A new wave of drugs that hit both the glucagon and GLP‑1 receptors—like retatrutide—are showing big weight‑loss results in early trials, often better than current meds. They may also help with diabetes and heart risk, but they’re still experimental and not yet on the market. The review flags that cost, access, and long‑term safety will be key issues as they move toward approval.

The global rise in obesity and its associated health risks has driven the need for more effective pharmacological treatments. Glucagon receptor (GCGR)-based multi-agonist drugs are emerging as promising treatments for obesity, with several in advanced stages of clinical development. Agents like mazdutide, pemvidutide, survodutide and retatrutide have demonstrated the ability to trigger significant weight loss in earlier phase trials, often surpassing the amount of weight loss obtained with existing therapies. Their potential to address obesity-related comorbidities, including type 2 diabetes mellitus and cardiovascular disease, positions them as important additions to future obesity treatment guidelines. As these GCGR-based multi-agonists advance through clinical trials, their impact on obesity management may be substantial, particularly for patients who have not achieved success with current medications or lifestyle interventions. Some are also being evaluated for cardiovascular outcomes, highlighting their relevance in populations at high risk with overweight and obesity. Key considerations as these drugs move forward in development to eventual approval include cost, access and long-term safety. This article is part of the <i>Real-world evidence on the use of GLP1 receptor agonists</i> Special Issue: https://www.drugsincontext.com/special_issues/real-world-evidence-on-the-use-of-glp1-receptor-agonists.