Review
This narrative review examines three incretin-based therapies — liraglutide, semaglutide, and tirzepatide — approved for weight management in non-diabetic individuals with obesity. The authors provide background on the physiological roles of the incretin hormones GIP and GLP-1 in the gastrointestinal tract, explaining how pharmacological analogues of these hormones, initially developed for type 2 diabetes, were subsequently found to produce clinically meaningful weight reduction. The review compares the three agents across efficacy, safety, cost-effectiveness, and real-world clinical trends. Lifestyle interventions (dietary modification, physical activity, sleep, and stress management) are discussed as foundational components of obesity management. The authors highlight that all three agents are now regulatory-approved for obesity in non-diabetic patients. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and is therefore subject to selection bias in the studies chosen. It does not conduct a formal systematic search or meta-analysis, limiting the objectivity of comparisons. No new clinical trial data are presented, and conclusions about relative efficacy and cost-effectiveness are drawn from the authors' interpretation of the existing evidence base.
Rambam Maimonides medical journal · Jan 2026DOI ↗ Review
This review examines the expanding therapeutic applications of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) beyond their original indication of glycemic control in type 2 diabetes. The authors survey clinical trial evidence supporting the use of GLP-1 RAs across several cardiometabolic conditions, including obesity, heart failure with preserved ejection fraction, chronic kidney disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). The review highlights that robust clinical trial data exist for weight loss, cardiovascular outcome improvements, and renal function preservation. The authors also note that additional trials are ongoing to further broaden and strengthen the evidence base. Practical challenges are discussed, including high costs, limited patient access, adherence difficulties, and implementation barriers—especially for indications outside of diabetes. The review identifies emerging innovations, such as oral GLP-1 RA formulations and combination therapies, as potential avenues to improve accessibility and long-term use. The authors conclude that as clinical guidelines continue to evolve, targeted integration of GLP-1 RAs into care pathways may reshape prevention and treatment strategies for complex chronic diseases. As a narrative review, this paper synthesizes existing literature but does not generate new primary data, which limits the directness of its evidence.
Reviews in cardiovascular medicine · Jan 2026DOI ↗ Review
This review examines the potential role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in managing diabetic foot ulcers (DFUs), a serious chronic complication of diabetes associated with high rates of disability, recurrence, and mortality. The authors note that DFU-related mortality is strongly tied to cardiovascular events, suggesting that treatment should extend beyond local wound care to include cardiovascular risk reduction. The review systematically describes personalized application strategies for GLP-1 RAs based on DFU clinical staging, and compares mono-, dual-, and triple-target GLP-1 RA agents in terms of their clinical translational potential and adverse effect profiles specific to DFU patients. Notably, the authors highlight a key tension: while GLP-1 RAs have demonstrated cardiovascular protective effects in outcome trials, their appetite-suppressing and gastric-emptying-delaying properties may worsen malnutrition in DFU patients during acute infection phases. The review synthesizes existing evidence to propose more rational, stage-specific treatment frameworks. As a narrative review, it does not generate new primary data, and its conclusions are limited by the quality and scope of the underlying studies it synthesizes.
Frontiers in endocrinology · Jan 2026DOI ↗ 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 ↗ 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 ↗ 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 ↗ 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 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 ↗ 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 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 ↗ Review
This review synthesizes evidence from approximately 108 priority studies—including RCTs, prospective cohorts, and mechanistic reports—identified through a systematic search of PubMed, Scopus, and Web of Science (2000–2025) to reframe heart failure with preserved ejection fraction (HFpEF) as a systemic cardio-metabolic syndrome rather than a purely cardiac condition. The authors argue that visceral adiposity, insulin resistance, chronic inflammation, and mitochondrial dysfunction collectively impair cardiac energetics and drive HFpEF pathophysiology. The review notes that conventional neurohormonal therapies (RAAS inhibitors, beta-blockers) showed neutral outcomes in heterogeneous HFpEF populations, whereas the landmark EMPEROR-Preserved and DELIVER RCTs demonstrated that SGLT-2 inhibitors reduced hospitalizations and cardiovascular events. GLP-1 receptor agonists were also reported to improve symptoms, exercise tolerance, and body weight, further supporting a metabolic-inflammation framework. The authors call for biomarker-driven patient phenotyping, advanced imaging, and adaptive trial designs to enable precision care. Limitations include the inherent heterogeneity of HFpEF populations and the reliance on synthesized rather than primary data, with mechanistic claims drawn partly from preclinical and observational sources.
Review
This narrative review synthesizes existing literature on obesity management strategies, drawing from PubMed, Scopus, ScienceDirect, and Google Scholar. It evaluates the comparative effectiveness, safety, sustainability, and real-world applicability of five broad intervention categories: lifestyle modifications, dietary approaches, behavioral therapy, pharmacotherapy, and bariatric or endoscopic procedures. Key findings reported by the authors include that lifestyle interventions, while foundational, are frequently undermined by physiological adaptations, behavioral challenges, and socioeconomic barriers. Dietary strategies tend to converge in weight-loss outcomes over time, with adherence emerging as the primary differentiator. Pharmacotherapy—particularly incretin-based agents such as GLP-1 receptor agonists and dual GIP/GLP-1 agonists—is highlighted as producing meaningful weight loss and cardiometabolic improvements, though the authors note concerns around cost, tolerability, and the need for continued use. Bariatric surgery is characterized as the most effective long-term option for severe obesity, with endoscopic procedures noted as an expanding alternative. Behavioral and psychological support is identified as a cross-cutting enabler of adherence. The authors conclude that personalized, multidisciplinary care is essential. As a narrative review, this paper does not conduct original data collection or meta-analysis, and findings are subject to selection bias inherent in non-systematic review methodology.
Journal of obesity · Jan 2026DOI ↗ Review
This review examines the evolving landscape of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies and their role in cardiorenal protection in metabolic diseases, particularly type 2 diabetes (T2D) and obesity. The authors synthesize evidence from clinical and real-world studies demonstrating that GLP-1RAs consistently reduce HbA1c and body weight, and that mounting data support cardiovascular and kidney benefits beyond glycaemic control in high-risk populations. The review highlights that in T2D, GLP-1RAs have been shown to improve hard cardiovascular outcomes and, more recently, kidney outcomes. In individuals with obesity without T2D, semaglutide at a higher dose was reported to reduce body weight by up to 15% and lower major adverse cardiovascular events by approximately 20%. The review also covers next-generation "multi-agonist" molecules combining GLP-1 receptor agonism with activity at GIP, glucagon, and amylin receptors, aiming for complementary or synergistic metabolic effects. Tirzepatide, a dual GLP-1/GIP receptor agonist approved for T2D and obesity, is highlighted as achieving up to 22.5% weight loss in phase 3 trials. Limitations include the inherent constraints of a narrative review: no new primary data are generated, and conclusions depend on the scope and quality of included studies.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · Jan 2026DOI ↗ Review
This review examines the potential neuroprotective role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) — a drug class established for managing type 2 diabetes and obesity — in the context of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The authors propose that neurodegeneration is driven by a self-reinforcing cycle of chronic neuroinflammation and central metabolic dysfunction, worsened by impaired insulin/IGF-1 signalling, mitochondrial dysfunction, and pro-inflammatory microglial activation triggered by misfolded protein aggregates. The review synthesizes preclinical and clinical trial data to argue that GLP-1RAs may disrupt this cycle via a dual mechanism: reducing central insulin resistance and directly suppressing neuroinflammatory cascades by modulating glial responses, inhibiting pro-inflammatory cytokines, and reducing oxidative stress in the CNS. The authors conclude that GLP-1RAs represent a promising, translatable therapeutic strategy for neurodegeneration and call for large-scale human trials. Limitations include the review's reliance on synthesizing heterogeneous preclinical and early clinical data, without original data collection, and the mechanistic conclusions remain to be validated in robust, adequately powered human studies.
Diabetes, obesity & metabolism · Dec 2025DOI ↗ Review
This review article examines the evolving landscape of engineered nutrient-stimulated hormonal (NUSH) peptide therapies for obesity and related metabolic conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. The authors describe the mechanistic basis of GLP-1 receptor agonists (GLP-1RAs) and their limitations as monotherapies, then explore how dual and triple co-agonist strategies — combining GLP-1 with GIP, glucagon, amylin, or peptide YY — aim to overcome those gaps. The review highlights clinical and preclinical data for specific agents: tirzepatide (GLP-1/GIP), CagriSema (GLP-1/amylin), and retatrutide (GLP-1/GIP/glucagon), noting reported benefits in weight reduction, glycemic control, liver health, cardiovascular outcomes, and inflammation. The paper also discusses non-peptidyl oral GLP-1 RAs such as orforglipron as adherence-improving alternatives. The authors frame these multi-agonist therapies as a paradigm shift analogous to the pleiotropic hormonal effects of bariatric surgery, and as building blocks for precision metabolic medicine. As a narrative review, it does not generate new primary data, and conclusions depend on the quality and heterogeneity of the underlying cited studies.
Clinical and molecular hepatology · Nov 2025DOI ↗ Review
This narrative review examines the current and emerging landscape of GLP-1 receptor agonists (GLP-1RAs) as treatments for obesity and related metabolic conditions. The authors survey the three FDA-approved agents for obesity—liraglutide, semaglutide, and tirzepatide—alongside off-label options, summarizing evidence for their efficacy in weight reduction and glycemic control. The review also discusses expanding indications, including potential benefits in neurodegenerative disorders, fatty liver disease, dyslipidemia, atherosclerosis, cardiovascular disease, chronic kidney disease, and heart failure. Emerging pipeline agents—such as CagriSema, orforglipron, mazdutide, retatrutide, and survodutide—are highlighted alongside innovations like ultralong-acting formulations, combination therapies, higher-dose oral delivery, and AI-integrated drug development. The authors note that generic liraglutide and evolving insurance coverage may reshape affordability and access. Key limitations acknowledged include adherence challenges, safety concerns, disparities in global access, and the need for long-term data on sustained weight loss and disease modification. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and conclusions are therefore subject to the quality and selection of included studies.
Journal of obesity · Nov 2025DOI ↗ Review
This scoping review examines the biological rationale and existing evidence for using glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of psoriatic disease (PsD), a chronic systemic inflammatory condition frequently accompanied by cardiometabolic comorbidities such as obesity, type 2 diabetes mellitus, and cardiovascular disease. The authors explored three main areas: (1) how obesity, diabetes, and cardiovascular disease influence PsD severity and treatment resistance; (2) the established efficacy of GLP-1RAs in managing these comorbidities; and (3) early evidence from rheumatologic and dermatologic conditions including rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, and hidradenitis suppurativa. The review highlights shared immunopathogenic mechanisms — particularly Th1/Th17-driven cytokines such as TNF, IL-6, and IL-17 — as a rationale for GLP-1RA use beyond metabolic indications. The authors report that early clinical and preclinical data suggest GLP-1RAs may reduce systemic inflammation and PsD burden, but acknowledge this evidence is preliminary. Key limitations include the scoping review design (which maps available evidence rather than synthesizes effect sizes), reliance on preclinical and indirect data, and the absence of dedicated randomized controlled trials in PsD populations. The authors conclude that further clinical trials are needed to establish disease-modifying potential.
Inflammation research : official journal of the European Histamine Research Society ... [et al.] · Nov 2025DOI ↗ Review
This paper examines the socioeconomic and systemic barriers that limit equitable access to glucagon-like peptide-1 (GLP-1) receptor agonist medications as obesity treatments. The authors note that obesity disproportionately burdens socioeconomically disadvantaged populations, yet the high cost and limited supply of GLP-1 agonists mean these effective therapies remain largely accessible only to those who can afford to pay privately. The paper frames this disparity through Julian Tudor Hart's "inverse care law," which describes how access to effective healthcare tends to be inversely correlated with clinical need. The authors argue that current rollout patterns risk deepening existing health inequalities rather than alleviating them. They call for evidence-informed policies to prioritize access based on clinical need, equitable global distribution strategies, and complementary investment in preventive and population-level public health measures. As a narrative review and commentary, the paper does not present original clinical data or trial results, and its conclusions are based on synthesized existing evidence and policy analysis rather than empirical study. Its primary value is as a framework for health policy discussion around GLP-1 access equity.
Review
This review synthesizes current scientific understanding of ghrelin, a hormone originally characterized primarily for its role in appetite stimulation and growth hormone release. The authors trace the full arc of ghrelin biology: from its biosynthesis (preproghrelin processing and O-acylation by the enzyme GOAT to produce the active acyl-ghrelin form), through its receptor pharmacology at GHSR1a, to its wide-ranging physiological roles. The review highlights that des-acyl ghrelin—the predominant circulating form—can exert effects independently of or with lower potency at GHSR1a, and that truncated "mini-ghrelins" may act as competitive antagonists. Recent cryo-EM structural data on GHSR1a are discussed as a framework for understanding biased signaling and drug design. The authors also review ghrelin's roles in glucose regulation, gastric function, cardiovascular tone, bone remodeling, renal hemodynamics, innate immunity, and the central nervous system—including links to neuroprotection, depression, Alzheimer's disease, and addiction. Translational topics covered include ghrelin stabilization strategies, synthetic ligands (agonists, antagonists, inverse agonists), LEAP-2-based approaches, and GOAT inhibitors. As a narrative review, the paper does not generate new experimental data, so primary evidence quality depends on the underlying cited studies.
International journal of molecular sciences · Nov 2025DOI ↗ Review
This review examines the role of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) in kidney protection among people living with type 2 diabetes and obesity. The authors trace the evolution of GLP-1 research from its original characterization as a metabolic hormone—regulating insulin secretion, suppressing glucagon, and reducing insulin resistance partly through weight loss—toward a broader understanding of its effects on kidney physiology and clinical outcomes. The review summarizes preclinical data alongside landmark clinical trial findings, noting that renoprotective effects have been observed despite only modest GLP-1 receptor expression in the kidney. Key clinical outcomes discussed include changes in albuminuria, estimated glomerular filtration rate decline, and cardiovascular-renal endpoints drawn from large outcomes trials. The authors frame GLP-1 RAs as an area of intensive ongoing investigation for chronic kidney disease management in the relevant patient population. As a narrative review, this paper does not conduct original data collection or meta-analysis, and conclusions are therefore subject to the selection and interpretation choices of the authors. It provides a useful synthesis of the existing evidence base but does not itself constitute primary clinical trial data.
The Journal of clinical investigation · Nov 2025DOI ↗