Are GLP-1 receptor agonists a ‘magic bullet’ for cancer?

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists are widely prescribed for weight loss. Here, we discuss the need to monitor long-term use for cancer risk and to couple dietary and physical activity recommendations to prevent skeletal muscle atrophy and maintain metabolic health among people using these drugs.

Rising global obesity rates have fuelled the search for an effective solution. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have emerged as such and are now used by more than 16 million individuals in the USA alone¹. Amid widespread public interest and rapidly increasing prescription rates¹, crucial questions about the long-term consequences, namely ifthis reduces obesity-related cancer risk, remain unanswered.

Therapeutic benefits and long-term risks

The well-established link between obesity and cancer is driven by metabolic dysfunction associated with excess adipose tissue, particularly visceral adipose tissue (VAT) and ectopic fat deposition, which together promote the tumour development of over 13 different cancer types². Quantification of fat distribution and lean body mass (LBM) provides a nuanced metric for assessing metabolic health and obesity-related disease risk: VAT is pro-inflammatory and tumour-promoting, and LBM, particularly skeletal muscle, is metabolically protective³.

GLP-1RAs result in substantial loss of body weight, with metabolic benefits including a reduction in VAT, improved insulin sensitivity and lower systemic inflammation — all factors that countervail meta- bolically unhealthy obesity, a state strongly associated with increased cancer risk⁴. Recent meta-analyses and retrospective studies of data from patients with type 2 diabetes suggest that GLP-1RA use may reduce the incidence of some obesity-related cancers such as hepatocellular, endometrial, colorectal and kidney cancers⁵. Given the recency of their widespread use for weight loss and the long latency period of cancer development, a critical need exists for long-term studies, including well-designed clinical trials, to evaluate the impact of GLP-1RAs on long-term cancer risk and intermediate cancer risk biomarkers. Additionally, causal inference analyses using large epidemiological datasets are needed to clarify potential biological pathways and to determine long-term associations with cancer outcomes.

GLP-1RA use may also be accompanied by serious metabolic complications with important cancer-related implications, including that LBM, especially skeletal muscle, losses are possible in some cases⁶. In ageing and sedentary populations, loss of LBM (for example, skeletal muscle atrophy) undermines glucose homeostasis and, paradoxically, increases cancer susceptibility⁷. Although some studies suggest that with use of GLP-1RAs, loss of LBM may be an adaptive response leading to improved muscle quality, the current body of evidence points to a potentially maladaptive trajectory that warrants further investigation⁶. Clinical trials coupling the use of incretin mimetics such as GLP-1RAs with established approaches for reducing LBM loss, including resistance training and adequate protein intake, are needed to understand how to maximize their benefits for obesity reduction and, potentially, cancer prevention⁸.

The promise and problems of GLP-1RA-induced appetite suppression

GLP-1RAs function, in part, by increasing satiety, resulting in reduced food intake and weight loss. Yet, long-term appetite suppression with concomitant reduced food intake can also contribute to macronutrient and micronutrient deficiencies as well as lower dietary phytochemical and fibre intakes that are critical for modulating cancer-relevant mechanisms including oxidative stress and systemic inflammation. This is particularly relevant for older adults, in whom nutritional adequacy is already tenuous and muscle preservation is of utmost importance.

Pharmacologically induced satiety may suppress not just hunger, but also the behavioural cues needed to sustain healthy eating habits. As GLP-1RA users disengage from natural cues to regulate appetite, this can hamper long-term healthy eating behaviours, and could thus reinforce a medicalized approach to weight control that prioritizes pharmacology over food literacy and lifestyle autonomy. Conversely, substantial weight loss can provide functional improvements that enable patients to engage in more physical activity, and initial weight loss success can motivate patients to revise their dietary habits towards more healthful eating patterns. Studies are needed that characterize the variation in changes to lifestyle accompanying GLP-1RA therapies so that tailored diet and physical activity guidance and behaviour modification counselling can be provided for maximal health benefit. As enthusiasm for use of GLP-1RAs in managing obesity intensifies, the clinical and research community will benefit from testing comprehensive interventions that compare lifestyle interventions alone to those combining lifestyle (for example, resistance training or specific dietary patterns) with pharmacotherapy, surgery or both for obesity treatment.

Discontinuation leads to a rebound effect

GLP-1RA discontinuation is associated with VAT re-accumulation, elevated systemic inflammation and a return to insulin resistance. Discontinuation of incretin mimetic weight management therapy is also accompanied by complex hormonal shifts, including a decline in leptin and an increase in ghrelin, as well as disruptions in neuronal signalling, that can lead to increased appetite, reduced energy expenditure and VAT accumulation⁹. Together, these changes could be metabolically hazardous with pro-carcinogenic consequences. For example, rebound adipose tissue gain may increase cancer risk by reestablishing the metabolic dysfunction these therapies were meant to resolve. Following abrupt discontinuation of GLP-1RA pharmacotherapy, elevated inflammatory markers, insulin resistance and oxidative stress may return — potentially accelerating the development of cancer¹⁰, although studies of weight cycling using conventional lifestyle approaches and cancer risk have shown mixed results. Without durable solutions to support long-term weight loss maintenance among patients’ post-therapy, or access to lifelong pharmacotherapy, GLP-1RAs may offer a temporary fix at the expense of long-term metabolic competence.

Towards informed use and responsible integration into multidisciplinary care

The rise of GLP-1RAs presents a powerful obesity intervention with potential for obesity-related cancer prevention. Yet, rapid adoption for obesity treatment may outpace our understanding of the potential consequences for long-term cancer risk. Access to GLP-1RA therapy is complicated by cost and inconsistent insurance coverage that may disproportionately affect certain population groups already at elevated obesity-related cancer risk. Additionally, a focus on weight loss as a proxy for cancer risk ignores established drivers of both obesity and cancer, including diet composition, physical activity, other environmental exposures and genetic factors. Testing of rigorously designed, intensive lifestyle interventions before and during treatment with GLP-1RAs could help to establish appropriate behavioural targets to complement pharmacotherapy for obesity-related cancer prevention while also assessing the role of substrate partitioning — that is, directing metabolic fuels to oxidation in lean mass versus storage in adipose tissue¹¹.

The complexity of the obesity epidemic is well recognized. However, obesity pharmacotherapy may be inappropriate as an all-encompassing strategy for obesity-related cancer risk reduction. The best evidence to date suggests that obesity care should be informed by social and economic factors and is optimally delivered using multidisciplinary approaches for cancer risk reduction. For example, bariatric surgery may be very effective for patients with severe obesity or those with obesity-associated metabolic dysregulation who have had an incomplete response to dietary, lifestyle and pharmacological interventions. Therefore, a tiered approach would include diet and physical activity modification, as well as medication and bariatric surgery in some instances.

It is critically important that we understand the effect of GLP-1RA use on long-term cancer risk. Therefore, future research should focus both on short-term (that is, intermediate metabolic and other biomarkers) and long-term cancer-related outcomes in response to GLP-1RA use, including cancer incidence, co-morbidity, treatment tolerance, recurrence-free survival and mortality. Assessment of adipose tissue and metabolic health, muscle mass and function, nutritional status, microbiome dynamics and thermogenesis will further enlighten the field as to the risks and benefits of GLP-1RA use on cancer-relevant mechanisms. Research on the importance of preserving LBM and/or maintaining dietary adequacy will inform clinical practice guidelines within a multi-disciplinary approach.

Conclusions

The rising adoption of GLP-1RA use for obesity treatment highlights the current interest in and need for obesity treatments. Now, comparative health research is required to answer crucial questions about long-term cancer outcomes associated with pharmacological approaches. We must act deliberately, through multidisciplinary and translational research, clinical integration, policy reform and social commitment, to reimagine obesity care and associated cancer risks.