CKD progression and reduced mortality in diabetic patients with CKD. The review situates GLP-1RAs within a broader therapeutic framework alongside ACE inhibitors/ARBs, SGLT2 inhibitors, and non-steroidal mineralocorticoid receptor antagonists. The authors acknowledge key evidence gaps, including limited data in non-diabetic CKD populations and uncertainty around oral GLP-1RA efficacy and newer dual/triple agonists (GLP-1/GIP/glucagon). As a review, it does not generate new primary data and is subject to potential selection bias in the literature it incorporates. The authors conclude that GLP-1-based therapies represent a potentially transformative approach to improving weight, cardiovascular, and kidney outcomes in high-risk populations.
International journal of nephrology and renovascular disease · Mar 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed ocular adverse event (AE) reports associated with five GLP-1 receptor agonists (exenatide, tirzepatide, dulaglutide, liraglutide, and semaglutide) using the FDA Adverse Event Reporting System (FAERS) from 2005 to 2024. Ocular AEs comprised 3.61% of all GLP-1 RA-related reports; the median patient age was 63 years, and 62.6% of reports involved female patients. Disproportionality analysis using reporting odds ratios (RORs) identified a statistically significant signal for ocular AEs associated with semaglutide, while exenatide showed a significant annual decline in proportional reporting (-5.15% per year). The authors note that semaglutide's signal may partly reflect its growing market dominance rather than a true differential risk. Key limitations acknowledged by the study include the absence of exposure denominators and comparator groups, vulnerability of FAERS to reporting bias (including under- and over-reporting), and inability to establish causality. The authors characterize the findings as hypothesis-generating and recommend clinician vigilance regarding ocular monitoring, particularly in populations already at elevated risk for diabetic eye disease, while calling for further prospective research to validate these associations and explore potential mechanisms.
Journal of clinical medicine · Mar 2026DOI ↗ Review
This narrative review examines the rapidly evolving landscape of obesity pharmacotherapy, moving beyond currently approved injectable GLP-1 receptor agonists (GLP-1RAs). The authors contextualize the global obesity burden—affecting over 2 billion adults—and acknowledge the transformative but limited success of existing GLP-1-based therapies, citing weight loss plateaus, high inter-individual variability, and weight regain upon discontinuation as key unresolved challenges. The review synthesizes emerging drug classes including: oral GLP-1 agonists (e.g., orforglipron) aimed at improving global accessibility; multi-receptor agonists such as triple GLP-1/GIP/glucagon agonists (e.g., retatrutide, reportedly achieving 20–24% weight reduction) and dual GLP-1/glucagon agonists (e.g., survodutide, mazdutide) with potential benefits in metabolic-associated steatotic liver disease; novel dosing strategies via GLP-1/GIP combination agents (e.g., maridebart cafraglutide); amylin pathway agents (e.g., cagrilintide, amycretin); lean-mass-preserving agents (e.g., bimagrumab); and precision approaches for monogenic obesity (e.g., setmelanotide). The authors call for phenotype-stratified trials, long-term safety data, pediatric research, and equitable implementation. As a review, it does not present original trial data and is inherently subject to selection and interpretation bias.
Metabolism open · Mar 2026DOI ↗ Animal only
This review paper examines the preclinical and limited clinical evidence surrounding Body Protective Compound-157 (BPC-157), a synthetic pentadecapeptide derived from gastric proteins. The authors summarize experimental findings across a range of tissue types, noting that BPC-157 appears to support angiogenesis, collagen synthesis, fibroblast activity, and nitric oxide pathway modulation in animal models, with reported benefits to muscle, tendon, ligament, bone, and gastrointestinal healing. Anti-inflammatory effects, including reduced cytokine activity and improved microvascular integrity, as well as pain modulation via peripheral and dopaminergic mechanisms, are also described. The review notes that human research is limited to small pilot studies in musculoskeletal pain, interstitial cystitis, and intravenous administration contexts, with no major adverse effects reported. The authors acknowledge significant limitations: inconsistent preparation standards, lack of rigorous controlled trials, limited clinical validation, and ongoing regulatory restrictions. The paper concludes that BPC-157 represents a promising candidate for regenerative medicine but that robust clinical evidence is needed before therapeutic use can be recommended. As a narrative review drawing primarily on animal data, it does not establish efficacy in humans.
International journal of molecular sciences · Mar 2026DOI ↗ Review
This paper is a narrative review examining survodutide, a dual GLP-1 and glucagon receptor agonist, in the context of obesity, metabolic dysfunction-associated steatohepatitis (MASH), and related metabolic conditions including type 2 diabetes and cardiovascular disease. The authors summarize survodutide's proposed mechanism of action — encompassing appetite suppression, improved glucose metabolism, and increased energy expenditure — and compare its dual-agonist profile against single-target incretin-based therapies such as GLP-1 receptor agonists alone. The review synthesizes findings from early-phase clinical trials, which the authors report showed significant weight loss and improvements in metabolic markers. Safety and tolerability are also discussed, alongside broader cardiovascular and metabolic benefits suggested by preliminary data. The authors acknowledge that the evidence base remains limited, stressing that long-term safety, durability of effect, patient-specific responses, and cost-effectiveness have not yet been fully established. Ongoing and future trials are highlighted as essential for clarifying survodutide's clinical role. As a review article, this paper does not generate new primary data, and its conclusions are bounded by the early-stage evidence available at the time of writing.
Minerva endocrinology · Mar 2026DOI ↗ In vitro
This study addressed the growing global burden of obesity and type 2 diabetes by designing novel peptide-based triagonists that simultaneously activate three receptors: GLP-1R (glucagon-like peptide-1 receptor), GCGR (glucagon receptor), and GIPR (glucose-dependent insulinotropic polypeptide receptor). The researchers used computer-aided drug design, bioinformatics analyses, and molecular dynamics simulations to rationally identify key sequence determinants, optimal modification sites, and to understand how peptide "stapling" (a structural stabilization technique) affects alpha-helical stability and conformational rigidity. Based on these computational insights, 22 novel triagonist peptide structures were designed and synthesized. Their activity was evaluated in vitro using fluorescence membrane potential assays, with pharmacological balance assessed via a "balanced triagonism score" measuring consistency of activity across all three receptors. Most compounds showed highly balanced activity profiles. The lead compound, P2-L4, demonstrated low-nanomolar potency across all three receptor targets, with efficacy reported as comparable to existing incretin-based reference therapeutics. The study is limited to in vitro findings only, with no animal or human data reported. Further preclinical and clinical validation is required before any therapeutic conclusions can be drawn.
RSC medicinal chemistry · Mar 2026DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy and safety of cagrisema (a fixed-ratio combination of the amylin analogue cagrilintide and the GLP-1 receptor agonist semaglutide) and cagrilintide monotherapy compared with semaglutide monotherapy for obesity management. Researchers searched five major databases and ClinicalTrials.gov, ultimately including three randomized controlled trials comprising 3,545 participants. Using a random-effects model, the study found that cagrisema produced statistically significantly greater reductions in percentage body weight (mean difference –7.47%, 95% CI: –10.58 to –4.36) and absolute body weight compared with semaglutide alone. Cagrisema also demonstrated superior improvements in glycemic markers, including fasting plasma glucose and HbA1c, and in BMI. Lipid parameters and safety profiles were reported as broadly comparable between groups. The authors concluded that cagrisema showed greater weight-loss efficacy and glycemic benefit than semaglutide, with an acceptable tolerability profile. Limitations include the small number of included trials (n=3), potential heterogeneity across trial designs, and the relatively short follow-up durations typical of early-phase RCTs in this therapeutic area.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ In vitro
This study presents the first comprehensive structure-activity relationship (SAR) analysis of SLU-PP-332, a synthetic agonist of estrogen-related receptors (ERRα and ERRγ) — nuclear receptors that regulate mitochondrial metabolism and exercise-responsive gene transcription. The researchers synthesized a library of SLU-PP-332 analogues and systematically varied core pharmacophoric elements, evaluating their effects using cell-based functional assays, downstream gene-expression profiling, and computational modeling (docking and molecular dynamics simulations). The study found that specific structural features of the SLU-PP-332 scaffold govern ERR potency, transcriptional efficacy, selectivity, ligand efficiency, solubility, and metabolic stability. While SLU-PP-332 remained a strong benchmark, certain analogues showed comparable or context-dependent transcriptional activity alongside improvements in ligand efficiency, solubility, or metabolic stability. Computational analyses helped explain how subtle chemical modifications influence receptor engagement and downstream signaling. Limitations include reliance on cell-based and in silico methods with no animal or human data reported. The work establishes design principles for next-generation ERR agonists and positions these compounds as potential exercise-mimetic therapeutics, though extensive preclinical and clinical validation remains to be done.
International journal of biological macromolecules · Mar 2026DOI ↗ Animal only
This review paper examines the potential therapeutic role of BPC 157 (a synthetic 15-amino-acid peptide derived from a gastric protein) in treating severe electrolyte disturbances, drawing on a collection of animal and in-vitro experiments. The paper covers four electrolyte scenarios: (1) hyperkalemia — where BPC 157 was reported to counteract KCl overdose effects including arrhythmias, hypertension, sphincter dysfunction, and mortality in rat models; (2) hypokalemia — where BPC 157 administration (both prophylactically and therapeutically) was reported to prevent fatal outcomes, ECG abnormalities, AV block, and skeletal muscle myoclonus in furosemide-treated rats; (3) hypermagnesemia — where BPC 157 appeared to alleviate muscle weakness, brain lesions, and secondary hyperkalemia in rats; and (4) lithium intoxication — where BPC 157 was reported to promote collateral vascular pathways and resolve multiorgan failure features. In-vitro experiments using HEK293 cells suggested BPC 157 can modulate membrane potential changes induced by electrolyte imbalances. Key limitations include reliance on animal and cell-based data with no human clinical trials reported, and the review format limits independent assessment of individual study methodologies.
Current neuropharmacology · Mar 2026DOI ↗ Review
This narrative review synthesizes the existing literature on the metabolic benefits of GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists in individuals with overweight or obesity. The authors examine evidence supporting these agents' effectiveness for weight reduction and glycemic control, as well as their purported direct effects on multiple organ systems beyond glucose regulation. The review also explores the medium- to long-term implications for metabolic disease outcomes, including considerations of safety and cost-effectiveness with prolonged use. The authors conclude that GLP-1-based therapies show promise for both the improvement and prevention of metabolic disease, while noting that longer-duration studies are needed to broaden approved indications and confirm the safety profile of these agents. As a narrative review, the paper is subject to inherent limitations including potential selection bias in the literature chosen, the absence of a systematic search protocol or meta-analytic pooling, and reliance on the quality and duration of the underlying primary studies, which the authors themselves acknowledge are insufficiently long in many cases.
Healthcare (Basel, Switzerland) · Mar 2026DOI ↗ Animal only
This review paper proposes cytoprotection as a unifying therapeutic framework to address what the authors call the "hemorrhage-thrombosis paradox" — the clinical challenge that hemorrhage and thrombosis can coexist as phase-dependent manifestations of vascular dysregulation. The paper centers on BPC 157, a stable synthetic gastric pentadecapeptide, which the authors argue can simultaneously counteract both hemorrhage and thrombosis in rodent models without directly interfering with the coagulation cascade (as assessed by aggregometry and thromboelastometry). The review synthesizes preclinical and conceptual evidence to argue that BPC 157 achieves this bidirectional vascular regulation through preservation of endothelial integrity, normalization of microcirculation, modulation of the nitric oxide system, and recruitment of collateral adaptive pathways. The authors contrast this proposed "full cytoprotection" with the "partial cytoprotection" of conventional agents such as anticoagulants, antiplatelet drugs, fibrinolytics, beta blockers, calcium channel blockers, and statins, which they contend act in isolated or unidirectional ways. The paper also discusses applications in wound healing, arrhythmia control, and normalization of Virchow's triad. Notably, the authors explicitly acknowledge that findings are predominantly preclinical and that clinical validation in humans remains necessary.
Pharmaceuticals (Basel, Switzerland) · Mar 2026DOI ↗