Metabolic Modulation in Cancer Care: The Potential Role of Glucagon-Like Peptide-1 Receptor Agonists

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes and obesity by providing sustained improvements in glycemic control, weight loss, and cardiovascular outcomes. These benefits have led to increasing interest in their potential role in cancer treatment. Obesity and metabolic dysfunction are well-known factors that promote the development, progression, and resistance to therapy in various cancers, suggesting that drugs targeting these pathways may have anticancer effects. Emerging epidemiologic and clinical evidence shows that GLP-1RA therapy is linked to a lower risk of several obesity-related cancers, including GI, breast, endometrial, ovarian, prostate, and hematologic malignancies. Mechanistic studies also reveal effects on insulin signaling, long-term inflammation, angiogenesis, and immune system modulation. This comprehensive review integrates current knowledge of GLP-1RAs in cancer care, covering drug action, epidemiology, underlying mechanisms, and clinical application. We evaluate evidence for cancer prevention, their use as complementary treatments, and outcomes in patients with existing cancer. Overall, the evidence suggests that GLP-1RAs could become a novel class of agents linking metabolic health and cancer therapy, with potential applications in neoadjuvant treatment strategies, particularly in settings where prolonged neoadjuvant intervals allow for metabolic optimization before definitive surgical intervention.

INTRODUCTION

Cancer incidence continues to rise worldwide, with obesity and metabolic dysfunction emerging as key modifiable risk factors.¹ Excess adiposity accounts for about 20% of cancer-related deaths globally, mainly through its effects on insulin resistance, inflammation, and hormonal imbalance.² Alongside these epidemiologic trends, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially created for glucose control in type 2 diabetes (T2D), are now widely used for obesity treatment.³ Among adults in the United States, 6% report current use and 12% report current or past use; this rises to 22% among those diagnosed with overweight or obesity by a clinician.⁴

This expansion has strengthened the connection between endocrinology and oncology. An increasing number of patients with cancer are now prescribed GLP-1RAs at diagnosis or during treatment, and observational studies increasingly indicate that GLP-1RAs may lower cancer risk and improve patient outcomes.^5-7 Concurrently, mechanistic research shows effects on tumor cell growth, blood vessel formation, and immune evasion, highlighting possible biologic pathways for anticancer activity.^8,9

Given the growing clinical importance of GLP-1RAs, this review provides a comprehensive overview of their role in oncology. We analyze pharmacology and mechanisms, summarize epidemiologic and clinical evidence across cancer types, discuss safety considerations, and explore future directions for incorporating GLP-1RAs into cancer prevention and treatment.

What Are GLP-1RAs?

GLP-1RAs are synthetic analogues of the GLP-1 hormone, which binds to the GLP-1 receptor and helps regulate blood sugar levels and satiety signals.¹⁰ The GLP-1 receptor is primarily expressed on pancreatic beta cells. In the presence of glucose, this binding stimulates insulin release and suppresses glucagon secretion, thereby improving glucose uptake in the periphery.¹¹ In nonhuman primates, GLP-1 receptor expression was detected in brain regions involved in regulating food intake, such as the hypothalamus and brainstem.¹² The presence of the receptor in the brain also helps explain the effects of GLP-1RAs in reducing addictive behaviors.¹³ GLP-1RAs have been shown to slow gastric emptying, an effect believed to result from postprandial inhibition of myenteric neurons of the GI tract.¹⁴ The delay in gastric emptying contributes to both a reduction in food intake and side effects like nausea, which is common and leads to discontinuation of therapy in 10%-20% of patients.¹⁵ Owing to these combined effects, most patients with T2D using GLP-1RAs experience improved fasting serum insulin and insulin sensitivity, lower hemoglobin A1c levels, and reduced reliance on supplemental insulin.^16,17

The main GLP-1RAs currently available are semaglutide, dulaglutide, and tirzepatide. Tirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the GLP-1 receptor.¹⁸ The triple agonist (at the GIPR, GLP-1 receptor, and glucagon receptor) retatrutide is currently under clinical investigation with promising early results.¹⁹ Total spending on GLP-1RAs in the United States in 2023 was $71.7 billion US dollars (USD).²⁰ Data show they can cause weight loss of 5%-18% of body weight in obesity²¹ and a reduction in HbA1c of up to 2.1%.¹⁶ The safety profile of GLP-1RAs is generally favorable; most adverse events are GI (nausea, diarrhea, vomiting), which can be managed with dose titration.

T2D and Obesity in Cancer

Hyperglycemia and obesity are both chronic risk factors for cancer development and progression.²² Episodic hyperglycemia in patients with cancer has also been linked to poorer overall survival.²³ Hyperglycemia leads to the formation of advanced glycation end-products (AGEs), which bind to their receptors, triggering proinflammatory signaling and cellular stress.²⁴ Hyperglycemia and insulin resistance increase circulating insulin-like growth factor (IGF)1 and insulin levels, both of which are pro-oncogenic through pathways such as PI3K-AKT-mTOR and RAS-MAPK. These promote new blood vessel growth (ie, angiogenesis), thereby enhancing tumor growth.²⁵ Angiogenesis is essential for supplying tumors with nutrients and oxygen to grow and enlarge, and it also allows tumors to penetrate blood vessels and metastasize. Hyperglycemia has also been linked to immune evasion in the tumor microenvironment (TME) in several ways. One pathway is glucose-induced O-GlcNAcylation in tumor-associated macrophages (TAMs), which pushes them toward an M2 phenotype and away from cancer cell destruction.²⁶ These cells inhibit adaptive antitumor immunity through mediators such as IL-10 and TGF-beta.²⁷

Obesity can promote chronic inflammation through various pathways. Excess adipocytes release proinflammatory cytokines (such as TNF-alpha, IL-6, and IL-1-beta), fostering low-grade inflammation. Higher levels of circulating free fatty acids and glucose increase the activity of oxidative pathways, overactivating mitochondria and releasing reactive oxygen species. These, combined with others, can overactivate the immune system via signaling pathways such as NF-kB and JNK, driving both tumor initiation and progression.^28,29 In obesity, this TME pushes macrophages toward an immunosuppressed state and promotes tumor progression and metastasis.³⁰ TAMs release cytokines like TGF-beta, which induce epithelial-mesenchymal transition in tumor cells, allowing them to break down the extracellular matrix, invade surrounding tissues, and enter circulation.³¹ TAMs also release vascular endothelial growth factor, which stimulates angiogenesis in endothelial cells, supporting tumor survival and growth.³²

The Warburg effect is the ability of cancer cells to reprogram to preferentially use glycolysis to produce ATP (instead of oxidative phosphorylation, which typically occurs) even in the presence of oxygen. HIF-1-alpha acts as a transcription factor to upregulate this process, supporting rapid tumor growth and survival.³³ Hyperglycemia and obesity can exacerbate this by providing an excess of the glucose required for glycolysis. Glycolysis produces lactate, further acidifying the TME, stabilizing HIF-1-alpha, promoting angiogenesis, contributing to chemotherapy and radiotherapy resistance, and supporting cancer's immune evasion.³⁴ Preclinical evidence already shows that metformin can sensitize cancer cells to respond more effectively to immunotherapy by altering tumor oxidative metabolism, improving T-cell function, and enhancing tumor clearance.³⁵

Patients with T2D have been shown to have worse cancer outcomes than those without T2D.³⁶ Patients with cancer who already have T2D are more likely to experience adverse outcomes such as cachexia, recurrence, and death from any cause compared with patients without diabetes.³⁷ The data also indicate that patients with T2D are treated less aggressively for their cancer, possibly because of more frequent treatment breaks.³⁸ Therefore, addressing the risk factors linked to T2D in patients with cancer using GLP-1RAs may not only reduce the higher cancer risk but also enhance survival. By improving metabolic health, patients on GLP-1RAs may respond better to treatments and handle side effects more effectively. In fact, the overall data suggest this could be true for patients with T2D and suggest a possible benefit for patients with cancer who might not currently have T2D. As a result, using GLP-1RA therapy as a neoadjuvant to improve metabolic health could help achieve a better response in at least some patients with cancer.

PHARMACOLOGY AND MECHANISMS OF GLP-1 RECEPTOR AGONISTS

GLP-1 is an incretin hormone released by intestinal L-cells in response to nutrient intake. Its receptor, a G-protein–coupled receptor expressed in pancreatic beta-cells and various extrapancreatic tissues, mediates glucose-dependent insulin secretion, inhibits glucagon release, delays gastric emptying, and promotes satiety.³⁹

Clinically, GLP-1RAs lower HbA1c by 1%-2% and cause weight loss of 5%-18%, depending on the medication's strength and duration.^16,40 Cardiovascular outcome trials have shown reductions in major adverse events. The LEADER trial demonstrated that liraglutide significantly reduced the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with T2D at high cardiovascular risk (hazard ratio [HR], 0.87 [95% CI, 0.78 to 0.97]), with a notable reduction in cardiovascular mortality (HR, 0.78 [95% CI, 0.66 to 0.93]) compared with placebo.⁴¹

The potential anticancer effects of GLP-1RAs stem from several overlapping biologic mechanisms. A key pathway is metabolic regulation. By decreasing insulin resistance and reducing hyperinsulinemia, GLP-1RAs inhibit critical cancer-driven signaling pathways such as PI3K-AKT-mTOR and RAS-MAPK, which are essential for tumor growth and survival.⁴² In addition, GLP-1RAs influence hormonal and inflammatory pathways. Decreases in estrogenic activity, normalization of adipokine levels, and reductions in proinflammatory cytokines help transform the tumor environment into one less favorable for malignant development.⁶ Emerging evidence also suggests immunomodulatory effects. In murine cancer models, GLP-1RAs enhance dendritic cell activity, strengthen cytotoxic CD8⁺ T-cell responses, and reduce regulatory T-cell–mediated suppression, collectively strengthening antitumor immunity.⁴³ Additionally, there is evidence of direct receptor-mediated activity: GLP-1 receptor activation with exendin-4 in murine CT26 colon cancer cells increase intracellular cAMP, inhibits ERK1/2 and glycogen synthase kinase 3, and reduces proliferation and increases apoptosis in vitro and in vivo.⁴⁴ In human pancreatic cancer cell lines, GLP-1 receptor activation with liraglutide inhibits cell growth and promotes apoptosis through cAMP-dependent inhibition of Akt and ERK1/2 signaling; these effects are confirmed in mouse xenograft models.⁴⁵ In breast cancer cell lines, GLP-1 and exendin-4 reduce cell viability and enhance apoptosis, mediated by cAMP signaling, and attenuate tumor formation in athymic mice.⁴⁶ Exendin-4 also inhibits breast cancer cell proliferation via GLP-1 receptor activation and NF-kB signaling suppression.⁴⁷ These metabolic, hormonal, immunologic, and receptor-specific mechanisms likely work together, providing a biologic basis for the broad anticancer associations seen across epidemiologic studies (Fig 1).

FIG 1.

Proposed anticancer mechanisms of GLP-1 receptor agonists. GLP-1RAs may modulate tumor biology through effects on metabolic regulation, inflammation, hormonal and adipokine signaling, direct tumor-cell pathways, and immune responses, ultimately influencing angiogenesis, apoptosis, invasion, metastasis, and treatment outcomes. Akt, protein kinase B; cAMP, cyclic adenosine monophosphate; ERK, extracellular signal-regulated kinase; GLP-1RA, glucagon-like peptide-1 receptor agonists; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide-3-kinase; RAS-MAPK, rat-sarcoma–mitogen-activated protein kinase.

EPIDEMIOLOGIC AND CLINICAL EVIDENCE ACROSS CANCER TYPES

Global Cancer Risk Reduction

Large-scale population studies provide the strongest current evidence for GLP-1RAs in reducing overall cancer risk. In a nationwide analysis of 1.1 million obese individuals, Levy et al⁴² demonstrated that GLP-1RA therapy was associated with significant reductions in GI, breast, female genital, prostate, and hematopoietic cancers, with semaglutide showing the most pronounced protective effect. Wang et al⁴⁸ found that, in their analysis of 1.6 million patients with T2D, treatment with GLP-1RAs was associated with a significantly lower risk of 10 of 13 obesity-related cancers compared with patients treated with insulin. Specifically, GLP-1RA therapy was linked to reduced risks for esophageal, colorectal, endometrial, gallbladder, kidney, liver, ovarian, pancreatic cancers, meningioma, and multiple myeloma, with HRs ranging from 0.35 to 0.76 for these cancer types. These findings have been supported by multiple cohorts, including Dai et al,⁷ who confirmed a reduced overall cancer incidence among GLP-1RA users with obesity, particularly for endometrial, ovarian, and meningioma cancers. The network meta-analysis of 67 randomized controlled trials by Hsu et al⁴⁹ found that efpeglenatide significantly reduced the odds of metastatic cancer (odds ratio [OR], 0.26 [95% CI, 0.09 to 0.70]; P = .010).

Mavromatis et al⁵⁰ studied 85,000 patients and found a 16% lower colon cancer rate and a 28% lower rectal cancer rate among GLP-1RA users compared with DPP-4 inhibitors. Although these findings are observational, their consistency across large data sets strengthens the hypothesis that GLP-1RAs have protective effects against CRC. The same group also reported a 7% decrease in overall obesity-associated cancers and an 8% lower mortality rate among female patients on GLP-1RAs.⁵⁰ Wang et al⁵¹ reported a 19% reduction in 13 obesity-related cancers, with half the 15-year mortality in those treated with GLP-1RAs.

Meta-analyses of randomized trials (approximately 50 randomized controlled trials, >52 weeks) found no significant increase in overall cancer risk (Mantel–Haenszel odds ratio [MH-OR], 1.05 [95% CI, 0.98 to 1.13]) and observed reductions in uterine cancer. However, a slightly increased risk of thyroid cancer (MH-OR, 1.55) has been reported, consistent with preclinical rodent data, although its relevance to humans remains uncertain.⁵² In shorter-duration trials, a small apparent excess of colorectal cancer cases was noted; however, this was likely attributable to detection bias, reflecting earlier diagnosis because of closer monitoring of patients in the intervention arms, rather than a true drug-related effect.^52,53 The American Diabetes Association and the European Association for the Study of Diabetes state that there is no increased risk of thyroid tumors or thyroid cancer in the general population treated with GLP-1RAs, but that those with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 should avoid these medications.⁵⁴

GI Cancers

GI malignancies have some of the strongest associations. For esophageal cancer, GLP-1RA therapy was associated with a significantly lower risk compared with insulin therapy (HR, 0.60 [95% CI, 0.42 to 0.86]), representing an approximately 40% relative reduction in hazard.^48,55 For colorectal cancer, GLP-1RAs are associated with a 46% lower risk than insulin (HR, 0.54 [95% CI, 0.46 to 0.64]).^48,55 For gastric cancer, the risk is also lower with GLP-1RA use, although the association did not reach statistical significance (HR, 0.73 [95% CI, 0.51 to 1.03]).⁵⁶

Rationale for Combining GLP-1 RAs With Total Neoadjuvant Treatment in Rectal Cancer

Building on this emerging preclinical and translational evidence, our research group is actively exploring the potential role of GLP-1RAs in combination with neoadjuvant chemotherapy for rectal cancer. A prospective clinical study investigating this strategy has been registered at ClinicalTrials.gov (identifier: NCT07314528).⁵⁷

Reducing obesity and hyperglycemia would be expected to reduce tumor growth and metastasis by diminishing a TME that supports cancer hallmarks. Patients with T2D who receive GLP-1RAs and no longer require insulin have a lower incidence of GI cancers compared with those treated with insulin alone.⁵⁸ GLP's antitumor activity may extend beyond obesity and weight loss, however. In vitro and limited in vivo data suggest that direct stimulation of the GLP-1 receptor inhibits tumor growth and metastasis. In human pancreatic cancer cell lines, liraglutide attenuated growth and promoted apoptosis, and had a similar effect in a mouse xenograft model. This increased production of cAMP inhibits Akt and ERK1/2 signaling pathways, which are key for cancer cell survival, growth, metabolism, migration, and angiogenesis. Akt inhibition was dose-dependent.^45,59 In mouse colon cancer cells expressing GLP-1, exenatide increased cAMP and reduced signaling by the kinase's glycogen synthase kinase 3 and ERK1/2, leading to apoptosis and inhibiting proliferation.⁴⁴ Exenatide was also found to attenuate breast cancer cell proliferation in vitro and, in a mouse graft, to reduce tumor size in vivo. It significantly reduced NF-kB nuclear translocation and target gene expression.⁴⁷ In another preclinical study, liraglutide was found to directly inhibit colorectal cancer cell proliferation, migration, and invasion, while promoting apoptosis by inhibiting the PI3K/AKT/mTOR signaling pathway.⁶⁰

GLP-1RAs may increase antitumor immunity. In a mouse model of breast cancer, semaglutide was found to delay tumor appearance, growth, and progression. They observed increased dendritic cell activity, suggesting improved antigen presentation. They reduced FoxP3+ regulatory T cells and enhanced cytotoxic CD8⁺ T cells, thereby reducing immunosuppression and improving antitumor immunity.⁶¹

There is evidence supporting a synergistic effect between GLP-1RAs and chemotherapy in anticancer regimens. In colon cancer cell lines, exenatide augmented apoptosis induced by the chemotherapeutic agent irinotecan when given together.⁴⁴ Although gemcitabine-resistant pancreatic tumor cells expressed less GLP-1R than nonresistant cells, treatment with liraglutide increased GLP-1R expression, inhibited growth, and promoted apoptosis. Liraglutide increased the chemosensitivity of PANC-1 pancreatic tumor cells to gemcitabine, reducing cell growth and inducing more apoptosis when given together versus gemcitabine treatment alone in vitro. In a mouse model, codelivery of these drugs led to smaller tumor volume and weight than chemotherapy alone.⁶² In a study of 33 cancer cell lines, GLP-1 signaling was found to be altered in most, and lower signaling associated with lower immune cell infiltration, higher tumor mutation burden, microsatellite instability, lower immunotherapy response, and ultimately lower survival. Colon cancer cell lines treated with semaglutide showed reduced migration and increased activation of ITPR1, previously linked to paclitaxel cytotoxicity, suggesting synergistic potential.⁶³

Evidence against GLP-1RAs in this setting also exists. A real-world observational study published in 2025 focused on 343 patients with triple-negative breast cancer undergoing neoadjuvant chemotherapy, of whom 7.5% were on GLP-1RAs. The study found that pCR among patients on GLP-1RAs was significantly lower than among those not exposed to these medications (30.8% v 64.4%). However, this was confounded, as patients exposed to GLP-1 drugs were significantly older, had a higher BMI, and had higher rates of T2D, hypertension, and hyperlipidemia.⁶⁴ Additionally, direct antitumor and chemo-sensitizing effects depend on GLP-1R expression, which is heterogeneous across tumors.⁶⁵ Pretreatment molecular profiling of GLP-1R expression may be necessary to identify patients likely to benefit, consistent with precision medicine principles.

Future Directions: Planned Phase II Clinical Trial

Building on this emerging rationale, our center is preparing a multicenter, phase II, open-label randomized controlled trial to formally evaluate the integration of GLP-1 receptor agonists into TNT protocols for stage III rectal cancer. Eligible patients will be randomly assigned to receive standard TNT alone or TNT combined with weekly semaglutide, initiated 4 weeks before FOLFOX and continued until surgery. The primary end point will be percentage weight change from baseline to post-TNT, with secondary outcomes including pathologic complete response, disease-free and overall survival, local recurrence, and treatment-related morbidity and mortality.

Breast Cancer

Obesity is a significant risk factor for postmenopausal breast cancer, particularly for hormone receptor–positive disease, driven by increased peripheral estrogen production, chronic inflammation, and adverse adipokine and insulin signaling.⁶⁶ Sustained weight loss is associated with improved metabolic and inflammatory profiles, which may reduce recurrence risk and improve overall prognosis in this population.⁶⁷ Recent findings by Xande et al highlight the emerging use of GLP-1RAs for weight management in patients with breast cancer,⁶ demonstrating modest but sustained weight loss (2.3%-5% at 6-12 months), even in patients receiving concurrent endocrine therapy.

GLP-1RAs also confer positive metabolic and cardiovascular effects-including improved insulin sensitivity, reduced circulating insulin and IGF-1, and lower cardiovascular morbidity-which are mechanistically linked to better breast cancer outcomes and may indirectly benefit prognosis, although direct oncologic outcome data remain limited.^6,68,69

In a nationwide cohort of 1.1 million adults with obesity, GLP-1RA use was associated with a lower risk of breast cancer (HR, 0.72 [95% CI, 0.64 to 0.82]), with semaglutide showing the most pronounced protective effect among GLP-1RA agents.⁴² Similarly, a Mendelian randomization and meta-analysis found a reduced breast cancer risk with genetically proxied GLP-1RA exposure (OR, 0.92 [95% CI, 0.88 to 0.96]).⁷⁰

However, systematic reviews and meta-analyses of randomized controlled trials report no significant difference in breast cancer incidence between GLP-1RA-treated patients and comparators (RR, 0.98 [95% CI, 0.76 to 1.26]).^71,72 In summary, GLP-1RA therapy is associated with either neutral or modestly reduced breast cancer risk, with the strongest evidence from large real-world cohorts and genetic analyses, while randomized trial data support safety.

Prostate Cancer

GLP-1RA therapy is associated with a reduced risk of prostate cancer. In a nationwide cohort study of men age 50 years or older, GLP-1RA use was compared with basal insulin and found to be associated with a lower risk of incident prostate cancer: adjusted HR 0.91 (95% CI, 0.73 to 1.14) in the intention-to-treat analysis and HR, 0.80 (95% CI, 0.64 to 1.01) in the per-protocol analysis. The risk reduction was more pronounced in men age 70 or older (HR, 0.56 [95% CI, 0.38 to 0.82]) and in those with cardiovascular disease (HR, 0.60 [95% CI, 0.39 to 0.91]).⁷³

A large US cohort study of 1.1 million adults with obesity also demonstrated a significant reduction in prostate cancer risk among GLP-1RA users compared with matched controls (HR, 0.68 [95% CI, 0.58 to 0.80]), with semaglutide showing the strongest protective effect.⁴² These findings are supported by additional nationwide analyses in which GLP-1RA therapy was associated with lower incidence of obesity-related cancers, including prostate cancer, compared with insulin and other glucose-lowering drugs.⁵⁸

Meta-analyses of randomized controlled trials and umbrella reviews report no increased risk of prostate cancer with GLP-1RA therapy.⁵²

Lung Cancer

In a propensity-matched cohort of over 158,000 adults with T2D, GLP-1RA users had a lower incidence of lung cancer than dipeptidyl peptidase-4 inhibitor users (HR, 0.86 [95% CI, 0.80 to 0.94]) over a 10-year follow-up, with additional reductions in pulmonary infections and fibrosis.⁷⁴ In patients with non–small cell lung cancer (NSCLC) and obesity, GLP-1RA therapy is associated with improved recurrence-free survival after surgical resection (HR, 0.41 [95% CI, 0.16 to 1.04]; P = .026) and enhanced overall and progression-free survival when combined with immune checkpoint inhibitors (HR, 0.41 and 0.31, respectively).⁴³ Meta-analyses and Mendelian randomization studies report no increased risk of lung cancer with GLP-1RA therapy in patients with obesity or T2D.⁷⁵

Hematologic Malignancies

GLP-1RA therapy is associated with a significantly lower risk of hematologic malignancies in patients with obesity or T2D compared with insulin and other glucose-lowering therapies.^72,76,77 In a large multicenter cohort study, GLP-1RA use was linked to a 54% lower risk of hematologic cancers than with insulin, including myeloid leukemia (HR, 0.39), lymphoid leukemia (HR, 0.45), non-Hodgkin lymphoma (HR, 0.42), myelodysplastic syndrome (HR, 0.19), myeloproliferative neoplasms (HR, 0.50), monoclonal gammopathy (HR, 0.68), multiple myeloma (HR, 0.49), and amyloidosis (HR, 0.52).⁷⁶

Surgical Outcomes

Significant preoperative weight loss achieved through GLP-1RAs may lead to measurable improvements in surgical outcomes. Evidence from bariatric and colorectal surgery indicates that reduced visceral adiposity yields clearer operative fields, shortens procedure times, and decreases intraoperative bleeding rates.^78-81 Moreover, patients with lower BMI consistently experience lower conversion rates in minimally invasive rectal surgeries.⁸²

High BMI is a well-known risk factor for postoperative complications such as wound infections, cardiopulmonary events, and delayed recovery.⁸³ In bariatric-preconditioned patients with colorectal cancer, prior weight-loss strategies have been associated with a 6.5% absolute reduction in postoperative morbidity and lower health care costs.⁸⁴

GLP-1RAs' effects on glucose homeostasis and insulin sensitivity are also highly relevant in the perioperative setting. Reducing perioperative hyperglycemia significantly reduces thromboembolic events, improves wound healing, and shortens length of stay with fewer readmissions. Furthermore, the anti-inflammatory and cardioprotective effects of GLP-1 receptor agonists could attenuate the systemic stress response to surgery, reducing the incidence of cardiopulmonary complications.⁸⁵

By promoting satiety, GLP-1RAs preferentially reduce adipose tissue while preserving lean muscle mass, resulting in a more favorable body composition.⁸⁶ This may complement enhanced recovery after surgery (ERAS) pathways.

SAFETY CONSIDERATIONS

GLP-1RAs are contraindicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2 (MEN2), as recommended by the American Association of Clinical Endocrinology and the US Food and Drug Administration (FDA), based on rodent data showing GLP-1 receptor expression in thyroid C-cells and a dose-dependent increase in C-cell tumors.^87-89 Human data are less clear: Silverii et al⁵² meta-analysis reports a small but statistically significant increase in thyroid cancer risk, particularly with liraglutide (MH-OR, 1.55 [95% CI, 1.05 to 2.27), although most large cohort and randomized trial data do not confirm a clinically meaningful increase in the risk of thyroid cancer or MTC. The FDA does not recommend routine calcitonin monitoring for patients on GLP-1RAs.⁸⁷

For kidney cancer, observational studies such as Mao et al⁵⁸ and Dai et al⁷ report inconsistent findings, with some signals of increased risk (HR, 1.43 [95% CI, 1.06 to 1.92]) in certain subgroups, but no consistent or robust association across large populations.⁹⁰ These findings require further validation.

Short-term randomized trials have shown small increases in colorectal cancer incidence with GLP-1RA use (MH-OR, 1.27 [95% CI, 1.03 to 1.57]), but this is likely attributable to surveillance bias, as patients on GLP-1RAs experience GI symptoms that prompt increased diagnostic procedures, rather than a true carcinogenic effect.^52,91 Long-term data do not support an increased risk.

Overall, large-scale population studies and meta-analyses demonstrate no overall increase in cancer incidence with GLP-1RA therapy. The safety profile is favorable, with the exception of the specific contraindications for MTC and MEN2, and ongoing vigilance for rare cancer signals in long-term use.

FUTURE DIRECTIONS

Prospective, randomized clinical trials to evaluate cancer outcomes with GLP-1RAs, as most current data are derived from retrospective cohorts and meta-analyses of trials not powered for cancer end points.

Developing biomarkers and profiling GLP-1 receptor expression to identify patient groups and tumor types most likely to benefit. Multi-omics approaches and receptor profiling are proposed to refine patient stratification and guide the precision use of GLP-1RAs in oncology.^65,92

Preclinical studies support combination strategies with immunotherapy and targeted therapies, demonstrating that GLP-1RAs can enhance antitumor immunity, modulate the TME, and synergize with immune checkpoint inhibitors, particularly in obesity-driven cancers.^5,43

Cost-effectiveness analyses are necessary to assess the economic viability of GLP-1RAs in cancer prevention and survivorship programs, given the high cost and disparities in access associated with these agents.⁵² In the United States, annual spending on GLP-1RAs exceeded $71.7 billion USD in 2023.²⁰ Their cost-effectiveness in oncology will depend on whether clinical benefits translate into downstream cost savings, as has been demonstrated in surgical populations where improved metabolic status reduces postoperative expenditure. However, access to these agents remains uneven, with substantial disparities in insurance coverage for obesity indications. Widespread adoption without clear patient selection strategies could impose significant financial strain, highlighting the need for prospective oncology trials to incorporate cost-effectiveness and equity analyses alongside clinical end points.

In conclusion, GLP-1RAs, initially developed for metabolic diseases, are rapidly emerging as important in oncology. Epidemiologic studies consistently link their use to a lower risk of obesity-related cancers, and preclinical research identifies plausible biologic mechanisms. Clinical uses include prevention, adjunctive therapy, and survivorship care, although some safety concerns still warrant caution. As future trials and studies further explore the mechanisms, GLP-1RAs could become a key component of strategies that link metabolic health and cancer treatment.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Administrative support: Hugo C. Temperley

Collection and assembly of data: Michael E. Kelly

Data analysis and interpretation: Michael E. Kelly

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Metabolic Modulation in Cancer Care: The Potential Role of Glucagon-Like Peptide-1-1 Receptor Agonists

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