Review
This narrative review examines the skeletal consequences of modern obesity treatments, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs) and bariatric/metabolic surgery. The authors challenge the historical assumption that obesity is bone-protective due to mechanical loading, citing emerging evidence of qualitative bone deterioration and site-specific fracture risks in individuals with obesity. The review synthesizes findings showing that intentional weight loss via caloric restriction or bariatric surgery consistently accelerates bone turnover and reduces bone mineral density (BMD), with surgical approaches carrying the most pronounced skeletal impact. Regarding GLP-1RAs, the authors report that available data suggest modest BMD declines largely proportional to the degree of weight loss, potentially driven by mechanical unloading. Interestingly, the review also notes that preclinical studies suggest GLP-1 signaling may have direct osteoanabolic and anti-resorptive properties, though these effects remain to be confirmed in humans. The authors recommend integrating resistance exercise, adequate calcium, vitamin D, and protein intake, and skeletal monitoring for high-risk patients into obesity care. Limitations include reliance on heterogeneous primary literature and the absence of long-term fracture outcome data for newer pharmacological agents.
Endocrinology and metabolism (Seoul, Korea) · Apr 2026DOI ↗ Limited · human
This observational case-control study investigated whether serum MOTS-c levels and the mitochondrial m.1382A>C gene polymorphism are associated with polycystic ovary syndrome (PCOS) in adolescents. A total of 246 participants aged 12–18 were enrolled: 121 diagnosed with PCOS (based on irregular menstrual cycles and clinical/biochemical hyperandrogenism) and 125 healthy controls with regular menstruation. Serum MOTS-c levels were measured by ELISA, and the m.1382A>C polymorphism was assessed by gene sequencing. The study found that mean serum MOTS-c levels were slightly higher in the PCOS group compared to controls, but this difference did not reach statistical significance (p = 0.059). No significant associations were observed between MOTS-c levels and anthropometric or metabolic parameters within the PCOS group. Notably, all participants carried the wild-type (A/A) genotype for the m.1382A>C polymorphism, making genetic association analysis impossible in this cohort. The authors concluded that MOTS-c may play only a minor role in PCOS pathophysiology. Limitations include the modest sample size, the adolescent-only population, the absence of polymorphism variability, and the cross-sectional design precluding causal inference.
Archives of endocrinology and metabolism · Apr 2026DOI ↗ Animal only
This animal study compared the anti-atherosclerotic effects of tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a selective GLP-1 receptor agonist) in ApoE knockout mice. Mice were treated with streptozotocin to induce diabetes and divided into early diabetes, late diabetes, and non-diabetic groups, each receiving either agent or saline for 12 weeks. The study found that in the early diabetes group, both tirzepatide and semaglutide significantly reduced aortic plaque formation compared to controls, with modest improvements in blood glucose and lipid levels. No significant vascular effects were observed in the late diabetes or non-diabetic groups in terms of plaque reduction. Tirzepatide more broadly reduced inflammatory markers—including Mcp-1, Il-6, I-cam, and Cd68—compared to semaglutide. Anti-inflammatory effects were also detected in non-diabetic mice, suggesting possible vascular protective mechanisms independent of metabolic control. The authors conclude that dual incretin receptor agonism may offer cardiovascular benefits, though the specific contribution of GIP signaling requires further investigation. Key limitations include the use of an animal model, which may not translate directly to human cardiovascular disease.
Scientific reports · Apr 2026DOI ↗ Review
This comprehensive review examines the genetic underpinnings of obesity and the evolving landscape of pharmacological treatment informed by genetic insights. The authors distinguish between rare monogenic obesity — driven by mutations in single genes such as LEP, POMC, and MC4R within the leptin-melanocortin neuroendocrine signaling pathway — and common polygenic obesity, which results from the cumulative small effects of hundreds of genetic variants, including loci identified through genome-wide association studies (GWAS) such as FTO and SEC16B. The review also discusses how gene-environment interactions contribute to the heterogeneity of obesity phenotypes. On the pharmacotherapy side, the authors highlight recent advances including GLP-1 receptor agonists and dual/triple incretin agonists, noting their reported efficacy across diverse genetic backgrounds. The potential clinical utility of polygenic risk scores for early risk identification and prevention is explored. Limitations of this paper include its nature as a narrative review — it synthesizes existing literature rather than generating new empirical data — and it does not perform a systematic or meta-analytic evaluation. The authors acknowledge ongoing challenges in integrating genomic data into clinical practice and call for further research into genetic screening protocols and gene-environment interactions to advance precision medicine in obesity management.
Acta biochimica Polonica · Apr 2026DOI ↗ Review
This narrative review examines the expanding therapeutic landscape of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) beyond their established roles in glycemic control and the metabolic-cardiovascular-renal axis. The authors searched PubMed, Scopus, and Google Scholar for publications from 2014 to 2026, with over 80% of included studies published between 2020 and 2026. The review synthesizes findings across a broad range of conditions, reporting associations between GLP-1 RA use and potential benefits in substance use disorders, mental health disorders, neurodegenerative diseases, liver disease (including reduced hepatic steatosis and lower risk of hepatocellular carcinoma), genitourinary disorders, polycystic ovary syndrome (PCOS), male fertility and libido, prostate cancer, osteoarthritis, and sleep apnea. The authors note that GLP-1 RAs currently represent the most effective pharmacological agents for obesity treatment. Key limitations include the narrative (non-systematic) review design, which is susceptible to selection bias, and the authors' own acknowledgment that much of the supporting evidence is preliminary, requiring further large-scale, well-designed clinical trials to establish efficacy and safety across these emerging indications.
Journal of clinical medicine · Apr 2026DOI ↗ ReviewPreprint
This narrative review examines the pharmacological mechanisms, safety profiles, and regulatory status of twelve peptides commonly encountered in sports medicine and athletic performance contexts, including both approved agents (e.g., tesamorelin/Egrifta, sermorelin) and unapproved "gray market" compounds (e.g., BPC-157, CJC-1295, TB-500, ipamorelin, AOD-9604, FS-344, GHK-Cu, MOTS-C, SS-31, and thymosin beta-4). The authors note that while many unapproved peptides show promising tissue repair and metabolic outcomes in animal models, rigorous human safety and efficacy data remain scarce. The review highlights the emergence of a direct-to-consumer gray market operating outside regulatory oversight and the potential for serious patient harm. It further discusses the placebo effect as a potential mediator of perceived peptide efficacy, and how social media may amplify this effect. The authors provide a clinical framework to guide patient-provider discussions and promote evidence-based practice for musculoskeletal healing. Key limitations include the narrative (non-systematic) review design, reliance on preclinical literature for most unapproved compounds, and the absence of head-to-head human trials for the majority of agents discussed.
Unknown journal · Apr 2026DOI ↗ Review
This comprehensive narrative review examines nine therapeutic peptides with proposed applications in healthy aging and age-related conditions: tirzepatide (metabolic dysfunction), epitalon (telomere biology), GHK-Cu (dermal regeneration), BPC-157 and TB-500 (tissue repair), Semax (neuroprotection), CJC-1295 and ipamorelin (growth hormone modulation), and bremelanotide (sexual function). The authors searched PubMed, Scopus, and regulatory databases through January 2026, selecting 20 primary sources based on relevance and methodological quality. The review found that FDA-approved agents such as tirzepatide and bremelanotide have robust safety and efficacy data from large-scale trials, while investigational peptides such as epitalon, BPC-157, and TB-500 show promising signals primarily from preclinical and limited clinical studies. The authors highlight significant knowledge gaps, including the absence of long-term safety data for non-approved peptides, undefined optimal dosing regimens, unknown combination therapy effects, and lack of validated biomarkers for monitoring efficacy. The authors conclude that while therapeutic peptides offer mechanistically diverse approaches to aging hallmarks, investigational agents require rigorous clinical trial validation before clinical adoption. As a narrative review, findings are subject to selection bias and do not represent a quantitative synthesis of evidence.
Frontiers in aging · Apr 2026DOI ↗ Review
This review examines the acute contractile effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on the human heart, with a focus on isolated atrial and ventricular cardiac preparations from both failing and non-failing hearts. The paper discusses how GLP-1R stimulation in cell cultures, neonatal cardiomyocytes, and adult atrial cardiomyocytes elevates adenylyl cyclase activity and increases cAMP levels, a key intracellular signaling pathway. The authors explore the expanding landscape of receptor agonists — including single GLP-1R agonists as well as dual and triple agonists targeting the glucagon receptor (GCGR) and/or the GIP receptor (GIPR) — in the context of treating type 2 diabetes, obesity, liver disease, and cardiovascular conditions. GLP-1R expression across different cardiac regions of the human heart is also reviewed. The paper critically evaluates existing experimental and clinical data, notes that several newer agents remain in early clinical development phases, and identifies gaps requiring further research. A key limitation is that the review synthesizes heterogeneous experimental and early-phase clinical data rather than presenting original controlled trial findings, limiting the strength of conclusions about cardiac efficacy or safety in humans.
Pharmaceutics · Apr 2026DOI ↗ Strong · human
This systematic review and network meta-analysis compared the weight-loss efficacy and safety of three FDA-approved agents—tirzepatide (a dual GIP/GLP-1 agonist), semaglutide, and liraglutide—in non-diabetic adults with obesity. Researchers searched four major databases through May 2025 and identified 15 Phase 3 RCTs encompassing 14,059 patients. Using a frequentist random-effects network meta-analysis, the authors found that all three agents produced statistically significant body weight reductions compared to placebo. Ranking by magnitude of effect, the highest tolerated dose of tirzepatide demonstrated the greatest weight reduction, followed by lower tirzepatide doses, then semaglutide, and finally liraglutide. On the safety side, tirzepatide and semaglutide were each associated with a higher risk of any adverse event compared to placebo, while liraglutide was not. The authors note that the analysis was limited to Phase 3 RCTs and did not assess long-term outcomes such as weight regain after discontinuation, metabolic endpoints, cost-effectiveness, or patient preferences, which they identify as priorities for future research.
Obesity (Silver Spring, Md.) · Apr 2026DOI ↗ Moderate · human
This systematic review and meta-analysis pooled data from three head-to-head randomized or controlled trials comparing tirzepatide (a dual GIP/GLP-1 receptor agonist) with semaglutide (a selective GLP-1 receptor agonist) in adults with obesity and/or type 2 diabetes. Studies were identified through searches of PubMed, Embase, and ScienceDirect up to February 2026. Using a random-effects model, the authors found that tirzepatide was associated with significantly greater weight reduction compared to semaglutide (pooled mean difference: −5.19 kg) and a higher likelihood of achieving ≥10% weight loss (pooled risk ratio: 1.50). No statistically significant differences were observed in overall adverse events or gastrointestinal events between the two agents; however, serious adverse events were reported more frequently with tirzepatide (risk ratio: 1.83). Key limitations include a very small number of included studies (n=3), substantial statistical heterogeneity in weight-related outcomes (I² >86%), and insufficient follow-up duration to draw conclusions about long-term cardiovascular safety. The authors note that further studies with longer follow-up are needed to confirm the cardiometabolic safety profile of tirzepatide relative to semaglutide.
Nepal journal of epidemiology · Apr 2026DOI ↗ In vitro
This in vitro study examined the effects of three incretin-based therapies — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP agonist), and cagrilintide (amylin analogue) — on mitochondrial function in C2C12 skeletal muscle myotubes under both normal and lipotoxic conditions. Lipotoxicity was induced using palmitic acid (PA), which significantly reduced basal oxygen consumption rate and ATP production in treated cells. The study used Seahorse XFp metabolic flux analysis, mitochondrial DNA copy number quantification (qPCR), and oxidative phosphorylation complex protein expression (western blotting), with key findings replicated in primary human skeletal muscle cells. The researchers found that semaglutide and cagrilintide transiently reduced basal respiration in healthy myotubes, while tirzepatide demonstrated more sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions. The study's primary limitations include its reliance on cell culture models, meaning findings may not directly translate to whole-organism physiology, and the use of a single lipotoxic stimulus. The partial replication in human primary cells adds some translational relevance, but in vivo validation remains absent.
Journal of cachexia, sarcopenia and muscle · Apr 2026DOI ↗ Review
This review paper examines the role of amylin — a pancreatic hormone — in regulating food intake, body weight, and reward processing through its actions in the brain. The authors outline how early research focused on hindbrain regions as the primary sites where amylin suppresses feeding, but highlight more recent evidence pointing to mesolimbic brain structures (associated with reward and motivation) as additional key targets. The review discusses findings suggesting that amylin signaling in these reward-related areas influences not only consumption of palatable foods but also responses to drugs of abuse, raising important considerations for the development of amylin-based obesity therapies. The paper is contextualized within the broader landscape of obesity treatment, acknowledging the success of GLP-1 receptor agonists while arguing that amylin represents a complementary pharmacological avenue. As a narrative review, the paper synthesizes existing literature rather than presenting new experimental data, meaning its conclusions are only as strong as the individual studies it draws upon. It does not provide direct clinical trial evidence, and the breadth of findings discussed spans animal models and limited human data, which constrains the translational certainty of its conclusions.
Comprehensive Physiology · Apr 2026DOI ↗ Limited · human
This cross-sectional study conducted in Saudi Arabia (January–June 2025) investigated the frequency, characteristics, and predictors of hair loss among 254 adults using GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Ozempic), tirzepatide (Mounjaro), liraglutide (Saxenda), or liraglutide (Victoza) — primarily for weight loss. Data were collected via structured questionnaires covering demographics, clinical characteristics, and hair loss details such as timing, severity, and progression. The majority of participants were female (71.3%), with a mean age of approximately 33 years. The study found that overall hair loss prevalence did not differ significantly across GLP-1RA types (p = 0.116); however, severe hair loss was reported significantly more often among Mounjaro (43.4%) and Saxenda (42.9%) users. Female sex and Mounjaro use were identified as notable predictors of hair loss. The authors noted that the hair loss observed was generally non-scarring and potentially reversible, but associated with psychological distress and possible impacts on treatment adherence. Key limitations include the cross-sectional design (precluding causal inference), reliance on self-reported data, the single-country sample limiting generalizability, and the absence of a control group not using GLP-1RAs.
Journal of cosmetic dermatology · Apr 2026DOI ↗ Review
This review article provides a comprehensive overview of glucagon-like peptide-1 (GLP-1) receptor agonists, a class of incretin-based therapies used in the management of type 2 diabetes mellitus and obesity. The authors describe the multiple mechanisms of action of these agents, including glucose-mediated insulin stimulation, slowing of gastric emptying, glucagon inhibition, favorable shifts in the intestinal microbiome, and direct hypothalamic effects that promote satiety and weight loss. The review highlights findings from large-scale randomized controlled trials demonstrating that GLP-1 receptor agonists can reduce cardiovascular risk and slow progression to renal failure in high-risk individuals and those with type 2 diabetes. It also covers dual GLP-1 and glucose-dependent insulinotropic peptide (GIP) agonists. The authors note that adverse effects are predominantly gastrointestinal and raise concerns about potential loss of muscle and bone mass. Unresolved questions include long-term treatment adherence, weight regain following discontinuation, and the clinical significance of muscle and bone changes. Emerging research is exploring additional therapeutic applications. As a narrative review, it does not present original data, which limits its direct evidentiary weight.
The New England journal of medicine · Apr 2026DOI ↗ In vitro
This study characterized two novel pan-estrogen-related receptor (ERR) agonists, SLU-PP-332 and SLU-PP-915, which are being investigated as potential "exercise mimetics" — compounds that trigger physiological responses similar to physical exercise. Because of this property, the researchers assessed their relevance for sports anti-doping programs. Using liquid chromatography–high resolution tandem mass spectrometry (LC-HRMS/MS), the team analyzed the chemical profiles of both compounds and mapped their in vitro metabolic transformation products generated via human liver S9 fractions and human liver microsomes. For SLU-PP-332, nine metabolites were identified: six Phase-I and three Phase-II conjugates. For SLU-PP-915, seven Phase-I metabolites were identified. Three SLU-PP-915 metabolites were independently confirmed through chemical synthesis and nuclear magnetic resonance (NMR) spectroscopy. The study is limited to in vitro methodology and does not include in vivo human or animal pharmacokinetic data. The authors suggest these findings could serve as a foundation for developing urine or blood detection methods to identify illicit use of these compounds in competitive sports, but no conclusions about human efficacy or safety are drawn.
Rapid communications in mass spectrometry : RCM · Apr 2026DOI ↗ Review
This review examines the cardioprotective potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with autoimmune rheumatic diseases (ARDs), a population at elevated risk of premature cardiovascular death. The authors synthesize evidence from landmark randomized controlled trials in diabetes and obesity—where GLP-1RAs demonstrated cardiovascular, kidney, and metabolic benefits—alongside observational studies in ARD populations (including rheumatoid arthritis and systemic lupus erythematosus) that reported reductions in cardiovascular event risk comparable to those seen in broader populations. The review outlines proposed direct and indirect cardioprotective mechanisms: GLP-1RAs address type 2 diabetes and obesity as cardiovascular risk factors, reduce lipid levels by mitigating post-prandial hyperlipidemia, lower blood pressure via carotid body-mediated sympathetic suppression, and exhibit anti-atherogenic and anti-inflammatory properties observed in murine models. Anti-inflammatory effects are attributed to direct activation of GLP-1 receptors on gut intraepithelial lymphocytes and indirect modulation of myeloid cell inflammation through central neuronal GLP-1 receptor activation. The authors acknowledge remaining knowledge gaps and note that much mechanistic evidence derives from animal studies. Overall, they conclude existing evidence is supportive but not definitive for GLP-1RA cardioprotection in ARDs.
Rheumatology (Oxford, England) · Apr 2026DOI ↗ Review
This narrative review synthesizes evidence on how GLP-1-based therapies (liraglutide, semaglutide, tirzepatide, dulaglutide, exenatide) interact with the gut microbiome and influence metabolic dysfunction-associated steatotic liver disease (MASLD/MASH) in the context of type 2 diabetes mellitus (T2DM). The authors searched PubMed, Scopus, and ClinicalTrials.gov (2015–2026), ultimately including 33 studies (18 preclinical, 15 clinical) out of 363 identified. Preclinical findings suggest liraglutide normalized the Firmicutes/Bacteroidetes ratio and increased beneficial bacteria, while tirzepatide reduced hepatic steatosis and increased Akkermansia abundance in diabetic mice, and semaglutide improved gut barrier integrity in murine models. Clinically, tirzepatide achieved MASH resolution in 44–62% of patients in the phase 2 SYNERGY-NASH trial, and the FDA approved semaglutide for MASH with fibrosis in August 2025 based on the Phase 3 ESSENCE trial. A longitudinal study found baseline microbiome composition predicted glycemic response to semaglutide. Key limitations include the narrative (non-systematic) design, heavy reliance on preclinical data, and heterogeneous study populations. The authors conclude that personalized MASLD management informed by microbiome profiling warrants further dedicated clinical investigation.
Biomedicines · Apr 2026DOI ↗ Review
This narrative review synthesizes evidence from randomized controlled trials, meta-analyses, and observational studies through 2026 to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin-based therapies on a range of ocular outcomes. The authors report that recent meta-analyses indicate an overall neutral long-term risk profile for diabetic retinopathy and macular edema with these agents. They describe a transient early worsening of diabetic retinopathy observed primarily in patients with advanced baseline disease undergoing rapid HbA1c reduction, framing this as a "metabolic transition phenomenon" rather than direct retinal toxicity—an interpretation supported by data from the SELECT trial, in which no increased ocular risk was found in a non-diabetic population. The review also notes observational signals suggesting possible protective associations with glaucoma and age-related macular degeneration, a potential safety concern regarding nonarteritic anterior ischemic optic neuropathy at low absolute incidence, and emerging evidence of benefit in ocular surface homeostasis and uveitis. Limitations include reliance on observational data for several signals and the inherent constraints of a narrative review design. The authors conclude that risk-stratified ophthalmic monitoring, aligned with a cited 2025 expert consensus, is preferable to routine treatment avoidance in high-risk diabetic patients.
Journal of obesity & metabolic syndrome · Apr 2026DOI ↗ Review
This narrative review synthesizes the evolution of incretin-based pharmacotherapies for metabolic disorders, drawing on literature from PubMed, Scopus, and Google Scholar up to July 2025. The authors trace the trajectory from DPP-4 inhibitors—noted for modest glycaemic benefits—through GLP-1 receptor agonists (GLP-1RAs) such as liraglutide and semaglutide, which pivotal trials have associated with meaningful weight loss and cardiometabolic protection, to next-generation agents. Dual GIP/GLP-1 agonist tirzepatide and triple agonist retatrutide are highlighted as demonstrating particularly substantial efficacy, with the review citing up to 24% body weight reduction alongside improvements in hepatic and inflammatory markers in included trials. Agents such as cotadutide and efinopegdutide are discussed in the context of expanding indications to MASLD and MASH. The authors acknowledge several limitations across the field: high cost and accessibility barriers, underrepresentation of low- and middle-income country populations in major trials, and pharmacogenomic variability that may modify therapeutic response. As a review, this paper does not generate new primary data. Its conclusions depend on the quality and representativeness of the underlying trials it synthesizes, and no independent meta-analytic pooling appears to have been conducted.
The Indian journal of medical research · Apr 2026DOI ↗ Limited · human
This study investigated the role of MOTS-c, a mitochondrially encoded regulatory peptide, in protecting spermatogenesis. Researchers first measured serum MOTS-c levels in patients with oligoasthenozoospermia (a condition involving reduced and poorly motile sperm), finding these levels were significantly lower than in fertile controls and correlated positively with semen quality parameters. To model spermatogenic dysfunction mechanistically, the researchers used a microgravity-based mechanical stress model in mice, which induced decreased sperm concentration, disrupted seminiferous tubule architecture, and reduced spermatogonia counts. Exogenous MOTS-c administration was shown to ameliorate these impairments by suppressing oxidative stress and ferroptosis — a form of iron-dependent programmed cell death. The study identified SLC7A11 (Solute Carrier Family 7 Member 11), a known ferroptosis regulator, as a molecular target of MOTS-c. Loss- and gain-of-function experiments confirmed that SLC7A11 inhibits ferroptosis and oxidative stress while promoting spermatogonia proliferation. MOTS-c's protective effects were shown to depend, at least in part, on upregulating SLC7A11 under mechanical stress conditions. Limitations include the small and uncharacterized human cohort, reliance on an indirect mechanical stress model, and predominantly animal/cellular mechanistic data.
Free radical biology & medicine · Mar 2026DOI ↗