Preventing obesity-related cancer with the revolution in obesity management: the challenges of undertaking a clinical trial and potential solutions

# Preventing obesity-related cancer with the revolution in obesity management: the challenges of undertaking a clinical trial and potential solutions **Matthew Harris**, **Julia Brown**, **Andrew G. Renehan** 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, indicates that sustained long-term weight loss in individuals is associated with a reduction in 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 hinder public health success: 1. Awareness of the causal link between obesity and cancer risk. 2. Lifestyle interventions are typically linked with only moderate, non-sustained weight loss insufficient for clinically meaningful cancer prevention. However, a revolution in pharmacotherapy for obesity, specifically glucagon-like-peptide (GLP)-1 agonists and their extended family of dual and triple agonists, leads to significant rates of sustained weight loss as long as individuals continue medication. This raises a new research question: can this drug class reduce cancer risk with long-term use? The logistics and challenges of addressing this question in a clinical trial setting are discussed, along with potential strategies for overcoming these challenges. ## Introduction Obesity poses one of the most pressing global health challenges, with its prevalence surging alarmingly. In 2016, more than 1.9 billion adults were classified as overweight, including over 650 million individuals with obesity—a figure projected to exceed 1 billion by 2030. Despite decades of public health efforts, obesity rates continue to climb in nearly every country. For instance, between 1990 and 2022, 89% of countries experienced rising obesity rates in women, and 73% in men. This trend is fueling a parallel increase in obesity-related diseases such as type 2 diabetes, cardiovascular disease, and notably, cancer. The International Agency for Research on Cancer published a consensus in 2016, identifying 13 individual cancers directly affected by excess body adiposity, including oesophageal adenocarcinoma, colorectal cancer, and post-menopausal breast cancer. The causal mechanisms remain multifactorial, involving immune modulation, chronic inflammation, insulin resistance, and hormonal imbalance. The GLOBOCAN database analysis showed a steady rise in crude cancer rates in the UK from 2003 to 2017, demonstrating the correlation between increasing obesity rates and cancer incidences. The future landscape of obesity-related cancer is predicted to worsen, with the number of annual new cases likely to increase significantly over the next 25 years, further compounding healthcare burdens. ## Reversing obesity-related cancer risk Current policies and evidence suggest obesity is causally linked to cancer, yet there remains uncertainty about whether weight loss can reverse this risk. Treating obesity may potentially reduce cancer risk, achievable through three main strategies: bariatric surgery, behavioral interventions (diet and exercise), and pharmacotherapy. ### Bariatric Surgery Surgical management can yield long-term weight loss of 25–35% of total body weight and may protect against cancer, as seen in meta-analyses. However, surgery is not a feasible population-level solution due to complications, limited healthcare capacity, and societal acceptability. ### Behavioral Intervention Behavioral approaches have been central to obesity treatment, but their weight-loss efficacy is modest—2–5% of total body weight. No randomized controlled trial has significantly linked these interventions to a reduced risk of cancer. ### Pharmacotherapy Recent advancements in obesity pharmacotherapy include GLP-1 agonists, showing significant weight loss of 12% to 18% during trials, particularly beneficial for individuals without diabetes. RCTs indicate these medications additionally lower risks of obesity-related comorbidities, including type 2 diabetes and cardiovascular events. Early meta-analyses suggest no incidences of increased cancer risk, supporting the position that GLP-1 receptor agonists could serve as a cancer prevention strategy. ### The Need for a Clinical Trial To effectively influence clinical practice and public health policy, randomized controlled trials (RCTs) assessing GLP-1 receptor agonists' effects on cancer risk are crucial but fraught with challenges. These challenges include potential competing risks in long-term studies, the rarity of cancer events in general populations, intervention complexity, contamination from alternative weight-loss interventions, and the necessity for lengthy trial durations and significant financial resources. ### Clinical Trial Challenges 1. **Competing Risks**: Prolonged trials run the risk of interference from competing health outcomes. 2. **Rarity of Cancer Events**: Low baseline cancer incidence mandates large sample sizes to detect meaningful differences. 3. **Complexity of Intervention**: The pharmacological nature of obesity drugs demands consistent dosing and novice adherence planning, complicating trial standardization. 4. **Contamination**: Participants may switch drugs during prolonged trials, especially in control groups experiencing inadequate weight loss. 5. **Choice of Control**: Placebo or alternative drugs as controls could dilute the observed effects, posing ethical and methodological issues. 6. **Long Duration Needed**: Many obesity-related cancers have lengthy sojourn periods, necessitating trials of 10 years or more. 7. **Financial Cost**: The extensive resources required for such studies could jeopardize trial feasibility or lead to underpowered results. ## Conclusion The impending challenge of obesity-related cancer demands urgent consideration of targeted prevention strategies. A potential chemoprevention approach leveraging new pharmacotherapies can be revolutionary in managing obesity-related cancer incidence. Current observational studies have limitations; therefore, RCTs could provide pivotal evidence influencing future clinical management and public health initiatives. Despite the complexity, cost, and potential for trial challenges, the pursuit of evidence-based strategies in this arena is essential for mitigating the healthcare burden of obesity-related conditions over the coming decades. **References**: 1. World Obesity Federation. World Obesity Atlas. London: World Obesity Federation; 2024. 2. Phelps NH, et al. Worldwide trends in underweight and obesity from 1990 to 2022. Lancet. 2024;403:1027–50. 3. Khan MAB, et al. Epidemiology of type 2 diabetes – global burden of disease. J Epidemiol Glob Health. 2020;10:107–11. 4. Mensah GA, et al. Global burden of cardiovascular diseases. J Am Coll Cardiol. 2023;82:2350–473. 5. Lauby-Secretan B, et al. Body fatness and cancer — IARC Working Group report. N Engl J Med. 2016;375:794–8. 6. Ervik M, et al. Global Cancer Observatory: Cancer Over Time. Lyon, France: IARC. 7. Ferlay J, et al. Global Cancer Observatory: Cancer Tomorrow. IARC; 2024.