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 ↗ Review
This review examines the global burden of pediatric obesity and its cardiovascular consequences, drawing on data from PubMed, Scopus, and Springer databases. The authors report that over 381 million children worldwide are affected by obesity, and that childhood obesity substantially increases the risk of adult obesity and cardiovascular diseases (CVD) including atherosclerosis, coronary artery disease, hypertension, dysglycemia, dyslipidemia, arrhythmias, and stroke. The study identifies both genetic contributors (highlighted by genome-wide association studies) and lifestyle drivers such as physical inactivity, prolonged screen time, and poor diet. The authors evaluate public health frameworks including the WHO Global Action Plan on Physical Activity 2018–2030, as well as management strategies spanning lifestyle modification, pharmacotherapy (notably GLP-1 receptor agonists semaglutide and liraglutide), and bariatric surgery. They highlight data from the SURMOUNT-5 trial on tirzepatide and discuss emerging investigational agents including cagrilintide/semaglutide combination, orforglipron, danuglipron, and retatrutide. Gene therapy is noted as experimental. A key limitation is that this is a narrative review without systematic methodology or original data collection, limiting causal inference.
Clinical nutrition ESPEN · Mar 2026DOI ↗ Review
This narrative review examines emerging pharmacological approaches for managing obesity in patients with cardiovascular disease, with a focus on novel anti-obesity agents beyond the already-established semaglutide and tirzepatide. The authors surveyed the current landscape of investigational weight-lowering drugs, categorizing them by their primary mechanisms of action: reducing caloric intake, increasing basal metabolic rate, and increasing muscle mass. The review highlights that GLP-1 receptor agonists (GLP-1 RAs) have demonstrated both significant weight reduction and cardiovascular benefits, but notes a concern regarding muscle wasting associated with their use. The authors suggest that combination therapies using agents with complementary mechanisms may help mitigate this side effect. The review concludes that obesity treatment is likely to become more personalized over time and anticipates further cardiovascular benefits from pipeline agents. The authors also emphasize that the strongest evidence linking increased muscle mass and basal metabolic rate to improved cardiovascular health comes from diet and physical activity, positioning pharmacotherapy as a complement to—rather than a replacement for—healthy lifestyle changes. As a narrative review, this paper does not perform systematic synthesis or meta-analysis, and its conclusions reflect the authors' expert opinion rather than pooled quantitative data.
Biomedicines · Mar 2026DOI ↗ Review
This review paper systematically examines the patent landscape and therapeutic development trajectory of mazdutide, a dual GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist being investigated for obesity and type 2 diabetes. Using the Patentscope database, the authors analyzed 12 patent families filed between 2015 and 2025, covering composition-of-matter, process chemistry, formulation technologies, dosing regimens, and therapeutic applications. The review traces innovation from early peptide design work by Eli Lilly to formulation, clinical, and indication-expansion strategies later pursued by Innovent Biologics, including applications in obesity, type 2 diabetes, hyperuricemia, and adolescent obesity. The authors argue that mazdutide's development illustrates a "layered" intellectual property strategy — integrating molecular design, manufacturability, formulation stability, and clinical-use claims — as a model for securing durable market exclusivity for next-generation peptide therapeutics. Limitations include that this is a review and patent analysis rather than a clinical study, so it does not directly evaluate patient outcomes, safety, or comparative efficacy. The paper provides strategic and historical context for mazdutide's development rather than original experimental data.
Expert opinion on therapeutic patents · Mar 2026DOI ↗ 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 ↗ 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 ↗ 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 ↗ 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 ↗ 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 ↗ 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 ↗ 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 ↗ Review
This narrative review compares two incretin-based therapies — semaglutide, a selective GLP-1 receptor agonist, and tirzepatide, a dual GIP/GLP-1 receptor agonist — across their mechanisms of action, clinical efficacy, therapeutic indications, and cardiovascular/renal evidence. The authors describe semaglutide as having a well-established clinical profile with demonstrated benefits in glycaemic control, body weight reduction, and cardiovascular and renal outcomes. Tirzepatide is presented as a newer agent offering superior weight loss and improvements in insulin sensitivity, with an expanding range of therapeutic indications, though the authors note its cardiovascular outcomes evidence is less mature than that of semaglutide. The review emphasizes that despite shared benefits in reducing HbA1c and body weight, the two molecules differ meaningfully in their pharmacological mechanisms and evidence bases, requiring individualized clinical decision-making. The authors frame both agents within a broader "incretin revolution" relevant to cardio-reno-metabolic prevention. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and therefore does not provide independent experimental evidence to confirm or quantify any specific clinical claims.
European heart journal supplements : journal of the European Society of Cardiology · Mar 2026DOI ↗ Review
This paper is a narrative review examining the clinical evidence on retatrutide (LY3437943), a novel triple receptor agonist targeting the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). The authors conducted an electronic literature search across Scopus, PubMed/MEDLINE, and Google Scholar to synthesize available findings. According to the review, studies in people with type 2 diabetes mellitus (T2DM) reported reductions in HbA1c of up to 2.16% and fasting glucose reductions of up to 69.1 mg/dL, alongside weight loss of up to 16.94%. In individuals with overweight or obesity (without T2DM), weight loss reached up to 26.56% (approximately 24.15 kg). Additional findings included reductions in BMI, waist circumference, and systolic blood pressure in those with T2DM and overweight/obesity, as well as a relative liver fat reduction of up to 86% in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). The most commonly reported adverse events were mild-to-moderate gastrointestinal symptoms, particularly at higher doses. The authors conclude that retatrutide's effects on glycemic control, weight, and potential pleiotropic benefits warrant further investigation through larger, longer-duration trials.
Expert review of clinical pharmacology · Mar 2026DOI ↗ Review
This review examines the role of intestinal barrier dysfunction in coeliac disease (CD), a condition in which genetically predisposed individuals mount an immune-mediated response to dietary gluten that damages the small intestine. The authors explore the evidence that increased intestinal permeability is a central feature of CD pathophysiology, detailing the contributing mechanisms: dysregulation of the protein zonulin, pro-inflammatory cytokines, alterations in gut microbiota, and immune responses to gliadin peptides. The review then comprehensively surveys therapeutic strategies aimed at restoring barrier integrity, including dietary interventions, nutritional supplements, and investigational pharmacological agents such as larazotide acetate (a tight-junction regulator) and IMU-856 (a SIRT6 activator targeting mucosal regeneration). The authors also highlight a key limitation in the field: the absence of validated, reliable biomarkers for accurately measuring intestinal permeability in CD. They advocate for further research into barrier-restoring therapies, particularly as adjuncts to a gluten-free diet for maintaining disease remission. As a narrative review, the paper synthesises existing literature but does not generate new primary data, and conclusions are subject to the quality and heterogeneity of the underlying studies.
Review
This narrative review examines the current and investigational pharmacological treatments for erythropoietic protoporphyrias (EPP), a group of ultra-rare inherited disorders of heme biosynthesis causing severe, painful phototoxic reactions triggered by visible light exposure. The authors searched PubMed and clinical trial databases to synthesize available evidence on two investigational agents—dersimelagon (a melanocortin-1 receptor agonist) and bitopertin (a glycine transport inhibitor)—alongside the only currently approved therapy, afamelanotide. The review notes that afamelanotide effectively reduces pain and extends tolerable sun exposure time but does not address the underlying disease mechanism and is approved only for adults, leaving pediatric patients without a treatment option. The authors report that available trial data for both dersimelagon and bitopertin suggest treatment effects versus placebo, though they emphasize that the safety and efficacy profiles of both agents require further characterization. A key limitation highlighted is the absence of head-to-head comparison data against afamelanotide, which the authors argue is necessary to inform regulatory decisions and ensure meaningful patient access. The review concludes that both agents hold promise but that additional robust clinical evidence is needed before their roles in EPP management can be fully established.
Expert opinion on pharmacotherapy · Mar 2026DOI ↗ Review
This review examines the landscape of next-generation glucagon-like peptide-1 (GLP-1)-based therapeutics in clinical development for type 2 diabetes and obesity, building on the established success of semaglutide and tirzepatide. The authors survey a broad range of investigational agents that target multiple gastro-entero-pancreatic hormone receptors simultaneously — including GIP, glucagon, amylin, and peptide YY receptors — to produce synergistic effects on energy intake, storage, and expenditure. Specific agents discussed include maridebart cafraglutide (GLP-1 agonism/GIP antagonism), survodutide and mazdutide (GLP-1/glucagon coagonists), cagrilintide combined with semaglutide (CagriSema), amycretin (amylin/GLP-1 dual agent), and retatrutide (GIP/GLP-1/glucagon triple agonist). The review also highlights the emergence of oral small-molecule GLP-1 receptor agonists such as danuglipron and orforglipron, which resist enzymatic degradation and may improve patient convenience. The paper does not present original clinical trial data; it synthesizes existing preclinical and clinical development evidence. As a narrative review, it does not meta-analytically pool outcomes, and the included agents are largely at Phase 1–3 stages, meaning long-term efficacy and safety data remain limited.
Endocrine reviews · Mar 2026DOI ↗ Review
This paper examines the ethical landscape surrounding semaglutide (marketed as Ozempic, Rybelsus, and Wegovy), a glucagon-like peptide-1 (GLP-1) receptor agonist manufactured by Novo Nordisk and primarily used to treat type II diabetes. The authors note that semaglutide has garnered widespread attention beyond its diabetic indication due to its effects on appetite suppression and weight loss, earning it the popular label of a "miracle drug." The paper surveys a range of ethical concerns that have been raised in both governmental and public discourse — including issues around drug access and equity, medicalization of obesity, societal body-image pressures, and resource allocation — and critically analyzes whether these concerns are sufficient to advise against prescribing semaglutide for weight loss. The authors ultimately argue that, while many of the ethical objections raised are legitimate and deserve serious consideration, none individually or collectively constitute a conclusive reason to withhold semaglutide prescriptions for weight management purposes. As an ethics and policy review, the paper does not present original clinical trial data and offers no empirical findings on patient outcomes. Its conclusions are based on philosophical argument and literature synthesis rather than experimental evidence.
Journal of medical ethics · Feb 2026DOI ↗ Review
This review examines the development and clinical progress of long-acting amylin-related peptides as treatments for obesity and type 2 diabetes. It traces the field from the first-generation amylin receptor (AMYR) agonist pramlintide—which acts centrally to induce satiety, suppress glucagon, and reduce post-meal hyperglycemia but had limited use as an insulin adjunct—to a new generation of non-aggregating, long-acting analogues. The authors describe advances in understanding the heterodimeric structure of amylin-calcitonin receptor complexes that have guided the rational design of these newer agents. Highlighted compounds include the dual AMYR/calcitonin-receptor agonist cagrilintide, the combination product CagriSema (cagrilintide plus semaglutide), and the unimolecular tri-agonist amycretin. Several monotherapy candidates (eloralintide, petrelintide, Met-233, AZD6234) are also discussed. The review notes that gastrointestinal side effects—chiefly nausea—are common during initiation but typically resolve with continued use, and highlights emerging preclinical and early clinical signals for potential benefits in fatty liver disease, diabetic kidney disease, and resistant hypertension. As a narrative review, it synthesizes heterogeneous sources and does not itself generate new primary data.
Review
This review provides a broad educational overview of pharmacological agents used in diabetes management, spanning both traditional and newer-generation therapies, with particular attention to their off-label use for weight loss. The authors describe the mechanistic and clinical distinctions between type 1 and type 2 diabetes and survey established drug classes—insulin, metformin, sulfonylureas, and thiazolidinediones—noting their limitations such as hypoglycemia risk and weight gain. The review then highlights the clinical impact of incretin-based therapies, specifically GLP-1 receptor agonists and SGLT-2 inhibitors, which the authors associate with improved glycemic control, weight reduction, and cardiorenal benefits. Newer dual and triple agonists, including tirzepatide, are described as producing HbA1c and body weight reductions approaching those of bariatric surgery. The paper raises concerns about the rising off-label use of antidiabetic agents for weight management, citing gastrointestinal adverse effects and rare motility disorders. Limitations include the review's broad scope and lack of original data or formal systematic methodology. The authors call for ongoing pharmacovigilance, equitable access, and further research into long-term safety and emerging oral non-peptide incretin mimetics.
The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians · Feb 2026DOI ↗ Review
This Chinese clinical comprehensive evaluation systematically compared five long-acting GLP-1 receptor agonists (dulaglutide, semaglutide, polyethylene glycol loxenatide, tirzepatide, and mazdutide) for the management of type 2 diabetes within China's healthcare context. The researchers constructed a quantitative, six-dimensional scoring framework—covering efficacy, safety, economy, innovation, suitability, and accessibility—with indicator weights derived through a Delphi expert consultation process. Evidence sources included drug labels, systematic literature reviews, and real-world data. Semaglutide scored highest (76.6/100) followed by dulaglutide (72.6), polyethylene glycol loxenatide (64.8), tirzepatide (62.9), and mazdutide (55.1). Semaglutide and dulaglutide were classified as "Strong Recommendations," largely due to superior cardio-renal outcome evidence. Tirzepatide and polyethylene glycol loxenatide received "Conditional Recommendations," while mazdutide was "Not Recommended" owing to insufficient evidence, lack of national reimbursement listing, and high cost. Key limitations include the inherent subjectivity of the Delphi weighting process, the China-specific formulary and reimbursement context limiting global generalizability, and the composite nature of the scoring system potentially obscuring individual domain differences.
Diabetes, metabolic syndrome and obesity : targets and therapy · Feb 2026DOI ↗