Obesity and its related metabolic comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease, are increasingly recognized as heterogeneous and multisystemic disorders. Despite the significant benefits in glycemic control and weight loss exhibited by GLP-1 receptor agonists (GLP-1RAs), their limitations have initiated the development of engineered multi-agonist therapies targeting additional nutrient-stimulated hormonal (NUSH) pathways. Dual and triple peptide-based co-agonists combining glucagon-like peptide-1 (GLP-1) with glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, or peptide YY have demonstrated superior metabolic efficacy in preclinical and clinical studies. Tirzepatide (GLP-1/GIP dual agonist), CagriSema (GLP-1/amylin dual agonist), and retatrutide (GLP-1/GIP/glucagon triple agonist) have achieved unprecedented levels of weight loss and glycemic improvement, with certain agents also demonstrating hepatic, cardiovascular, and inflammatory benefits. Non-peptidyl oral GLP-1RAs, such as orforglipron, offer novel formulation strategies to enhance treatment accessibility and adherence. Multi-agonist incretin-based therapies represent a paradigm shift in the management of obesity and metabolic diseases. These agents offer broad clinical utility beyond glucose lowering by mimicking the pleiotropic hormonal responses observed after bariatric surgery. These therapies are poised to emerge as key components of precision metabolic medicine. This review article explores the mechanistic basis, pharmacological characteristics, and clinical data supporting the use of engineered NUSH-based peptide therapies for obesity and its related metabolic disorders, with particular emphasis on recent progress in the development and clinical application of dual and triple agonists.
Steatotic liver disease (SLD) is a leading cause of disease globally and demands new therapeutic approaches to mitigate underlying metabolic dysregulation. Incretin-based therapies are emerging as a viable prospect to fulfil this unmet niche. A literature review to inform the evidence base for incretin focussed pharmacology in the metabolic liver diseases space and an informed commentary on unmet areas of need. Incretin-based therapeutics demonstrate multifarious benefits across the chronic metabolic disease spectrum with promising data across the continuum of pathology.
Reply to correspondence on “Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: a network meta-analysis” Tian-Yi Ren, Mohammed Eslam, Jian-Gao Fan Clinical and Molecular Hepatology.2024; 30(4): 1039. CrossRef
AMPK Activation and Lipid Homeostasis Regulation in MASLD: Investigating the Hepatoprotective and Anti‐Inflammatory Effects of Meta‐Capridin Medium‐Chain Triglycerides Alireza Doagoo, Sajad Ehtiati, Reza Ataei kachouei, Seyyed Hossein Khatami, Shima Rajaei, Maral Jalilzadeh, Nastaran Hamed, Fatemeh Namvarjah, Reyhane Ahmadzade, Marjan Ajami, Farzaneh Salmani, Somayeh Mahmoodi Baram, Mitra Rezaei, Majid Sirati-Sabet, Hoj Journal of Food Biochemistry.2025;[Epub] CrossRef
Evaluating causal protective effect of dual GLP-1R/GIPR agonists on MASLD: A Mendelian randomization and colocalization study Yangke Cai, Siyuan Xie, Liyi Xu, Jiamin Chen, Jianting Cai European Journal of Pharmacology.2025; 1005: 178088. CrossRef
Reply to correspondence on “Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: a network meta-analysis” Tian-Yi Ren, Mohammed Eslam, Jian-Gao Fan Clinical and Molecular Hepatology.2024; 30(4): 1039. CrossRef
Correspondence to editorial on “Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: a network meta-analysis” Hayeon Kim, Min Jeong Park, Myeong Gyu Kim, Kyungim Kim Clinical and Molecular Hepatology.2024; 30(4): 989. CrossRef
Background/Aims Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP-1RA) and thiazolidinedione (TZD) can improve nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). However, comprehensive research comparing the effects of GLP-1RA and TZD is limited. Thus, this study aimed to compare the effects of GLP-1RA and TZD on NAFLD or NASH through a network meta-analysis.
Methods The PubMed, Embase, Web of Science, and Scopus databases were searched for randomized controlled trials (RCTs) that explored the efficacy of GLP-1RAs or TZDs in adult patients with NAFLD or NASH. The outcomes were liver biopsy-based (NAFLD activity score [NAS], fibrosis stage, and NASH resolution), noninvasive technique-based (liver fat content on proton magnetic resonance spectroscopy [1H-MRS] and controlled attenuation parameter [CAP]), biological, and anthropometric indicators. A random effects model was used to calculate the mean difference (MD) and relative risk with 95% confidence interval (CI).
Results Twenty-five RCTs with 2,237 overweight or obese patients were included. GLP-1RA was significantly superior in reducing liver fat content evaluated using 1H-MRS (MD –2.42, 95% CI –3.84 to –1.00), body mass index (MD –1.60, 95% CI –2.41 to –0.80), and waist circumference (MD –4.89, 95% CI –8.17 to –1.61) than TZD. In liver biopsy-based evaluation and liver fat content assessment using CAP, GLP-1RA tended to surpass TZD, albeit not significantly. Sensitivity analysis showed consistent results with the main results.
Conclusions Compared with TZD, GLP-1RA had better effects on liver fat content, body mass index, and waist circumference in overweight or obese patients with NAFLD or NASH.
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