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 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 narrative review synthesizes the current landscape of FDA-approved and investigational pharmacotherapies for obesity management. The authors examine six approved long-term agents — orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide — covering their mechanisms of action, pivotal efficacy data, safety profiles, indications, and prescribing considerations. The review notes that semaglutide and tirzepatide have substantially raised expectations for pharmacological weight loss compared to older agents. Emerging investigational compounds, including oral GLP-1 receptor agonists such as orforglipron and multireceptor agonists such as retatrutide, are highlighted as showing even greater early-phase efficacy signals. Common safety considerations discussed include gastrointestinal adverse effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, teratogenicity, and cost and access barriers. The authors emphasize that patient selection should be guided by BMI, comorbidities, and contraindications. Key limitations acknowledged by the review include a lack of direct head-to-head comparative trials, limited long-term cardiovascular outcomes data, and questions about weight durability after treatment discontinuation. The authors identify these gaps as priorities for future research.
Review
This review paper surveys the current landscape of obesity pharmacotherapy, covering both approved and emerging treatment options. The authors outline the clinical burden of obesity, noting its associations with diabetes, cardiovascular disease, hypertension, and hyperlipidemia, and briefly describe non-pharmacological management strategies such as nutritional therapy and exercise. The review catalogues FDA-approved anti-obesity medications — orlistat, setmelanotide, phentermine-topiramate, naltrexone-bupropion, liraglutide, semaglutide, and tirzepatide — and highlights semaglutide as having a favorable clinical and regulatory profile. Emerging agents discussed include orforglipron, a non-peptide oral GLP-1 receptor agonist positioned as a potentially convenient alternative to injectable therapies. The authors also explore adjunctive approaches such as probiotics, prebiotics, fecal microbiota transplantation, and mitochondrial uncouplers. Key barriers to obesity management — including financial constraints, inadequate clinician training, and lack of reimbursement — are identified. The paper concludes by advocating for innovative, multidisciplinary, and patient-centered care models. As a narrative review, the paper does not generate new primary data, and conclusions reflect the authors' synthesis of existing literature rather than independent experimental findings.
Review
This updated narrative review examines the efficacy and safety of anti-obesity medications (AOMs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). The authors synthesize evidence on several pharmacologic classes, with particular focus on incretin-based therapies. GLP-1 receptor agonists, specifically liraglutide and semaglutide, are reported to reduce hepatic steatosis, improve liver enzyme profiles, and attenuate fibrosis progression. Tirzepatide, a dual GLP-1/GIP agonist, is noted to produce superior weight loss compared to GLP-1 monotherapy, though data on hepatic histological outcomes in MASLD/MASH remain limited. Retatrutide, a triple GLP-1/GIP/glucagon agonist, showed the most pronounced metabolic effects overall, but its liver-specific histological impact is described as underexplored. The review also flags safety concerns with other AOMs such as bupropion-naltrexone and phentermine-topiramate, citing potential hepatotoxicity risks. The authors note that advanced MASLD may alter drug pharmacokinetics, complicating treatment decisions. Key limitations include the review's narrative design, heterogeneity of cited primary studies, and a general lack of large-scale, liver-histology-focused trials for newer agents.
World journal of gastroenterology · Oct 2025DOI ↗ Review
This review examines the expanding cardiovascular applications of glucagon-like peptide-1 (GLP-1) receptor agonists, a class of peptide-based agents originally developed for type 2 diabetes management. The authors synthesize molecular mechanistic data alongside clinical evidence from major cardiovascular outcome trials (CVOTs) to characterize how GLP-1 agonists may reduce risk across conditions including atherosclerosis, heart failure, stroke, and vascular dementia. Proposed mechanisms discussed include anti-inflammatory, anti-atherogenic, endothelial-protective, and direct cardioprotective effects. The review highlights findings from multiple CVOTs reporting reductions in major adverse cardiovascular events (MACEs), myocardial infarction, stroke, and cardiovascular mortality. Notably, the SELECT trial is cited as evidence extending potential benefit to non-diabetic individuals with obesity and established CVD. The review also addresses emerging dual GLP-1/GIP agonists such as tirzepatide and its own CVOT data. The authors acknowledge important limitations, including high drug costs, unresolved long-term safety questions, and real-world implementation barriers. As a narrative review, this paper does not generate primary data and is subject to the inherent risk of selective literature synthesis. It provides a useful conceptual overview but does not independently establish causality or efficacy.
Journal of clinical medicine · Sep 2025DOI ↗ Review
This scoping review examined the potential role of incretin mimetics — specifically GLP-1 receptor agonists (e.g., semaglutide), dual GLP-1/GIP receptor agonists (e.g., tirzepatide), and the investigational triple agonist retatrutide — as treatments for polycystic ovarian syndrome (PCOS). Following PRISMA guidelines and drawing on literature from EBSCO Medline and PubMed, the authors explored how these agents compare to traditional PCOS pharmacotherapy such as metformin and estradiol-progesterone combination pills. The review found that all three classes of incretin mimetics were associated with meaningful improvements in weight loss and insulin sensitivity relative to conventional treatments. Dual- and triple-acting agonists, which additionally target the GIP receptor, appeared to produce greater reductions in weight and improvements in insulin sensitivity than GLP-1-only agents. Some included studies also reported PCOS-specific symptom improvements, such as reductions in dysmenorrhea and changes in ovarian morphology. The authors note that the precise mechanisms by which incretin mimetics may address the hormonal dysregulation of PCOS remain unclear, and they call for further research to optimize the integration of these agents with existing standard-of-care therapies. Key limitations include the scoping review design, heterogeneity of included studies, and limited long-term human trial data.
Review
This review paper examines the challenge of preserving muscle mass during weight loss induced by GLP-1–based pharmacotherapies, including GLP-1 receptor agonists (e.g., semaglutide), dual GLP-1/GIP agonists (e.g., tirzepatide), and triple GLP-1/GIP/glucagon agonists (e.g., retatrutide). The authors note that while these agents can produce clinically meaningful weight loss (5–10% or more of body weight), a portion of that loss comes from lean mass, including skeletal muscle, which may contribute to long-term weight regain and increase the risk of sarcopenia. The paper discusses the biology of myokines—over 600 signaling proteins released during muscle contraction identified in human myocyte research—as potentially important targets for protecting or expanding muscle mass. The authors explore emerging anti-obesity agents and their potential combinations with incretin-based therapies to preferentially reduce fat mass while sparing or building muscle. The paper calls for further research to clarify the functional consequences of lean mass changes during weight loss and maintenance. As a narrative review, it synthesizes existing literature without conducting original trials, and no new clinical data are presented. Generalizability is limited by the review format and the evolving evidence base for newer agents.
World journal of diabetes · Sep 2025DOI ↗ Review
This review examines the evolving pharmacological landscape for obesity management, with a focus on gut-brain axis hormones and their therapeutic potential. The authors describe how nutrient-stimulated gastroenteropancreatic hormones — including GLP-1, GIP, glucagon, and amylin — have become central targets in obesity drug development. The review covers both marketed agents and those in ongoing clinical trials. GLP-1 receptor agonists (e.g., weekly injectable or daily oral semaglutide) are reported to achieve roughly 15–17% weight loss with a favorable safety profile. The dual GLP-1/GIP agonist tirzepatide is described as achieving up to approximately 22.5% weight loss at higher doses. Combination therapies under investigation — such as cagrilintide plus semaglutide (Cagrisema), GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GLP-1/GIP/glucagon) — are noted as potentially reaching weight loss comparable to bariatric surgery. The review also discusses cardiometabolic benefits and challenges around long-term treatment adherence for both patients and clinicians. As a narrative review, it synthesizes existing trial data rather than generating new primary evidence, and conclusions depend on the quality of the underlying studies cited.
Medicina clinica · Aug 2025DOI ↗ Review
This evidence review examines the evolving landscape of incretin-based pharmacotherapy, focusing on GLP-1 receptor agonists (GLP-1RAs) and newer multi-receptor co-agonists for cardiometabolic disease management. The paper surveys established GLP-1RAs — including liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide — noting their reported benefits on glycated hemoglobin, body weight, lipid profiles, liver fat, and cardiovascular outcomes (reduction in major adverse cardiovascular events, or MACE). It also covers emerging agents: dual GIP/GLP-1 agonist tirzepatide (approved for diabetes and obesity), dual GLP-1/glucagon co-agonists (notable for synergistic weight loss), and triple GLP-1/GIP/glucagon receptor agonists such as retatrutide and efocipegtrutide, described as achieving the highest pharmacotherapy-associated weight loss observed to date. Additional novel classes reviewed include GLP-1/amylin agonists (CagriSema, Amycretin), non-semaglutide oral GLP-1 agents, and peptide YY/GLP-1 dual agonists. As a narrative review, the paper does not present original trial data, and its conclusions are based on synthesized existing literature, which may introduce selection bias. The authors anticipate that metabolic benefits will translate into cardiometabolic outcomes, though direct evidence for many newer agents remains limited.
World journal of cardiology · Aug 2025DOI ↗ Review
This review examines the rationale and emerging clinical evidence for triple receptor agonist therapies targeting GLP-1, GIP, and glucagon receptors as next-generation treatments for obesity and type 2 diabetes (T2D). The authors focus primarily on retatrutide, the most clinically advanced triple agonist, which has completed Phase 2 trials. In people with obesity, retatrutide achieved up to 24.2% mean weight loss over 48 weeks; in people with T2D, it produced 16.9% mean weight loss over 36 weeks, alongside a 2.2% reduction in HbA1c and 82% of participants reaching HbA1c ≤ 6.5%. The review also highlights improvements in blood pressure, lipid profiles, waist circumference, and liver fat (82% reduction in hepatic steatosis). Gastrointestinal side effects were the most commonly reported adverse events, with no major safety signals identified in Phase 2. The authors also briefly discuss other unimolecular triple agonists and combination regimens in development. Key limitations include that this is a narrative review of Phase 2 data; Phase 3 confirmatory trials are still ongoing. Conclusions about long-term efficacy, safety, and cardiovascular/renal outcomes remain premature pending those results.
Current cardiovascular risk reports · Jul 2025DOI ↗ Review
This review paper provides a comprehensive overview of the current and emerging pharmacological landscape for metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD). The authors describe MASH as a growing global health burden, closely tied to obesity and type 2 diabetes, and carrying significant risks of cirrhosis, hepatocellular carcinoma, and liver failure. The review synthesizes evidence from advanced-stage clinical trials evaluating several therapeutic classes, including incretin-based therapies (GLP-1 receptor agonists, dual, and triple agonists such as semaglutide, tirzepatide, and survodutide), metabolic modulators (PPAR agonists like lanifibranor, FGF21 analogues like pegozafermin, and thyroid hormone receptor-beta agonists like resmetirom), and novel agents such as fatty acid synthase inhibitors. The authors note that regulatory endpoints currently rely on histological assessment, while noninvasive biomarkers and personalized approaches are gaining traction. Genetic factors, such as PNPLA3 polymorphisms, and artificial intelligence are highlighted as emerging tools for patient stratification and trial design. Key limitations acknowledged include unresolved questions about treatment duration, response heterogeneity, long-term adherence, and the evolving definition of therapeutic success.
The Journal of clinical investigation · Jul 2025DOI ↗ Review
This narrative review examines the current landscape and future directions of Type 2 Diabetes Mellitus (T2DM) treatment. The authors begin by describing conventional therapies — including metformin, sulfonylureas, and insulin — noting their limitations such as adverse effects, declining efficacy over time, and suboptimal glycemic control in many patients. The review then surveys a range of emerging therapeutic strategies. Dual incretin receptor agonists (e.g., tirzepatide), which co-activate GLP-1 and GIP receptors, are highlighted for their effects on insulin secretion, glucagon suppression, and weight loss. Dual SGLT1/2 inhibitors (e.g., sotagliflozin) are discussed for their dual gut-and-kidney glucose-lowering mechanism. Additional experimental approaches covered include glucagon receptor antagonists, GPR119 agonists, FGF21 analogs, AMPK activators, and CRISPR-Cas9 gene editing technologies. The authors acknowledge that while these novel therapies demonstrate promise in early-stage research, long-term safety and efficacy data in humans remain limited. As a narrative review, this paper does not present original clinical data, does not include a systematic search protocol or meta-analytic methodology, and is subject to selection bias in the literature discussed.
Biochemistry and biophysics reports · May 2025DOI ↗ Review
This scoping review systematically examined clinical research on anti-obesity medications (AOMs) conducted in Arab countries, drawing on five databases and covering publications up to October 2024. Researchers identified 59 eligible clinical studies published between 2014 and 2024, the large majority of which (89.8%) were observational in design. Most research originated from Saudi Arabia (40.7%) and the United Arab Emirates (20.3%). Glucagon-like peptide-1 (GLP-1) receptor agonists were the most studied drug class, appearing in 72.9% of studies, with liraglutide being the single most investigated agent (54.2%). The primary efficacy outcomes reported across studies were changes in total body weight, body mass index, and proportion of weight loss. Gastrointestinal side effects were noted in 32.2% of patients across studies. Risk of bias was assessed using the Newcastle-Ottawa scale and a modified randomized controlled trial tool. The authors highlight a notable gap: newer agents such as semaglutide and tirzepatide are underrepresented in the literature. Key limitations include the predominance of observational designs, geographic concentration, and limited data on diverse Arab subpopulations, which collectively constrain causal inference and generalizability.
Saudi medical journal · May 2025DOI ↗ Review
This review article provides a comprehensive overview of approved and emerging hormone-based anti-obesity medications (AOMs), situating them within the broader context of obesity as a complex, chronic, global disease. The authors summarize the current regulatory landscape, noting that the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide have received FDA and EMA approval for weight management. The review also covers pipeline agents, including oral GLP-1RAs (semaglutide, danuglipron, orforglipron), the amylin receptor agonist cagrilintide (alone and in combination with semaglutide), and dual agonists such as tirzepatide (GIP/GLP-1), survodutide, mazdutide, and pemvidutide (GLP-1R/GCGR). The authors highlight tirzepatide's placebo-subtracted weight reduction of 17.8% in a 72-week RCT and retatrutide's (a GLP-1R/GCGR/GIPR tri-agonist) placebo-subtracted reduction of 22.1% in a 48-week phase-II trial. The review cautions that long-term safety and cardiovascular outcome data for many of these agents remain incomplete. As a narrative review, it does not conduct original research or meta-analysis, and conclusions are limited by the quality and heterogeneity of the underlying primary studies it synthesizes.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗ Review
This review article examines the evolving landscape of glucagon-like peptide-1 (GLP-1)-based therapies for obesity management. The authors describe how obesity, a major risk factor for type 2 diabetes and cardiovascular disease, often resists traditional lifestyle interventions, motivating the development of more targeted pharmacological approaches. The review focuses on incretin mimetics — drugs that mimic nutrient-stimulated hormones — which act on G-protein-coupled receptors including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors. Specific agents highlighted include semaglutide and tirzepatide, as well as emerging multiagonist compounds such as GLP-1/glucagon and GIP/GLP-1/glucagon receptor co-agonists. The authors argue that glucagon receptor activation in particular represents a meaningful frontier in the field. The review surveys clinical efficacy data, neuroendocrine mechanisms, and signaling pathways underlying these therapies, while also outlining remaining challenges and future research directions. As a narrative review, it synthesizes existing literature rather than presenting original trial data, and does not conduct a formal meta-analysis. Its conclusions are therefore dependent on the quality and selection of the underlying primary studies reviewed.
Endocrinology and metabolism (Seoul, Korea) · Apr 2024DOI ↗