Review
This review synthesizes existing preclinical and emerging translational evidence on Thymosin β4 (Tβ4), a conserved 43-amino-acid peptide, and its N-terminal metabolite Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro), as potential therapeutic candidates in kidney disease. The authors map the intracellular and extracellular mechanisms of the Tβ4–Ac-SDKP axis, including its roles in actin sequestration, cytoprotection, anti-inflammatory signaling, and antifibrotic actions across both glomerular and tubular compartments. Evidence is evaluated across models of both acute and chronic kidney injury. The review acknowledges contradictory findings regarding fibrosis and proposes conceptual frameworks to explain bidirectional effects and model-dependent mechanisms. Translational considerations discussed include peptide pharmacokinetics, stability challenges, and drug delivery strategies. The authors note that key barriers to clinical translation remain, including the need for validation in additional clinically relevant models, resolution of peptide instability, and comprehensive safety profiling. As a narrative review, this paper does not generate new experimental data, and its conclusions are limited by the quality and heterogeneity of the underlying studies, most of which appear to be animal-based.
Review
This review examines the evolving therapeutic role of amylin, a pancreatic peptide hormone, in managing "diabesity" — the coexistence of diabetes and obesity — over the past five years. The authors describe amylin's physiological mechanisms, including postprandial glucose regulation through delayed gastric emptying and glucagon suppression, as well as appetite control via central nervous system pathways. The review covers preclinical development of long-acting amylin analogs with improved pharmacokinetics and reduced aggregation, which demonstrated significant metabolic benefits in animal models. Clinically, the review highlights pramlintide, a synthetic amylin analog shown to modestly improve glycemic control and promote weight loss in diabetic patients. It also discusses cagrilintide, a newer long-acting analog, which the authors report has produced substantial weight reduction in individuals with obesity. Notably, the review emphasizes that combining amylin analogs with GLP-1 receptor agonists may achieve synergistic weight loss exceeding 15%. Limitations include the inherent constraints of a review design — it does not present new primary data, and the breadth of evidence cited spans preclinical to early clinical stages, meaning conclusions about long-term efficacy and safety remain preliminary.
Journal of obesity & metabolic syndrome · Jan 2026DOI ↗ 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.
Strong · human
This meta-analysis pooled data from five randomized controlled trials (RCTs) to evaluate the effects of tesamorelin — a synthetic growth hormone-releasing hormone (GHRH) analogue — compared with placebo in adults living with HIV who have lipodystrophy. The authors conducted a systematic search of five major databases through July 2025 and applied a random-effects meta-analysis model, assessing risk of bias with RoB 2.0 and certainty of evidence using GRADE. The analysis found that tesamorelin was associated with a statistically significant reduction in visceral adipose tissue (mean difference of approximately −27.71 cm²), as well as improvements in hepatic fat content, lean body mass, and IGF-1 levels. The study authors reported that these benefits occurred without clinically significant adverse effects on glucose metabolism or serious safety signals. Limitations of the analysis include the small number of included trials (n=5), potential variability across trial populations and durations, and the inherent constraints of meta-analytic methodology in establishing causality. The findings suggest tesamorelin may offer metabolic and body composition benefits in HIV-associated lipodystrophy, though the authors note the results should be interpreted within the context of the underlying evidence base.
Obesity research & clinical practice · Jan 2026DOI ↗ Review
This commentary is aimed at clinicians and provides practical guidance for counseling patients who are hesitant about starting glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy due to concerns about its perceived "newness" or unproven long-term safety. The paper briefly traces the history of GLP-1, from its discovery in the 1980s through nearly two decades of clinical use, to contextualize these agents as well-established rather than experimental. It distinguishes native GLP-1 from structurally modified agents such as semaglutide and tirzepatide, arguing that modifications prolong drug action without fundamentally changing the hormone's core mechanism. The authors summarize available safety data, noting that known side effects are predominantly mild and transient gastrointestinal in nature, and that there is currently no established evidence linking GLP-1RAs to feared risks such as cancer. The paper includes a practical counseling checklist and sample patient-friendly language intended to support shared decision-making conversations. Key limitations include the absence of original data, lack of systematic literature review methodology, and potential for author bias in evidence selection. Findings and reassurances are the authors' interpretive positions rather than conclusions drawn from a primary study.
American journal of preventive cardiology · Jan 2026DOI ↗ Animal onlyPreprint
This preclinical study investigated whether mazdutide — a dual GLP-1/glucagon receptor agonist that has shown clinical promise for weight management and metabolic disorders — could alleviate non-alcoholic fatty liver disease (NAFLD) and explored its potential mechanism of action. Researchers induced NAFLD in mice via a 12-week high-fat diet, then treated animals with subcutaneous mazdutide for four weeks. Complementary in vitro experiments exposed hepatocytes to free fatty acids to model hepatic steatosis, followed by mazdutide co-treatment. The study measured serum and liver lipid profiles, liver injury markers, inflammatory cytokines, oxidative stress indicators, and key protein expression via Western blot and immunohistochemistry. Results indicated that mazdutide treatment was associated with reduced hepatic fat accumulation, lower liver injury markers, attenuated inflammation, and decreased oxidative stress in both models. Mechanistically, the authors attributed these effects to modulation of the PERK–eIF2α–ATF4–CHOP endoplasmic reticulum (ER) stress pathway, suppression of NF-κB-driven inflammation, and downregulation of lipogenic regulators (SREBP-1, C/EBPβ, PPARγ). Key limitations include the exclusive use of animal and cell-based models, lack of human data, and preprint status meaning findings have not yet undergone formal peer review.
Unknown journal · Jan 2026DOI ↗ In vitro
This study investigated the chemical and physical stability of afamelanotide (melanotan-1), a synthetic 13-amino acid peptidomimetic of α-melanocyte stimulating hormone (α-MSH) approved as an orphan drug for erythropoietic protoporphyria. Researchers subjected the compound to a range of stress conditions — acidic, basic, neutral, oxidative, UV light exposure, and elevated temperature (60°C) — following International Council for Harmonisation (ICH) guidelines Q1A(R2) and Q5C. Using gradient reversed-phase HPLC coupled with ultra-high-performance liquid chromatography–high resolution tandem mass spectrometry (UHPLC-HRMS/MS), the team identified and structurally characterized 14 distinct degradation products. Collision-induced dissociation fragmentation patterns enabled detailed elucidation of each product's structure. Key degradation pathways identified included truncation, methylation, deacetylation, and oxidation. The analytical method was validated per ICH Q2(R1) guidelines. This work is purely analytical and pharmaceutical in nature — it does not involve human subjects, animals, or cell-based experiments. Its primary value lies in establishing a comprehensive stability profile of afamelanotide to inform rational drug formulation design. No clinical outcomes, efficacy, or safety data in biological systems were assessed.
Journal of pharmaceutical and biomedical analysis · Jan 2026DOI ↗ Animal only
This 7-day rat study investigated the course of surgically created tracheocutaneous fistulas and whether the pentadecapeptide BPC 157 could promote healing, with a focus on the nitric oxide (NO) system's role. Rats with tracheocutaneous fistulas displayed severe respiratory distress, including open-mouth breathing, abdominal "heaving," cyanosis, abundant fistula secretion, weight loss, failed skin and tracheal wound healing, a well-formed fistulous tract, and tracheal shrinking below the fistula site. Tissue analyses showed decreased NO levels and increased malondialdehyde (MDA), a marker of oxidative stress. BPC 157, administered either intraperitoneally or in drinking water, was reported by the authors to accelerate fistula closure, improve macro- and microscopic healing of skin and tracheal defects, reduce respiratory distress signs, and counteract the NO and MDA changes observed in untreated controls. Using a "triple NO-agent" approach (L-NAME to block NO synthesis, L-arginine to enhance it, or both combined), the study further reported that BPC 157 could override L-NAME-induced worsening, enhance L-arginine-induced improvement, and restore healing even under combined NO immobilization. Key limitations include the exclusive use of an animal model, small experimental groups typical of rat studies, and the absence of human data.
Pharmaceuticals (Basel, Switzerland) · Jan 2026DOI ↗ Review
This paper examines the growing use of glucagon-like peptide-1 (GLP-1) receptor agonists — specifically semaglutide and tirzepatide — in the context of obesity management. The authors discuss how these medications have meaningfully shifted the landscape of obesity care, while simultaneously raising important questions about their safety profile, long-term outcomes, and the risks associated with unregulated or compounded versions of these products. The paper highlights the tension between rapidly increasing patient demand and the need for robust clinical oversight. Key concerns addressed include adverse side effects, the consequences of unsupervised use, and the importance of coordinated clinical frameworks to ensure patients access these therapies safely. The authors advocate for structured monitoring systems and regulatory vigilance to keep pace with the surge in prescribing. As a review or commentary piece rather than an original clinical trial, the paper does not generate new primary data; its conclusions are based on synthesis of existing evidence and expert perspective. This limits its ability to independently establish causality or quantify risk with precision, and readers should interpret its claims in that context.
PLoS medicine · Jan 2026DOI ↗ Animal only
This mouse study investigated whether Growth Hormone Releasing Peptide-6 (GHRP-6) could protect against acute lung injury (ALI) and its progression to pulmonary fibrosis. Researchers used two established animal models: intratracheal lipopolysaccharide (LPS) instillation and a combined zymosan (ZYM) plus platelet-activating factor (PAF) injection. Both acute (24-hour to 15-day) and chronic (28-day) scenarios were examined. In the acute setting, GHRP-6 treatment was associated with reduced neutrophilic alveolitis, improved lung compliance, better alveolar-capillary permeability, and lower serum interleukin-1 beta levels compared to saline controls. In the chronic setting, GHRP-6-treated animals showed better preservation of lung parenchymal architecture and notably less collagen accumulation, suggesting reduced progression to fibrosis. The authors describe this as the first assessment of GHRP-6's protective potential in lung injury models. Key limitations include exclusive use of mouse models with no human data, multiple treatment variables across scenarios, and the lack of mechanistic depth regarding GHRP-6's specific molecular targets in lung tissue. The authors conclude that findings warrant future investigation into GHRP-6's pneumoprotective effects.
International immunopharmacology · Jan 2026DOI ↗ Animal only
This animal study investigated whether orally administered salmon acylated ghrelin (sAG) could stimulate food intake in common carp (Cyprinus carpio) and sought to identify the local mechanism behind any such effect. Carp were fed experimental diets containing a range of sAG concentrations in single-shot feeding trials, and additional voluntary feed intake was measured afterward. The study found that diets containing sAG at or above a certain threshold produced a significant, dose-dependent increase in feed intake that plateaued at higher concentrations. Notably, plasma ghrelin levels did not rise following oral administration, as confirmed by two separate radioimmunoassay methods, suggesting that sAG was not absorbed into the bloodstream. To probe the mechanism, researchers used a ghrelin receptor antagonist ([D-Lys3]-GHRP-6) and capsaicin — both abolished the orexigenic effect — pointing to a local signaling pathway involving growth hormone secretagogue receptors and peripheral sensory (likely vagal afferent) neurons. The authors propose this represents a non-circulatory gut-brain axis mechanism in fish. Limitations include that results are limited to a single fish species under controlled laboratory conditions, and translation to other vertebrates or aquaculture settings requires further research.
Review
This narrative review examines the problem of lean body mass (LBM) loss associated with weight loss, with particular focus on incretin-based therapies such as GLP-1 receptor agonists (e.g., semaglutide) and dual GIP/GLP-1 receptor agonists (e.g., tirzepatide). The authors queried PubMed, Medline, and Scopus for randomized controlled trials and Phase II/III trials related to obesity, muscle loss, and lean mass preservation, excluding animal studies. The review outlines the physiological mechanisms driving muscle loss during caloric deficit—including reduced anabolic signaling, increased protein catabolism, and hormonal changes—and surveys pharmacological agents under investigation to counteract these effects. Key drug classes discussed include bimagrumab (an activin receptor antagonist targeting the myostatin pathway), tesamorelin (a growth hormone-releasing hormone agonist), and enobosarm (a selective androgen receptor modulator). The authors note that while incretin-based therapies represent a major advance in obesity management, the accompanying loss of muscle mass is a clinically meaningful concern. Most agents targeting LBM preservation are in early research phases. Limitations include reliance on narrative rather than systematic methodology, potential selection bias in study inclusion, and the rapidly evolving evidence base in this area.
Journal of clinical medicine · Jan 2026DOI ↗ Review
This paper examines the ethical dimensions of prescribing semaglutide (marketed as Ozempic, Wegovy, and Rybelsus) to children in the context of its expanding regulatory approvals for paediatric obesity management across several countries, including Germany, the UK, Denmark, and the United Arab Emirates. The authors explore tensions between the potential benefits of semaglutide — such as reducing cardiovascular risk and preventing obesity-related illness in children — and significant concerns including uncertainties about long-term safety, effects on child development, and unanswered efficacy questions in younger populations. The paper focuses particularly on three ethical challenges: access barriers and health equity, the risk of reinforcing weight-based stigma, and the tendency to overlook structural and social determinants of childhood obesity. The authors offer ethical recommendations for clinicians aimed at minimising harm, respecting children's autonomy, and promoting overall health. As an ethics and policy review paper, it does not present original clinical trial data, and its conclusions are based on normative argument and synthesis of existing literature rather than empirical evidence from controlled studies.
Archives of disease in childhood · Jan 2026DOI ↗ 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.
Review
This state-of-the-art narrative review examines the potential role of innovative diabetes therapies — specifically incretin-based therapies (GLP-1 receptor agonists), SGLT2 inhibitors, and emerging dual/triple receptor agonists — in modifying the course of diabetic peripheral neuropathy (DPN) and autonomic diabetic neuropathy. The authors synthesize evidence from preclinical models, clinical trials, and real-world observational studies, arguing that GLP-1 RAs and SGLT2 inhibitors may offer neuroprotective benefits beyond their established glucose-lowering effects, potentially through attenuation of inflammation and oxidative stress, improved mitochondrial function, and reduced neuronal damage. The review also highlights novel dual and triple receptor agonists as emerging agents with theoretical synergistic neuroprotective potential via simultaneous activation of multiple metabolic pathways. Limitations inherent to this paper include its narrative (non-systematic) design, which introduces selection bias, and the authors' own acknowledgment that clinical data on newer agents in the context of DN remain limited. The review does not generate new primary data. Overall, it provides a useful conceptual synthesis of an evolving therapeutic landscape but cannot establish causality or definitive efficacy for any agent in DN.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Jan 2026DOI ↗ 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 ↗ Review
This narrative review synthesizes mechanistic and clinical trial evidence on incretin-based therapies — GLP-1 receptor agonists (GLP-1RA), DPP-4 inhibitors, and newer dual/triple agonists — for cardiovascular (CV) and renal protection in type 2 diabetes (T2DM) and related conditions. The authors draw on multiple pivotal randomized cardiovascular outcome trials (CVOTs), including SELECT (semaglutide in obesity without diabetes), FLOW (semaglutide in chronic kidney disease), SOUL (oral semaglutide in T2DM with ASCVD/CKD), and SURPASS-CVOT (tirzepatide vs. dulaglutide). Key findings attributed to these trials include reductions in major adverse cardiovascular events (MACE), CV and all-cause mortality, heart-failure hospitalization, and hard kidney endpoints across GLP-1RA programs. A 2019 pooled analysis and a 2025 update reportedly confirm these cardiorenal benefits independent of baseline HbA1c. Mechanistically, the review describes GLP-1R signaling via Gs-cAMP/PKA, β-arrestin, and Gq pathways, linked to anti-inflammatory, natriuretic, and antifibrotic effects. Oral small-molecule GLP-1R agonists (e.g., orforglipron) showed phase 2 efficacy but lacked long-term outcome data at time of publication. As a narrative review, it is subject to selection bias and does not conduct formal meta-analytic pooling.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Jan 2026DOI ↗ Review
This narrative review examines the potential role of therapeutic peptides in orthopaedic care, synthesizing preclinical and mechanistic literature across several peptide classes. The authors categorize peptides by their primary proposed function: wound-healing agents (BPC-157, TB-500, GHK-Cu), growth hormone secretagogues (ipamorelin, CJC-1295, tesamorelin, sermorelin, AOD-9604), recovery-enhancing peptides (epithalon, delta sleep-inducing peptide, pinealon), and neuroactive peptides (selank, semax, dihexa). The review describes how these compounds are theorized to interact with signaling pathways—including PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK—to promote tissue regeneration, resolve inflammation, and support neuromuscular recovery. The authors acknowledge that, while preclinical evidence is promising, robust human clinical trial data are largely absent, representing a significant gap in the literature. Limitations include the review's reliance on animal and in vitro studies, the absence of a systematic search methodology, and the lack of direct clinical evidence supporting efficacy or safety in human orthopaedic populations. The authors call for future controlled trials to validate these mechanistic findings in clinical settings.
Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews · Jan 2026DOI ↗ Animal only
This study characterized growth hormone (GH) secretion patterns and responsiveness to exogenous GH-releasing hormone (GHRH) in adult male cynomolgus monkeys, with the goal of evaluating their suitability as a model for pituitary toxicity research. Two groups of ten animals were used to assess diurnal and day-to-day GH variation via serial serum sampling, while a separate four-animal-per-group crossover examined GH responses to intravenous pralmorelin hydrochloride (a GHRH analog) versus saline. GH was measured by ELISA. The study found a diurnal pattern resembling that of humans, with GH rising in the late morning, dipping around midday, and peaking at night. Considerable inter- and intra-individual daily variation was also observed over five consecutive days. In the stimulation test, GHRH-treated animals showed significantly higher GH concentrations at 0.5 and 1 hour post-administration compared to controls. The authors conclude that cynomolgus monkeys share key GH secretion characteristics with humans and may serve as a relevant non-clinical model. Limitations include small sample sizes, male-only subjects, and the non-human primate setting, meaning direct translation to human physiology or clinical applications requires caution.
In vivo (Athens, Greece) · Jan 2026DOI ↗ Review
This perspective article examines retatrutide (LY3437943), a novel triple receptor agonist that simultaneously targets GLP-1, GIP, and glucagon receptors, positioning it as a significant advancement in obesity pharmacotherapy. The authors contextualize retatrutide within the broader evolution of incretin-based therapies, arguing that its multi-hormonal mechanism addresses limitations of existing GLP-1 and dual GIP/GLP-1 agonists. The article highlights Phase 2 trial findings, which reportedly demonstrated weight reductions comparable to bariatric surgery, along with potential benefits for metabolic comorbidities including non-alcoholic steatohepatitis (NASH) and cardiovascular disease. The authors frame retatrutide as a proof-of-concept for rational multi-agonist peptide engineering and advocate for broader scientific engagement, health equity considerations, and proactive policy planning in anticipation of wider clinical adoption. As a perspective/review piece, this paper synthesizes existing evidence rather than presenting original trial data, and does not provide head-to-head comparisons or long-term safety data. Its conclusions are largely interpretive, and the characterization of Phase 2 findings as surgery-comparable warrants cautious interpretation pending Phase 3 results and regulatory review.
Clinical pharmacology in drug development · Jan 2026DOI ↗