PADRIAC project: Ten-year trial testing GLP-1 drugs to prevent obesity-related cancers

A global panel of 21 obesity and cancer experts have suggested that to test the potential efficacy of the new generation of obesity drugs such as semaglutide and tirzepatide in preventing obesity-related cancer (ORC), a trial of the drugs for some 5,000 participants at high risk of cancer due to their having a cancer pre-cursor condition will provide the required answers.

The group of experts, convened at the European Congress on Obesity (ECO2026) in Istanbul, Turkey, including many well-known from large obesity and cancer trials published to date, as well as industry experts and funders, is led by Dr Matthew Harris from University of Leeds and Professor Andrew Renehan, Division of Cancer Sciences, University of Manchester, Manchester, UK.

The global obesity epidemic is, in addition to its many other problems, predicted to cause a surge in obesity-related cancers (there are 13 obesity-related cancers, including most commonly colorectal, post-menopausal breast, endometrial, oesophageal adenocarcinoma and kidney). The teams at Manchester and Leeds are working together on designing cancer prevention trials (the PADRIAC project).

Harris explains, "We now have drugs that can achieve levels of weight loss that were previously only possible with surgery. The critical next step is to understand whether this can actually prevent cancers. Our study shows that, by focusing on high-risk groups, a definitive trial is potentially feasible and scientifically robust."

They now believe that the evidence is so strong for the new generation of obesity drugs (that include glucagon-like peptide-1 (GLP-1) agonists and also GLP-1 / glucose-dependent insulinotropic polypeptide (GIP) dual agonists) that a clinical trial for these medications in obesity-related cancer prevention is needed, to give a definitive evaluation of their potential prior to their use in this area.

However, despite the excitement around these drugs, the practicalities such as expense and duration must be considered in any clinical trial. As such, a trial that involved the general population living with obesity, at low risk of developing cancer over 10 years, would need some 50,000 participants to be adequately powered, and thus would be too expensive.

Thus, the expert panel, which met during July and October 2025 before putting together their recommendations, has instead proposed a 1:1 randomised trial including 5,000 participants with overweight or obesity (BMI 27–35 kg/m2), and with a cancer pre-cursor condition including: Barrett's oesophagus, endometrial hyperplasia, colonic polyps or metabolic-associated steatohepatitis with fibrosis.

The intervention group will receive a GLP-1 or dual receptor agonist (GLP-1/GIP or GLP-1/amylin), with a behavioural weight loss intervention. The "control" group will receive just a behavioural weight loss intervention. The experts, using computer simulations, ran a number of trial scenarios and estimated a 10-year trial in this population will provide results with near-certainty as to whether the use of obesity drugs will reduce the risk of developing ORC.

The authors say, "This novel methodology and the inclusion of multi-disciplinary experts have defined a deliverable clinical trial protocol for the investigation of interventional prevention of obesity-related cancer using this new generation of medications. In particular, expert consensus and simulations allowed us to propose the selection of an optimal high-risk population, and enabling progression to real-world trial planning."

Prof Renehan adds, "There has been a lot of excitement among cancer experts that obesity drugs might offer a real opportunity to prevent hundreds of thousands of cancers globally."

On the question as to whether trials can distinguish if it is the weight loss, a specific effect of obesity drugs, or both, that could reduce the risk of ORC, the authors explain that further analysis using observational data in the LookAhead and SELECT trials (and others) should help provide answers.

On this, Prof Renehan explains, "We have learned from trials in non-cancer diseases, obesity drugs might work through weight loss and also through direct biological actions. The same might be true for cancer. In future trials using obesity drugs to prevent cancer, we will need to carefully design the trials to test whether both of these ways to prevent cancer might be working."