Newer incretin-based peptide therapies — from dual GIP/GLP-1 agonists like tirzepatide to triple agonists like retatrutide — are achieving unprecedented weight loss and cardiometabolic improvements, reshaping treatment for diabetes and obesity.
~15%Weight reduction achieved by orforglipron, an oral GLP-1 receptor agonist in development
What the researchers found
The review maps the incretin co-agonist landscape across multiple drug classes. GLP-1 receptor agonists improve glycated hemoglobin, weight, lipid profiles, and liver fat, with many reducing major adverse cardiovascular events (MACE). The oral GLP-1RA orforglipron achieves approximately 15% weight reduction.
Tirzepatide, the first approved dual GIP/GLP-1 agonist, offers comparable efficacy with notably fewer gastrointestinal side effects than GLP-1 monoagonists. Triple agonists targeting GLP-1, GIP, and glucagon receptors (retatrutide, efocipegtrutide) have demonstrated the highest pharmacotherapy-achievable weight loss to date. Emerging combinations include GLP-1/amylin agonists (CagriSema, amycretin) and peptide YY/GLP-1 dual agonists.
Why it matters
Obesity and type 2 diabetes are global epidemics driving cardiovascular disease. Incretin co-agonists represent the most significant pharmacological advance in metabolic medicine in decades, with each new generation of multi-receptor agonists achieving greater weight loss and broader cardiometabolic benefits. Understanding this rapidly evolving drug landscape is essential for clinicians and researchers.
How the study worked
This is an evidence review synthesizing data from clinical trials and published studies on incretin-based therapies. The authors compiled efficacy and safety data across GLP-1 receptor agonists, dual agonists, triple agonists, and emerging combination peptide drugs to provide a comprehensive overview of the cardiometabolic benefits.
What this study cannot tell us
As a review article, this paper synthesizes existing trial data rather than presenting original research. The abstract does not detail specific trial sizes, follow-up periods, or comparative effect sizes across drug classes. Many of the newer agents (retatrutide, efocipegtrutide, amycretin) are still in clinical trials, so long-term safety and real-world effectiveness data are limited.
How to read the evidence
This is a narrative evidence review synthesizing data from multiple clinical trials. While it provides a broad overview, it does not follow systematic review methodology, and many of the newer agents discussed are still in clinical trials.
When this study was published
Published in 2025, this review captures the current state of a rapidly evolving field, including drugs in late-stage clinical trials.
The bigger picture
This review captures a pivotal moment in metabolic medicine. The progression from single GLP-1 receptor agonists to dual and triple agonists mirrors a broader trend of designing peptide drugs that simultaneously engage multiple hormone pathways. The cardiometabolic benefits extend well beyond glucose control — these drugs are reducing heart attacks, strokes, and mortality, fundamentally changing how obesity and diabetes are treated.
Questions still open
- Will triple agonists like retatrutide maintain their weight loss advantage over dual agonists in long-term real-world use?
- How will the cardiovascular benefits of these newer co-agonists compare head-to-head with established GLP-1RAs like semaglutide?
- Can oral formulations of incretin co-agonists achieve efficacy comparable to injectable versions?
Common questions
What is the difference between a GLP-1 agonist and an incretin co-agonist?
Why is tirzepatide considered an advance over older GLP-1 drugs?
Read the original research
Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare.
World journal of cardiology, 17(8), 107991
Citation
Bhat, Sowrabha; Fernandez, Cornelius J; Lakshmi, Vijaya; Pappachan, Joseph M. (2025). Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare.. World journal of cardiology, 17(8), 107991. https://doi.org/10.4330/wjc.v17.i8.107991