Bhat S, Fernandez CJ, Lakshmi V, Pappachan JM. Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare. World J Cardiol 2025; 17(8): 107991 [DOI: 10.4330/wjc.v17.i8.107991]
Corresponding Author of This Article
Joseph M Pappachan, MD, MRCP, FRCP, Professor, Senior Researcher, Faculty of Science, Manchester Metropolitan University, Oxford Road, Manchester M15 6BH, United Kingdom. drpappachan@yahoo.co.in
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Evidence Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Cardiol. Aug 26, 2025; 17(8): 107991 Published online Aug 26, 2025. doi: 10.4330/wjc.v17.i8.107991
Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare
Sowrabha Bhat, Cornelius J Fernandez, Vijaya Lakshmi, Joseph M Pappachan
Sowrabha Bhat, Department of Endocrinology, Yenepoya Medical College & Center for Nutrition Studies, Yenepoya University, Mangalore 575018, Karnātaka, India
Cornelius J Fernandez, Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom
Vijaya Lakshmi, Department of Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal 576104, Karnātaka, India
Joseph M Pappachan, Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
Joseph M Pappachan, Department of Endocrinology & Metabolism, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnātaka, India
Co-first authors: Sowrabha Bhat and Cornelius J Fernandez.
Author contributions: Bhat S, Fernandez CJ, and Lakshmi V participated in the literature search and interpretation of relevant data; Pappachan JM conceived the idea, contributed to the conceptualisation and design of the article, revision and overall supervision of the article drafting process and contributed to the revision of the paper. All authors have read and approved the final version of the manuscript. Bhat S and Fernandez CJ, substantially contributed to article drafting, created the figures, and revision and share the first authorship.
Conflict-of-interest statement: There are no conflicts in interests among authors.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Joseph M Pappachan, MD, MRCP, FRCP, Professor, Senior Researcher, Faculty of Science, Manchester Metropolitan University, Oxford Road, Manchester M15 6BH, United Kingdom. drpappachan@yahoo.co.in
Received: April 2, 2025 Revised: May 28, 2025 Accepted: July 14, 2025 Published online: August 26, 2025 Processing time: 141 Days and 13.8 Hours
Abstract
The ground-breaking development of the incretin agonists by manipulation of the incretin system, including the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as the pancreatic hormone glucagon, has led to the emergence of promising pharmacotherapy for metabolic health. The GLP-1 receptor agonists (GLP-1RAs), namely liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide, have been found to have beneficial effects on glycated hemoglobin, weight, lipid profile, and liver fat and thereby improving cardiometabolic health. Other drugs of the same group in development include Orforglipron, which has a high weight loss efficacy (-15% weight reduction). Long-acting GLP-1RAs in trials are Ecnoglutide, Efpeglenatide, TG103, and Visepegenatide. Many of these have cardiovascular benefits in terms of reduction in MACE (Non-fatal MI, Non-fatal stroke, and mortality). Tirzepatide is a dual GIP/GLP-1RA, the first drug of the group to be approved for diabetes and obesity with remarkably lower gastrointestinal side effects compared to GLP-1 monoagonists. The dual GLP-1/glucagon co-agonists cause tremendous weight loss due to the synergistic action. Most drugs in this class are long-acting and developed for once-weekly administration. The revolutionary triple agonists at the GLP-1, GIP, and Glucagon receptors have demonstrated the highest achievable weight loss with pharmacotherapy. Retatrutide and Efocipegtrutide belong to this novel group of drugs. The newer drugs in the broad category of incretin co-agonists include the GLP-1/amylin receptor agonist like CagriSema and Amycretin, oral GLP-1 agonists other than semaglutide, and the peptide YY/GLP-1 receptor dual agonists. The profound biochemical and weight loss outcomes associated with incretin co-/poly-agonists are expected to translate into outstanding cardiometabolic benefits, the theme of this evidence review.
Core Tip: Several incretin co-agonists have been developed in the recent years with outstanding metabolic and weight loss benefits revolutionising management of obesity and type 2 diabetes mellitus (T2DM). Management of obesity and T2DM with these glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide/glucagon co-agonists/poly-agonists are associated with remarkable weight loss, improvement of glycated hemoglobin, albuminuria, lipid profile, liver fat and sleep apnea among patients. All these benefits are also associated with marked improvement in cardiovascular outcomes in patients treated with these medications. This clinical update review explores current evidence and emerging research questions regarding the cardiometabolic benefits associated with rational use of incretin co-agonists.
