PADRAIC

Background: Obesity, commonly approximated by body mass index (BMI) ≥ 30 kg/m², is causally associated with at least 13 cancer types (obesity-related cancers) but it is unclear whether weight loss interventions among obese individuals result in risk reduction of cancer. Recently, several trials of short-term use of glucagon-like peptide-1 (GLP-1) receptor agonists, originally designed for use as anti-diabetes medications, have shown substantial weight loss outcomes compared with placebo. Notably, high-dose semaglutide is associated with approximately 15% weight loss in individuals with obesity without diabetes. With these impressive results, hypotheses are emerging that these drugs might have a role in the prevention of obesity-related cancers, mediated through weight loss.

Objectives/methods: The aim of this opinion paper is to critically appraise the methodological challenges and pitfalls associated with studying the question ‘does weight loss through use of GLP-1 receptor agonists reduce cancer risk’ through observational studies, and exemplify this through critique of a recent study published in this journal.

Results: We modified the ROBINS-E framework for assessing risk of bias, identifying seven methodological criteria specific to this research question, against which data should be interpreted. These include adequate adjustment for key parameters of body fatness; immortal time bias; treatment allocation bias; survival bias; cumulative drug dose effect; sufficient sojourn time between drug intervention and cancer presentation; and treatment effect specific to obesity-related cancers. We found that 6 out of 7 methodological criteria were at high risk of bias.

Conclusions: Cancer prevention through GLP-1 receptor agonist use should be explored; however, there are several methodological challenges to overcome in understanding this link before it can inform clinical practice and policy.

Evidence from conventional and Mendelian Randomisation epidemiological studies support the conclusion that obesity is causally associated with increased risk of several common cancer types. Some evidence, notably from quasi-experimental bariatric surgery studies, support the concept that sustained long-term weight loss in individuals is associated with reduction of cancer incidence, particularly in women. Yet, there are no authoritative public health policies directed specifically at large-scale weight management interventions to prevent obesity-related cancers. At least two adversities conspire against public health success: (i) awareness of the causal link between obesity and cancer risk; and (ii) lifestyle interventions are associated with only moderate weight loss that is generally not sustained long enough to result in clinically meaningful cancer prevention. However, there is now a revolution of effective pharmacotherapy for obesity, namely glucagon-like-peptide (GLP)-1 agonists and their extended family of dual and triple agonists, which leads to substantial rates of weight loss, sustained while individuals continue to take the drug. There is now a key new cancer prevention research question, whether this drug class might significantly reduce cancer risk with long-term use. The logistics of addressing this question in a clinical trial setting are discussed and potential strategies to overcome these challenges are proposed.

Obesity is associated with increased risk of at least 13 cancer types. Evidence from bariatric surgery cohorts and some behavioural intervention trials supports the notion that weight loss can prevent obesity-related cancers. The introduction of glucagon-like peptide (GLP)-1 agonist drugs has rapidly revolutionised pharmacotherapy options. A cancer prevention clinical trial would be complex, lengthy, and costly; therefore, we undertook an international expert consensus to assess the need for and design of a weight-loss intervention cancer prevention trial. We used a combination of two nominal group meetings, sandwiching 3 Delphi rounds. A panel of 54 international, multi-disciplinary researchers was established, informed by patient groups. Feedback was incorporated iteratively, and borderline statements, those that did not reach consensus, were addressed in a final meeting. Through the Delphi rounds, retention rates were high (98%, 85%, 88%). Consensus was achieved on 25 statements. Including: (i) there is a need for clinical trial evidence to inform obesity-related cancer prevention strategies; (ii) a trial should reflect high-risk populations; (iii) trials should prioritise GLP-1 agonists; and (iv) future research should explore mechanistic pathways and relevant cancer precursors. This consensus underscores the need for trial evidence to inform strategies for obesity-related cancer prevention.