Review
This review examines the evolution of GLP-1–based pharmacotherapies for obesity, tracing the discovery of glucagon-like peptide-1 (GLP-1) and assessing the clinical efficacy of GLP-1 receptor agonists (GLP-1RAs), with particular focus on semaglutide. The authors explore proposed central mechanisms by which GLP-1RAs may reduce appetite and body weight. A substantial portion of the review addresses the "paradox" surrounding glucose-dependent insulinotropic polypeptide receptor (GIPR) targeting: both dual GLP-1R/GIPR agonism (as seen with tirzepatide) and GLP-1R agonism combined with GIPR antagonism (as seen with maridebart cafraglutide) appear to yield favorable metabolic outcomes. The authors note a lack of evidence that GIPR agonism or antagonism alone produces meaningful anorectic effects in humans, raising mechanistic questions about how GIPR modulation enhances GLP-1RA efficacy. The review concludes by exploring additional explanations for why dual-targeting compounds appear to outperform semaglutide monotherapy. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and its conclusions are dependent on the quality and scope of the studies reviewed.
Annual review of nutrition · May 2026DOI ↗ Review
This narrative review critically examines BPC-157 (body protection compound 157), a synthetic pentadecapeptide derived from a gastric protein fragment, through a biopharmaceutical and drug development lens rather than a purely pharmacodynamic one. The authors searched multiple major databases and patent/regulatory sources through April 2026, synthesizing evidence on physicochemical properties, pharmacokinetics, formulation challenges, and translational barriers. Key findings include: BPC-157 demonstrates unusual gastric stability and reported preclinical activity across multiple organ systems via oral, parenteral, and topical routes; a formal two-species preclinical ADME study confirmed a sub-30-minute plasma half-life, linear dose-proportional kinetics, and intramuscular bioavailability of 14–51%; a preliminary two-subject human pilot reportedly corroborated the short half-life; and a striking disconnect exists between this rapid clearance and prolonged biological effects lasting hours to days. Critically, the review identifies that no pharmaceutical-grade formulation has been developed or validated, BPC-157 lacks BCS classification data and formal excipient compatibility studies, and available human clinical data span fewer than 30 subjects across three uncontrolled pilot studies with no standardized pharmaceutical preparations. No Phase II trial has been completed. The authors conclude that the primary barrier to clinical translation is the absence of foundational pharmaceutical science, not biological activity.
Pharmaceutics · May 2026DOI ↗ Review
This structured narrative review synthesized contemporary evidence (January 2020–August 2025) on injectable peptides used in orthopaedics and sports medicine, drawing from PubMed/MEDLINE, Embase, and Web of Science. The authors identified five functional peptide classes: GLP-1 receptor agonists (e.g., semaglutide), collagen-derived injectables, regenerative peptides (e.g., BPC-157, thymosin derivatives), growth hormone secretagogues (e.g., CJC-1295, ipamorelin, tesamorelin), and related compounds. The review found that GLP-1 receptor agonists were the only class supported by reproducible randomized evidence for musculoskeletal benefit—specifically symptomatic improvement in knee osteoarthritis—attributing this primarily to weight loss and putative anti-inflammatory effects rather than proven structural cartilage modification. Collagen-derived preparations showed only preliminary signals from small, single-center prospective studies. All remaining classes were deemed investigational, carrying unresolved safety profiles, significant product quality concerns, and widespread antidoping restrictions. Risk of bias was appraised for included human trials. The authors concluded that clinical use of injectable peptides should be restricted to approved agents for established indications or rigorously designed research protocols, and that clinicians should counsel athletes about uncertain efficacy, safety risks, and antidoping consequences. The study was assigned Level V evidence and a predominantly Grade C strength of recommendation.
JBJS reviews · May 2026DOI ↗ Review
This narrative review examines the relationship between diabetes mellitus (DM) and stroke, and evaluates the cerebrovascular potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide). The authors summarize evidence from large cardiovascular outcome trials (CVOTs), noting that agents such as semaglutide and liraglutide were associated with reductions in non-fatal stroke incidence, fewer hospitalizations, and improved neurological outcomes in patients with prior stroke or high cardiovascular risk. The review highlights that stroke reduction may represent a class effect of GLP-1 RAs, though differences between individual agents exist, attributed to variations in pharmacokinetics, receptor affinity, and study populations. Evidence in the acute stroke setting is described as preliminary, coming largely from early-phase or ongoing trials. The authors also discuss emerging agents—orforglipron, retatrutide, Maridebart cafraglutide, and CagriSema—as potential future options. Limitations acknowledged include the narrative (non-systematic) design, reliance on trial-level rather than individual patient data, and the absence of large-scale, long-term randomized trials specifically targeting post-stroke populations. The authors conclude that GLP-1-based therapies should currently be considered tools for long-term vascular risk reduction rather than established acute stroke treatments.
Pharmaceutics · May 2026DOI ↗ Review
This paper introduces and quantifies the concept of "mercy sex" — defined as sexual activity engaged in by women diagnosed with hypoactive sexual desire disorder (HSDD) despite a documented absence of sexual desire or receptivity. The authors reviewed baseline data on sexually satisfying events (SSEs) drawn from a convenience sample of published, peer-reviewed, prospective, randomized, placebo-controlled clinical trials evaluating HSDD pharmacotherapies (including testosterone, flibanserin, and bremelanotide) conducted over nearly a decade. Baseline SSE data were analyzed across variables including time, age, reproductive status, and geographic region. The study found that women enrolled in these trials reported engaging in sexual activity approximately 2.5 times per month at baseline, despite meeting criteria for HSDD. The authors propose biopsychosocial explanations for this behavior and argue that mercy sex may confound HSDD trial outcomes by inflating baseline SSE rates, potentially skewing assessments of therapeutic efficacy, influencing sample size calculations, and complicating the definition of a clinically meaningful treatment response when SSEs serve as a primary endpoint. Limitations include reliance on secondary analysis of existing trial data and the use of a convenience sample. The paper does not conduct a new primary trial but offers a methodological and conceptual critique of HSDD clinical research design.
Journal of sex & marital therapy · May 2026DOI ↗ ReviewPreprint
This scoping review systematically mapped the published and registered evidence on Thymosin Beta-4 (TB4) and the related synthetic peptide TB-500 in tissue healing, regeneration, and musculoskeletal repair. Searching PubMed, Europe PMC, and ClinicalTrials.gov through March 2026, the authors identified 1,772 records and included 80 studies after screening. Key findings include: (1) the evidence base is heavily skewed toward in vitro and animal (preclinical) designs rather than human trials; (2) most research has examined TB4, while direct evidence on TB-500 was limited to a single included study; (3) the most studied tissue categories were wound/skin/soft tissue, vascular/endothelial, and ocular/corneal, with the strongest human evidence concentrated in ocular and wound-healing contexts; and (4) musculoskeletal-specific tissues—such as tendon, ligament, muscle, cartilage, and intervertebral disc—were comparatively underrepresented. The authors concluded that while the literature supports interest in several repair-related biological pathways, it remains unevenly distributed and largely preclinical, and does not yet provide a robust human evidence base for musculoskeletal applications. Scoping reviews do not perform meta-analyses or quality appraisal of individual studies, which limits causal conclusions.
Unknown journal · May 2026DOI ↗ Review
This scoping review examined the relationship between glucagon-like peptide-1 receptor agonists (GLP-1RAs) — a class of medications used for type 2 diabetes and weight management — and hair loss (alopecia). Researchers searched PubMed for relevant articles published through April 2026. The review found conflicting evidence overall: some data suggested an association between GLP-1RA use (particularly semaglutide and tirzepatide) and telogen effluvium (a stress-related, diffuse hair shedding) as well as androgenic alopecia, with risk potentially tied to longer treatment duration, greater magnitude of weight loss, and higher doses. Proposed biological mechanisms included weight loss-induced physiological stress, changes in dermal white adipose tissue, and hormonal shifts, though the authors note their relative contributions remain poorly understood. Conversely, a smaller subset of literature indicated possible improvement in inflammatory forms of alopecia, especially in patients with underlying metabolic dysfunction. Key limitations include the scoping design's reliance on heterogeneous existing literature, absence of original clinical trial data, and the difficulty of disentangling drug effects from weight-loss effects. The authors conclude that dermatology practitioners should be aware of this association and consider patient counseling and monitoring.
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] · May 2026DOI ↗ Review
This review examines the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) — including exenatide, semaglutide, dulaglutide, and the dual GLP-1R/GIP-R agonist tirzepatide — as pharmacological treatments for alcohol use disorder (AUD). The authors synthesized data from preclinical rodent and non-human primate studies, registered clinical trials, observational/pharmacoepidemiologic studies, and social media reports. In animal models, multiple GLP-1RAs were found to reduce alcohol consumption, alcohol-seeking behavior, alcohol-induced locomotor stimulation, reward memory, and relapse drinking, while also appearing to blunt alcohol's activation of the mesolimbic dopamine system. In the limited available human data, clinical trials of exenatide, semaglutide, and dulaglutide reported reductions in alcohol consumption, and pharmacoepidemiologic studies observed decreased rates of alcohol-related events among AUD patients prescribed GLP-1RAs or tirzepatide. The authors conclude that the GLP-1 system appears to be involved in AUD-related processes and that GLP-1RAs represent a promising but still tentative treatment avenue. Key limitations include the small number of human trials, heterogeneous study designs, and reliance on observational data for most clinical findings.
International journal of molecular sciences · May 2026DOI ↗ Review
This narrative review examines the potential role of incretin-based therapies in treating metabolic dysfunction-associated steatotic liver disease (MASLD), a condition strongly linked to metabolic syndrome and a leading cause of chronic liver disease. The authors highlight that no approved pharmacological treatments currently exist for MASLD and that progression to advanced fibrosis poses a significant clinical challenge. The review synthesizes evidence on GLP-1 receptor agonists, which the authors report have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, largely attributed to weight loss and improved insulin sensitivity. Dual agonists such as tirzepatide (GLP-1/GIP) are described as demonstrating superior hepatic and metabolic outcomes. Emerging agents including cotadutide (GLP-1/glucagon dual agonist) and retatrutide (GLP-1/GIP/glucagon triagonist) are presented as a novel frontier, with early clinical data suggesting potent hepatoprotective effects and favorable metabolic remodeling. The authors acknowledge that evidence on fibrosis progression remains limited. As a narrative review without systematic search methodology or meta-analysis, this paper is susceptible to selection bias and does not establish causality. It provides a useful synthesis of the current landscape but should be interpreted with appropriate caution.
Medicina (Kaunas, Lithuania) · May 2026DOI ↗ Review
This narrative review synthesizes current evidence on glucagon-like peptide-1 (GLP-1)-based therapies—primarily semaglutide and tirzepatide—for the management of obesity-related heart failure with preserved ejection fraction (HFpEF). Drawing on PubMed and Scopus literature published between January 2020 and March 2026, the authors incorporated randomized trials, pooled analyses, mechanistic studies, and observational data. The review describes how obesity-related HFpEF arises from a complex interplay of excess lipids, chronic inflammation, and metabolic dysregulation, which also interact with GLP-1 pathways. According to the authors, GLP-1-based therapies demonstrated meaningful improvements in symptoms, exercise capacity, and quality of life in this population, with benefits attributed to weight reduction, decreased systemic inflammation, and improved congestion indices. Tirzepatide was additionally associated with reductions in heart failure-related complications. Proposed mechanisms include coordinated effects on metabolism, inflammation, hemodynamics, and cardiac remodeling. The authors note that evidence for improvements in morbidity appears stronger than evidence for reductions in mortality. Key limitations include the narrative (non-systematic) review methodology, potential selection bias in study inclusion, and the absence of long-term mortality data. The authors conclude that further research is needed to clarify long-term outcomes, refine patient selection, and guide clinical integration.
Journal of clinical medicine · May 2026DOI ↗ Review
This review examines the ocular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual-incretin therapies, which are increasingly used for diabetes and obesity management. The authors synthesize experimental and clinical evidence across multiple ocular conditions. Preclinical data suggest plausible protective mechanisms, including antioxidant and neuroprotective effects on retinal and optic nerve tissues. In diabetic retinopathy, the review identifies transient early worsening as a key concern, attributed to rapid glycemic improvement rather than direct drug toxicity. A potential signal linking semaglutide to non-arteritic anterior ischemic optic neuropathy (NAION) is noted, though the authors characterize absolute risk as low and causality as unproven. Emerging associations are discussed for glaucoma, ocular surface diseases, and retinal vascular outcomes, while evidence on age-related macular degeneration and cataract is described as conflicting or preliminary. The authors conclude that ocular outcomes likely reflect an interplay of drug pharmacology, systemic metabolic changes, and individual patient factors rather than a uniform class effect. They suggest baseline ophthalmic assessment and individualized follow-up for high-risk patients, and call for prospective ophthalmology-focused trials. A key limitation is its reliance on heterogeneous and largely indirect evidence.
Vision (Basel, Switzerland) · May 2026DOI ↗ Review
This registry-based cross-sectional qualitative analysis examined the landscape of completed clinical trials investigating GLP-1 receptor agonists (GLP-1 RAs) for obesity, using data retrieved from ClinicalTrials.gov in October 2025. The authors identified 227 completed interventional studies and analyzed their design characteristics, research themes, and outcome domains. Liraglutide was the most studied agent (n = 86), followed by semaglutide and tirzepatide (n = 18 each) and exenatide (n = 15). Phase 3 and 4 trials predominated, though most studies enrolled fewer than 200 participants, suggesting relatively modest individual sample sizes. The authors reported a notable surge in completed trials after 2018, coinciding with the emergence of newer GLP-1 analogues. Primary outcomes were predominantly weight-related, but the synthesis identified a growing research focus on hepatic, cardiometabolic, and inflammatory endpoints. The study's key limitation is its registry-based, qualitative design — it does not synthesize individual-level patient outcome data or conduct meta-analysis, and therefore cannot draw conclusions about comparative efficacy or safety. Rather, it maps the structural and thematic evolution of the GLP-1 obesity research field. The authors conclude that the field is maturing beyond glycaemic and weight outcomes toward broader organ-specific endpoints.
Diabetes, metabolic syndrome and obesity : targets and therapy · May 2026DOI ↗ Review
This narrative review, aimed at obstetricians and gynecologists, synthesizes current evidence on GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP agonists (e.g., tirzepatide) as they relate to women's health. The authors highlight that phase 3 trials have reported 15–21% body weight reduction with these agents, with tirzepatide showing greater efficacy than semaglutide. In women with polycystic ovary syndrome (PCOS), the authors cite meta-analyses finding improvements in insulin resistance, androgen levels, and ovulation rates. Regarding contraception, the review notes that tirzepatide's gastric-emptying delay has prompted manufacturer guidance about backup contraception around initiation and dose escalation. On pregnancy safety, the authors describe emerging human cohort data suggesting no significantly increased risk of major congenital malformations from inadvertent early pregnancy exposure, while noting that animal teratogenicity data still warrant caution. Perioperative guidance has shifted toward individualized risk-stratified approaches rather than blanket discontinuation. The authors call for formal pregnancy registries to address persistent knowledge gaps. As a review, this paper does not generate new primary data, and its conclusions are limited by the underlying evidence base, which in several areas remains preliminary or indirect.
Current opinion in obstetrics & gynecology · May 2026DOI ↗ Review
This narrative review examines whether tirzepatide — a dual GIP/GLP-1 receptor agonist — may act as a disease-modifying therapy in obesity-related obstructive sleep apnea (OSA), beyond its well-established effects on weight reduction. The authors searched PubMed, Scopus, and Web of Science through January 2026, synthesizing evidence from randomized controlled trials, meta-analyses, and mechanistic studies on incretin-based therapies in obesity and OSA. The review reports that tirzepatide is associated with meaningful reductions in apnea-hypopnea index (AHI) alongside significant weight loss. Notably, the authors propose that OSA improvements may not be fully explained by weight loss alone, highlighting potential weight-independent mechanisms such as modulation of systemic inflammation, improvements in insulin sensitivity, changes in adipokine profiles, and effects on autonomic regulation and ventilatory chemosensitivity. The authors acknowledge that current evidence is insufficient to definitively separate weight-dependent from weight-independent effects, and they call for dedicated mechanistic and long-term clinical studies. A key limitation is the review's narrative — rather than systematic — design, which introduces selection bias. The paper frames tirzepatide as a potential shift from purely device-based OSA management toward integrated, pathophysiology-driven treatment strategies, but stops short of confirming disease-modifying status.
Life (Basel, Switzerland) · May 2026DOI ↗ Review
This narrative review evaluates whether incretin-based therapies — specifically GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide) — warrant consideration as first-line antihypertensive agents. The authors synthesize findings from recent large-scale trials demonstrating that these agents are associated with significant reductions in body weight, blood pressure, and adverse cardiovascular outcomes. Mediation analyses cited in the review suggest that weight loss accounts for a substantial portion of the observed blood pressure reductions; however, the authors also highlight putative direct mechanisms, including improvements in vascular function, renal sodium handling, and neurohumoral pathway modulation. The review notes that beneficial effects on blood pressure appear consistent across diverse patient populations, including those without established hypertension. A key limitation acknowledged by the authors is the absence of randomized controlled trials specifically designed with blood pressure as a primary endpoint. Based on the available evidence, the authors conclude that incretin-based therapies may have an emerging role in hypertension management guidelines, particularly for selected high-risk populations. As a review article, conclusions are dependent on the quality and interpretation of the underlying primary studies cited.
Current hypertension reports · May 2026DOI ↗ Review
The 11th Cardiovascular Outcome Trial (CVOT) Summit (November 2025) was a virtual multidisciplinary conference convening experts in endocrinology, diabetology, cardiology, nephrology, hepatology, and general practice to review recent outcome trials and emerging therapies along the cardiovascular-kidney-metabolic (CKM) disease continuum. The report summarizes key 2025 developments, including the first head-to-head CVOT (SURPASS-CVOT), the CONFIDENCE trial examining combination therapy with finerenone (a non-steroidal mineralocorticoid receptor antagonist) and empagliflozin (an SGLT2 inhibitor), the ATTAIN-1 trial of the oral GLP-1 receptor agonist orforglipron, and the BaxHTN trial of the aldosterone synthase inhibitor baxdrostat. The report also covers updated clinical guidelines, policy developments, advances in continuous glucose and ketone monitoring technology, and emerging pharmacological strategies for metabolic liver disease and type 1 diabetes. As a conference summary report rather than a primary trial, this document does not present original trial data and primarily synthesizes and contextualizes findings from multiple studies. Key limitations include the narrative, consensus-driven format and the absence of new primary data.
Cardiovascular diabetology · May 2026DOI ↗ Review
This review traces the historical development and clinical adoption of FDA-approved drugs that incorporate d-amino acids — the non-natural mirror-image enantiomers of standard l-amino acids. The authors survey more than 20 FDA-approved drugs spanning therapeutic areas including infectious diseases, endocrine disorders, rare dermatologic conditions, and diagnostic imaging. Key examples discussed include naturally derived compounds such as gramicidin D and synthetic analogs including desmopressin, leuprolide, bremelanotide, and etelcalcetide — the latter highlighted as the first fully d-amino acid peptide to receive FDA approval. The review explains why d-amino acids are pharmacologically attractive: their resistance to proteolytic degradation, enhanced conformational rigidity, and reduced immunogenicity make them well-suited for long-acting and receptor-selective drug design. The authors also discuss enabling technologies, particularly solid-phase peptide synthesis and mirror-image phage display, that have accelerated the field. As a narrative review, the paper does not present new experimental data, conduct meta-analytic comparisons, or include a systematic literature search, which limits its ability to draw novel evidence-based conclusions. Its primary value lies in synthesizing the historical trajectory and mechanistic rationale of a growing drug class.
Drug development research · May 2026DOI ↗ Review
This paper is a commentary/review examining the rapidly evolving landscape of weight-loss pharmacotherapy, focusing on the progression from standard GLP-1 receptor agonists to dual and triple agonists capable of achieving 30–40% body weight reduction — outcomes previously only attainable through bariatric surgery. The authors argue that the pharmaceutical industry's competitive focus on maximizing weight-loss percentages is creating a disconnect between the metric of total body mass reduction and the broader goal of metabolic health. A central concern raised is that aggressive pursuit of high weight-loss targets may come at the cost of metabolic integrity and lean muscle mass preservation. The paper also touches on how escalating clinical benchmarks are influencing investor expectations and market dynamics. Notable limitations include the absence of primary data; the piece offers no original clinical trial results, relies on narrative argument rather than systematic evidence synthesis, and does not present a structured methodology for evaluating the compounds discussed. It does not provide specific dosing guidance but situates the debate within a broader physiological and economic context.
Molecules and cells · May 2026DOI ↗ Review
This review examines the perioperative safety implications of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug class increasingly used for type 2 diabetes and obesity management. The authors focus on the mechanism by which GLP-1 RAs delay gastric emptying and how this pharmacological effect may elevate the risk of pulmonary aspiration during general anesthesia—specifically at induction and emergence—even when patients have followed standard preoperative fasting protocols. The review distinguishes between short-acting GLP-1 RAs, which reportedly cause more pronounced gastric emptying delays, and long-acting agents, whose residual effects may vary by dose and duration of treatment. The authors also survey updated guidance issued by international anesthesia societies in response to these concerns. Key limitations acknowledged include the overall scarcity and inconsistency of available clinical evidence. The review concludes by advocating for individualized, interdisciplinary perioperative management involving collaboration between endocrinologists and anesthesiologists. As a narrative review, it does not generate new primary data, and the conclusions are constrained by the quality of the underlying literature.
The Korean journal of internal medicine · May 2026DOI ↗ Review
This state-of-the-art review synthesizes available evidence on how glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — drugs used for type 2 diabetes and weight management — affect blood pressure (BP). The authors examined data across populations including people with diabetes, obesity, and high cardiovascular risk. The review reports that GLP-1 RAs are associated with modest systolic BP reductions, typically in the range of 2–5 mm Hg, which the authors attribute primarily to weight loss, with potential additional contributions from weight-independent mechanisms such as natriuresis (increased urinary sodium excretion), improved endothelial function, and reduced vascular inflammation. The review notes that while these reductions are smaller than those achieved with traditional antihypertensive medications, they may translate to meaningful cardiovascular risk reduction at a population level and may offer additive benefit alongside conventional therapies. The authors also highlight that small increases in heart rate and possible interactions with volume-regulating medications may require clinical monitoring. Limitations acknowledged include the indirect and heterogeneous nature of the synthesized evidence. The review concludes by calling for further research as newer GLP-based therapies emerge to better inform integrated cardiometabolic care strategies.
American journal of hypertension · May 2026DOI ↗