Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Incretin-based therapies have revolutionized the treatment of obesity and related metabolic disorders. On World Obesity Day (4 March), we discuss incretin-based therapies as go-to treatments for obesity and its comorbidities, highlighting triumphs and cautionary tales. The global rise in obesity and associated disorders over the past decades has spurred a multitude of therapeutic approaches, from bariatric surgery to novel weight loss drugs. However, none of these strategies have taken the world by storm as much as incretin-based therapies. Traditionally used for glycaemic regulation, glucagon-like peptide 1 receptor (GLP1R) agonists, and more recently dual and multi-agonist incretin-based therapies, have increasingly emerged as mainline therapies to combat obesity and induce weight loss. GLP1R agonists, such as semaglutide, and dual gastric inhibitory polypeptide receptor (GIPR)/GLP1R agonists, such as tirzepatide, consistently achieve 15–25% reductions in body weight, as shown in the STEP and SURMOUNT trials, respectively. In addition to weight loss, these drugs also lead to improvements in glycaemia (SURPASS and SUSTAIN trials), hepatic steatosis (ESSENCE trial), cardiovascular outcomes (SUSTAIN-6, SUMMIT and LEADER trials) and renal diseases (FLOW trial), as well as potential effects on cognitive function and neurodegeneration that are currently being evaluated. These myriad effects suggest that these drugs are not merely appetite suppressants but affect a variety of metabolic signalling pathways and tissues. Their broad efficacy also underscores that obesity, although druggable, is a multi-factorial and multi-faceted disease, and is not simply a result of ‘eating too much’ or ‘exercising too little’. As our preclinical and clinical experience with incretin-based therapies grows, their limitations are also becoming more apparent. One main concern is weight regain upon treatment cessation. Similar to other anti-obesity treatments, many patients regain weight and cardiometabolic benefits diminish after stopping incretin-based treatments (STEP 1 Extension Study). Studies also reveal that a subset of patients do not respond, or respond insufficiently, to these treatments. Moreover, different incretin-based therapies have varying efficacies. Together, these data suggest that the need for long-term solutions against obesity and its comorbidities persists. In addition to weight regain, adverse effects of long-term use of GLP1R agonists have become apparent, including gastrointestinal symptoms, which were reported in the STEP, SURPASS and SURMOUNT trials, and effects on the gallbladder. Other potential adverse effects, such as pancreatitis and behavioural changes in people with pre-existing mental health conditions, have been postulated but require further analyses. Nonetheless, not all side effects are necessarily negative. These include anti-inflammatory effects, better reproductive health and reduced ‘food noise’ or cravings, which can improve mental health and quality of life. In fact, the anti-inflammatory effects of incretin-based therapies spurred the EVOKE and EVOKE+ trials to study the effects of semaglutide on Alzheimer’s disease. Although preliminary reports suggest that these trials have not yet demonstrated a clear clinical benefit, they do highlight the overlapping yet divergent nature of neurodegeneration and metabolic disease, and the need to consider multi-pronged therapeutic approaches rather than monotherapies. In that vein, ongoing and future research is likely to explore synergistic therapeutic approaches such as dual (GIPR/GLP1R) and triple (GLP1R/GIPR/glucagon receptor) agonists, or combinations with amylin receptor agonists, such as CagriSema, which is being investigated in the REDEFINE trials. These studies further signal the need to understand the underlying tissue crosstalk, hormonal interactions and mechanistic intricacies informing disease presentation and, ultimately, treatment of obesity and its comorbidities. From a global public health perspective, it is also important to consider socio-economic constraints and geopolitical inequities that affect access to treatment. Tackling weight regain upon treatment cessation, inconsistent coverage by insurance, high costs and unprescribed or off-label use are all factors that can limit accessibility of these treatments to socio-economically or geographically disadvantaged populations and exacerbate existing disparities in healthcare. The expiration of the Novo Nordisk patent on semaglutide in Canada, India, China and Brazil in 2026 will offset some concerns related to affordability through the introduction of generic versions of the drug. World Obesity Day offers an opportunity to not only highlight the incredible progress made in this field but also to reiterate the need for well-informed research strategies and public health policies. Future studies investigating oral, less frequent administration of these drugs, as well as devising strategies to reduce production costs and increase patient compliance, and synergy with other therapeutic strategies will benefit at-risk populations and patients worldwide. In fact, the recent OASIS, PIONEER and SOUL trials on orally administered semaglutide have yielded positive results, highlighting potential alternatives for weekly injections and associated concerns and discomfort. Altogether, we look forward to seeing the next chapter of this story unfold and sharing exciting scientific advances related to incretin-based therapies in our pages and beyond. Rights and permissions Reprints and permissions About this article Cite this article Weighing in on the incretin revolution. Nat Metab 8 , 523 (2026). https://doi.org/10.1038/s42255-026-01490-3 Download citation

Published : 04 March 2026 Published : 04 March 2026 Version of record : 04 March 2026 Version of record : 04 March 2026 Issue date : March 2026 Issue date : March 2026 DOI : https://doi.org/10.1038/s42255-026-01490-3 DOI : https://doi.org/10.1038/s42255-026-01490-3 Share this article Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative Explore articles by subject Guide to authors Editorial policies Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.