Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is a class of incretin-based therapies widely used in the management of type 2 diabetes mellitus (T2DM). By mimicking endogenous GLP-1, these agents enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and promote satiety [1,2]. GLP-1 effects are mediated through the GLP-1 receptor (GLP-1R), a G-protein coupled receptor expressed not only in pancreatic β-cells but also in the cardiovascular system, adipose tissue, and central nervous system. Activation of GLP-1R supports glucose homeostasis while also influencing weight regulation, appetite, and cardiovascular function, underscoring its physiological relevance beyond glycemic control [3]. Upon receptor activation, GLP-1 elevates intracellular cAMP, which activates protein kinase A (PKA) and EPAC (Exchange Protein directly Activated by cAMP), thereby facilitating insulin secretion and attenuating glucagon release. In addition, GLP-1 signaling engages the PI3K/AKT pathway, which is essential for β-cell survival and function, and can also activate MAPK/ERK cascades involved in cell growth and proliferation [3,4]. By addressing both hyperglycemia and excess body weight, GLP-1 RA have become a cornerstone in the treatment of patients with T2DM, particularly those with concurrent obesity [2,5]. Beyond glycemic control, GLP-1 RA have demonstrated cardiovascular benefits in numerous large-scale randomized controlled trials. [6] Agents such as liraglutide, semaglutide, and dulaglutide have been associated with reductions in major adverse cardiovascular events (MACE) and cardiovascular mortality [7–9]. These findings have expanded the therapeutic role of GLP-1 RA to include cardiovascular risk reduction in patients with T2DM.

Despite these favorable outcomes, concerns remain regarding the long-term safety of GLP-1 RA, particularly their potential oncogenic effects. Preclinical rodent studies have shown that GLP-1 receptor activation can stimulate thyroid C-cell proliferation, raising concerns about the risk of medullary thyroid carcinoma (MTC). Supporting this theoretical risk, some epidemiological studies have suggested a possible association between prolonged GLP-1 RA exposure and an increased risk of thyroid malignancies, including MTC [10,11]. In contrast, a recent large multisite cohort study across six countries found no significant association between GLP-1 RA use and thyroid cancer compared with DPP-4 inhibitors (HR 0.81; 95% CI, 0.59–1.12), and no dose–response relationship was observed [12]. In addition to thyroid cancer, observational and pharmacovigilance studies have investigated potential associations between GLP-1 RA use and other malignancies—including pancreatic, colorectal, and breast cancers—with inconsistent results [13–15]. Some studies suggest protective effects, while others raise concerns about increased risk. However, many of these findings are complicated by population heterogeneity, underlying comorbidities, and differences in study design.

Given the growing use of GLP-1 RA in both diabetic and non-diabetic populations (e.g., for obesity management), it is important to critically evaluate their potential association with cancer risk. Importantly, there has been a shift in clinical practice toward initiating these agents earlier in the T2DM disease course. Previously, GLP-1 RA were typically introduced several years after diagnosis; now, they are often prescribed within months of diagnosis. However, the oncologic implications of such early use remain poorly understood. Accordingly, the present study seeks to explore the association between early initiation of GLP-1 RA therapy—defined as within three months of T2DM diagnosis—and the subsequent risk of developing cancer, with particular focus on site-specific malignancies potentially influenced by GLP-1 receptor signaling. We also conducted stratified analyses by body mass index (BMI) to assess whether the relationship between GLP-1 RA use and cancer risk differs according to obesity status.

As GLP-1 RA therapy has been adopted progressively earlier in the T2DM disease course, understanding its long-term safety—particularly oncologic outcomes—has become increasingly important. Previous evidence indicates that GLP-1 RA therapy was typically initiated a median of 6.1 years after T2DM diagnosis, reflecting delayed adoption in clinical practice [17]. However, growing evidence suggests that earlier initiation may lead to better glycemic outcomes and more durable long-term control [18,19]. Despite these metabolic benefits, the potential impact of early GLP-1 RA use on cancer risk remains unclear and warrants further investigation. This historical delay in GLP-1 RA initiation—often several years post-diagnosis—introduces potential confounding, as interim exposure to other antidiabetic agents may influence cancer risk. Consequently, isolating the specific effects of GLP-1 RA has been challenging. Our study aimed to specifically evaluate the impact of early initiation—defined as within three months of diagnosis—on subsequent cancer development. This design confers several methodological advantages. First, restricting GLP-1 RA exposure to the early disease stage minimizes exposure misclassification and ensures a consistent temporal sequence between treatment and cancer onset. Second, it helps mitigate reverse causality by reducing the likelihood that preclinical malignancies influenced treatment decisions. Together, these elements strengthen causal inference by upholding the core epidemiologic principle that exposure must precede outcome.

Compared with non-use, GLP-1 RA use was associated with a modest but statistically significant reduction in overall cancer incidence (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.90–0.97). Subgroup analyses by cancer type revealed decreased risk for several malignancies, including cancers of the respiratory tract (HR, 0.63; 95% CI, 0.45–0.89), digestive organs (HR, 0.80; 95% CI, 0.72–0.89), and colorectum (HR, 0.79; 95% CI, 0.66–0.96). The risk of pancreatic cancer was also modestly lower among GLP-1 RA users (HR, 0.84; 95% CI, 0.69–1.00), although the upper bound of the confidence interval approached unity. In contrast, GLP-1 RA use was associated with an increased risk of malignant melanoma (HR, 1.31; 95% CI, 1.01–1.70), while no statistically significant increase was observed for breast cancer (HR, 1.04; 95% CI, 0.94–1.15) or thyroid cancer (HR, 1.09; 95% CI, 0.88–1.34). The reduced risk of colorectal, digestive tract, and respiratory tract cancers among early GLP-1 RA users aligns with findings from several recent population-based studies [15,20,21]. Earlier observational studies had raised concerns about a potential increase in site-specific cancers—particularly thyroid, pancreatic, and breast malignancies—associated with GLP-1 RA exposure [10,22,23]. However, more recent large-scale cohort studies have not substantiated these associations, instead reporting neutral or null findings [12,24]. Our results support these more contemporary observations, showing no significant association in the risk of thyroid or breast cancer among early GLP-1 RA users.

The elevated risk of malignant melanoma observed in our cohort warrants cautious interpretation. To date, this association has not been consistently reported in the literature, and no well-established biological mechanism has been proposed. A recent population-based cohort study found no significant increase in the risk of melanoma (HR, 0.96; 95% CI, 0.53–1.75) or non-melanoma skin cancers (HR, 1.03; 95% CI, 0.80–1.33) among GLP-1 RA users compared to sulfonylurea users [25]. This discrepancy may reflect differences in population characteristics, confounding control, or outcome ascertainment. Further research is needed to validate our findings and determine whether the observed signal reflects a true drug-related effect or residual bias. To further explore the heterogeneity of cancer risk reduction associated with GLP-1 RA use, we performed a stratified analysis based on BMI. Notably, the risk reduction in overall cancer incidence was more pronounced among individuals with BMI ≥ 30 (HR, 0.91; 95% CI, 0.87–0.96), compared to those with BMI < 30 (HR, 0.97; 95% CI, 0.89–1.05).

While our findings are broadly consistent with a recent nationwide analysis of GLP-1 RA use and cancer risk in individuals with obesity [26], our study provides additional insights by focusing on a clearly defined early exposure period within a diabetes-specific population. In contrast to the prior study, which enrolled obese individuals regardless of glycemic status, our analysis was limited to patients with confirmed T2DM, allowing for a more targeted assessment within the population for whom GLP-1 RA are primarily indicated. Similarly, a study by Wang et al., which focused on overweight and obese drug-naïve patients initiating antidiabetic therapy, found that GLP-1 RA were associated with a 50% lower risk of colorectal cancer compared to insulin, and a 42% lower risk compared to metformin during a median follow-up of 3 years [15]. Site-specific analyses showed a significant reduction in digestive organ cancers (HR, 0.82; 95% CI, 0.72–0.93) and pancreatic cancer (HR, 0.74; 95% CI, 0.56–0.99) in the higher BMI subgroup, whereas no such benefit was observed in the lower BMI group. These findings suggest that the potential antineoplastic effects of GLP-1 RA may be more pronounced in individuals with obesity, potentially reflecting the compounds’ dual metabolic and weight-reducing properties.

Several biological mechanisms may provide plausible explanations for the associations observed in our study. From a mechanistic perspective, GLP-1 RA activates the PI3K/AKT/mTOR signaling cascade, a pathway that is indispensable for pancreatic β-cell survival and glucose homeostasis, yet simultaneously represents a canonical oncogenic axis [3]. This dual role highlights the necessity of carefully evaluating the long-term oncologic safety of GLP-1 RA in clinical populations.

Emerging evidence further indicates that GLP-1 RA can modulate the gut microbiota, promoting the expansion of beneficial genera [27,28]. As dysbiosis of the gut microbiome has been implicated in chronic inflammation and tumorigenesis, these observations suggest that microbiota–immune interactions may represent an additional pathway through which GLP-1 RA influences cancer risk.

Furthermore, GLP-1 RA exhibit immunomodulatory properties, including the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, reductions in pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-6, and the promotion of IL-10 secretion through T cell and microglial regulation [29,30]. Together, these pleiotropic effects provide a biologically plausible framework linking GLP-1 RA to cancer-related outcomes. Diabetes is increasingly recognized as a chronic inflammatory condition. A recent meta-analysis identified the ICAM-1 rs5498 polymorphism as a risk factor for T2DM, particularly in Asian populations [31], underscoring the role of immune–inflammatory pathways in diabetes pathogenesis.

In addition to these general mechanisms, the more pronounced cancer risk reduction observed in individuals with obesity may be explained by several factors. First, patients with elevated BMI inherently carry a higher baseline risk for various malignancies, including colorectal, pancreatic, and liver cancers [32,33]. Recent evidence demonstrates that obesity impairs CD8⁺ T cell function within the tumor microenvironment, leading to compromised immune surveillance and inefficient immunoediting, thereby increasing susceptibility to malignancy [34]. Key pathways linking obesity and cancer include PI3K/Akt/mTOR and JAK/STAT3 activation. More recent concepts further implicate the kynurenine–aryl hydrocarbon receptor axis and serine protease–mediated degradation of dependence receptors such as deleted in colorectal cancer and neogenin as additional routes promoting carcinogenesis [35]. Second, beyond glycemic control, GLP-1 RA exert metabolic and anti-inflammatory effects—such as weight reduction, improved insulin sensitivity, and lowered systemic inflammation—that are particularly relevant in the context of obesity [36]. Lastly, obese individuals may exhibit greater physiological responsiveness to GLP-1 RA, achieving more substantial reductions in body weight and metabolic burden, which could synergistically enhance the compounds’ potential antineoplastic effects.

Beyond clinical implications, our findings should be viewed within the broader context of medical innovation and health system resilience. The concept of health system resilience has been increasingly elaborated in recent literature, highlighting how governance, adaptability, and institutional networks enable systems to withstand shocks and sustain essential services under stress [37–39]. In parallel, the rapid adoption of GLP-1 RA illustrates how novel therapies can shape both patient outcomes and healthcare sustainability.

At the individual level, the heterogeneity of cancer risk reduction—particularly the more pronounced effects observed in patients with obesity—underscores the importance of precision medicine. Potential biomarkers such as BMI, systemic inflammatory markers, genetic variations (e.g., ICAM-1 polymorphisms), and gut microbiota composition could inform stratification strategies in future studies. Incorporating these factors into trial design and clinical practice may enable more individualized risk–benefit assessments, ensuring that GLP-1 RA are deployed not only for metabolic control but also as part of tailored strategies to mitigate diabetes-associated cancer risk.

Diverse limitations should be acknowledged in the interpretation of these results. First, although propensity score matching was applied to balance baseline characteristics, some covariates (e.g., HbA1c [SMD 0.136] and CRP [SMD 0.162]) remained slightly imbalanced. In addition, residual confounding from unmeasured variables—such as family history of cancer, lifestyle factors (including diet and physical activity), and environmental exposures—cannot be excluded. Second, the TriNetX platform lacks detailed information on medication adherence, dosage, and duration, limiting the ability to assess dose-response relationships or the effects of long-term GLP-1 RA exposure. Third, cancer outcomes were identified using ICD-10 codes, which may be subject to misclassification or underreporting, particularly for early-stage or subclinical cancers. Fourth, because the data were derived from U.S.-based health care institutions within the TriNetX network, the generalizability of these findings to other populations or health systems may be limited. Finally, as an observational study, causal inference cannot be established. The observed associations between GLP-1 RA use and cancer risk may be influenced by indication bias or other clinical decision-making factors not captured in the database.

In conclusion, early initiation of GLP-1 receptor agonist was associated with a reduced overall cancer risk, particularly for digestive, respiratory, and female-genital malignancies. These agents also provide significant weight-loss benefits, which may contribute to their protective effect. The risk reduction was especially evident in individuals with obesity, highlighting the dual metabolic and oncologic advantages of timely treatment.