GLP-1 Receptor Agonists Demonstrate Anti-Cancer Effects Independent of Weight Loss

A groundbreaking study presented at the European Congress on Obesity (ECO) in Malaga, Spain, unveils compelling evidence that first-generation glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as liraglutide and exenatide may confer significant anti-cancer benefits extending beyond their established weight loss effects. Published in the prestigious journal eClinicalMedicine, this research challenges the traditional understanding of how these medications operate, suggesting that their role in cancer prevention, particularly obesity-related cancers, is far more direct and complex than previously recognized.

In one of the most comprehensive observational cohort studies to date, researchers drew comparisons between the cancer incidence rates of patients undergoing bariatric surgery and those treated with GLP-1RA medications over an extensive follow-up period averaging eight years. Bariatric surgery is widely acknowledged as the most effective weight loss intervention, significantly reducing the risk of obesity-related illnesses, including certain cancers. However, the study’s co-lead author, Dr. Yael Wolff Sagy of Clalit Health Services in Tel-Aviv, notes an intriguing anomaly: despite bariatric surgery’s superior efficacy in weight reduction, the incidence of obesity-associated cancers was comparable between the two groups. This phenomenon prompted an in-depth statistical adjustment for the degree of weight loss, which revealed that GLP-1RAs demonstrated a 41% greater relative effectiveness in preventing obesity-related cancers than surgery alone.

This discovery adds a new dimension to the understanding of GLP-1 receptor agonists, medications primarily recognized for their ability to mimic the incretin hormone GLP-1. By stimulating GLP-1 receptors, these pharmaceuticals enhance insulin secretion, inhibit glucagon release, slow gastric emptying, and suppress appetite—mechanisms that collectively facilitate blood glucose control and induce significant weight loss. However, such pharmacodynamics appear to be just the tip of the iceberg. The protective effect against certain malignancies hints at underlying biological pathways unrelated directly to weight loss or glycemic control, warranting further mechanistic exploration.

Obesity and type 2 diabetes have long been established as risk factors for a variety of cancer types, including but not limited to post-menopausal breast cancer, colorectal cancer, endometrial carcinoma (corpus uteri), meningioma, renal cell carcinoma, hepatobiliary malignancies, pancreatic neoplasms, thyroid cancer, gastric malignancies, ovarian carcinoma, and multiple myeloma. The mechanistic link usually involves chronic systemic inflammation, insulin resistance, and altered levels of adipokines and sex hormones, fostering an oncogenic milieu. The present study’s observations suggest that GLP-1RAs may interrupt one or more of these pro-tumorigenic routes, potentially through anti-inflammatory or immunomodulatory effects.

To elucidate their findings, the researchers harnessed an electronic health record dataset sourced from Clalit Health Services, Israel’s largest healthcare provider covering nearly half the nation’s population. The cohort consisted of over 6,300 patients aged 24 years or older with obesity (body mass index ≥35 kg/m²) and type 2 diabetes, all having no prior history of cancer. Participants were rigorously matched 1:1 based on demographic and clinical parameters: sex, age, baseline BMI, smoking status, and treatment initiation date. This methodological rigor minimized confounding variables and bolstered the reliability of comparisons between those treated surgically and pharmacologically.

Over a median observation period of 7.5 years, 298 new cases of obesity-related cancer emerged. Surprisingly, the distribution of cancer incidence was virtually identical between the bariatric surgery arm (5.76 cases per 1,000 person-years) and the GLP-1RA treatment group (5.64 cases per 1,000 person-years). Among these cancers, postmenopausal breast cancer was the most prevalent, accounting for 26% of cases, followed sequentially by colorectal cancer and uterine cancer. This comparable occurrence rate was unexpected since bariatric surgery is known to produce more substantial and sustained weight loss, historically correlated with lower cancer risk.

When the research team adjusted their analysis to account for maximal BMI changes during follow-up—a surrogate for the extent of weight loss—the anti-cancer potency of GLP-1RAs became evident. The medications demonstrated a direct protective effect independent of weight loss, effectively reducing the relative risk of obesity-related cancer by 41% compared to surgical intervention. This finding signifies that GLP-1RAs possess unique pharmacological properties that may interrupt carcinogenic pathways beyond the conventional benefits of weight management.

Professor Dror Dicker, co-lead author and distinguished researcher at Hasharon Hospital and Rabin Medical Center, highlighted possible mechanisms that might underpin these observations, including GLP-1-mediated modulation of inflammatory processes. Chronic inflammation is a well-established promoter of tumor genesis and progression, especially in obesity-linked malignancies. The anti-inflammatory properties of GLP-1RAs could represent a critical therapeutic pathway for mitigating oncogenic risk. Additionally, the long-term follow-up period allowed assessment of potential latent effects, which is crucial given the protracted development timeline of many cancers.

While the study provides groundbreaking insights, the authors prudently acknowledge certain limitations inherent to its observational, retrospective design. Definitive causal associations require validation via randomized controlled trials and larger prospective studies. There is also a need to explore whether newer generations of GLP-1 receptor agonists, characterized by enhanced potency and greater efficacy in inducing weight loss, provide amplified anti-cancer benefits or present unforeseen risks, including the possibility of increasing susceptibility to non–obesity-related cancers.

The broader implications of these findings reverberate across oncology, endocrinology, and metabolic medicine. If GLP-1RAs’ direct anti-cancer properties are further substantiated, these drugs could revolutionize strategies for cancer prevention in high-risk populations, particularly patients grappling with obesity and type 2 diabetes. The dual utility of managing metabolic disease while simultaneously reducing cancer risk aligns with an emerging paradigm of integrated care aiming to mitigate comorbidities in chronic illness.

Moreover, the economic and public health impacts are substantial. Obesity-related cancers contribute significantly to healthcare burdens worldwide. Pharmacological interventions like GLP-1RAs, if proven to lower incidence rates independently, could reduce the morbidity and mortality associated with these malignancies, ultimately decreasing costs and improving patient quality of life. These insights also prompt reconsideration of treatment sequencing and combination strategies involving surgery and pharmacotherapy in managing obesity and its complications.

The study was conducted by researchers affiliated with Clalit Health Services in Israel, with no direct financial support from pharmaceutical companies for this specific investigation, helping to mitigate potential conflicts of interest. However, disclosures note that some authors have received funding and personal fees from pharmaceutical firms such as NovoNordisk and Eli Lilly outside of this work. This transparency bolsters the credibility of the study’s conclusions while underscoring the importance of independent validation by the wider scientific community.

Taken together, this pioneering research highlights a fascinating and potentially paradigm-shifting role for GLP-1 receptor agonists far beyond their current use as antidiabetic and anti-obesity agents. Their ability to significantly reduce the risk of obesity-related cancers through mechanisms not solely attributed to weight loss opens new frontiers in understanding metabolic-cancer interactions. Continued scientific inquiry will be critical in unraveling the exact pathways involved and translating these findings into clinical practice that can save lives.

In summary, the interplay between obesity, diabetes, and cancer is complex and multifactorial, but emerging therapeutics like GLP-1 receptor agonists are reshaping how clinicians approach these interconnected diseases. As new generation drugs enter the market with accompanying research, the prospect of multifaceted interventions targeting metabolic dysfunction and oncogenic risk simultaneously may become a reality in personalized medicine. This study marks an important step toward that future, illuminating the path forward with robust data and compelling hypotheses that challenge conventional wisdom.

Subject of Research: Comparative analysis of the effectiveness of first-generation GLP-1 receptor agonists versus bariatric surgery in preventing obesity-related cancers.

Article Title: Glucagon-like peptide-1 receptor agonists compared with bariatric metabolic surgery and the risk of obesity-related cancer: an observational, retrospective cohort study

News Publication Date: 11-May-2025

Keywords: GLP-1 receptor agonists, bariatric surgery, obesity-related cancer, liraglutide, exenatide, type 2 diabetes, cancer prevention, metabolic therapy, inflammation, retrospective cohort study

Tags: anti-cancer effects of GLP-1RAsbariatric surgery versus GLP-1RAcancer incidence in obesity treatmentseClinicalMedicine study findingsEuropean Congress on Obesity 2023exenatide and obesity-related cancersGLP-1 receptor agonistsglucagon-like peptide-1 medicationsliraglutide cancer benefitslong-term effects of GLP-1RAsobesity-related cancer preventionweight loss independent cancer prevention