A 2026 systematic review and meta-analysis synthesized data from 48 randomized placebo-controlled trials involving 94,245 adult patients with type 2 diabetes mellitus (T2DM) or overweight/obesity to evaluate the risk of various cancers associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists. The included trials assessed FDA-approved agents such as semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide, and tirzepatide. Cancer outcomes evaluated encompassed a spectrum of obesity-related malignancies, including thyroid, pancreatic, colorectal, gastric, esophageal, liver, gallbladder, breast, ovarian, endometrial, kidney cancers, multiple myeloma, and meningioma. Most trials had low risk of bias, although cancer detection was not a primary endpoint, and median follow-up ranged from roughly 70 to 243 weeks, highlighting a limitation in evaluating long-latency malignancies. The pooled results revealed that GLP-1RA and dual agonist therapy probably has little or no effect on the risk of thyroid cancer (OR 1.37, 95% CI 0.82 to 2.31), pancreatic cancer (OR 0.84, 95% CI 0.53 to 1.35), breast cancer (OR 0.95, 95% CI 0.60 to 1.49), and kidney cancer (OR 1.12, 95% CI 0.78 to 1.60) with moderate certainty evidence, corresponding to minimal absolute risk differences per 10,000 patients treated. For colorectal, esophageal, liver, gallbladder, ovarian, and endometrial cancers, as well as multiple myeloma and meningioma, the evidence suggested little or no effect but was of low to very low certainty, largely due to imprecision and sparse events. Notably, subgroup analyses uncovered a potential increased risk of gallbladder cancer in studies with longer treatment durations, consistent with the known association between GLP-1RA use and gallstone disease, though this finding remained tentative given the small number of events and wide confidence intervals. Sensitivity analyses restricted to low-bias trials, specific agents (semaglutide or tirzepatide), and longer follow-up durations corroborated the primary findings, with no consistent increase in site-specific cancer risks. These comprehensive results provide reassuring evidence on the cancer safety profile of GLP-1RAs and dual agonists in the studied populations but underscore the need for longer-term and cancer-specific trials to conclusively determine potential risks or benefits, particularly for malignancies with longer latency periods. [1]
A systematic review and meta-analysis comprehensively evaluated the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and cancer incidence by synthesizing data from 78 observational cohort and case-control studies encompassing diverse adult populations receiving GLP-1RAs for any indication. Meta-analyses using random-effects models pooled data across various cancer types, comparator treatments, and geographical settings. Sensitivity and subgroup analyses accounted for heterogeneity sources, including comparator drug classes (e.g., insulin, metformin, SGLT2 inhibitors) and publication types, while publication bias was evaluated with funnel plots and Egger’s test. The meta-analytic results demonstrated that GLP-1RA use was significantly associated with reduced risk of 10 out of 13 established obesity-associated cancers (OACs), notably colorectal (RR 0.72; 95% CI 0.66–0.78), endometrial, esophageal (RR 0.77; 95% CI 0.66–0.91), gallbladder, liver (RR 0.73; 95% CI 0.62–0.85), ovarian, pancreatic (RR 0.74; 95% CI 0.67–0.82), and gastric cancers. Protective effects were particularly pronounced when GLP-1RAs were compared to insulin, with marked risk reductions for colorectal (RR 0.54), liver (RR 0.35), and pancreatic cancers (RR 0.41). Conversely, a slight but statistically non-significant increase in thyroid cancer risk was observed among GLP-1RA users (RR 1.09; 95% CI 0.98–1.21), especially when compared with metformin. Additional analyses revealed reduced risks for certain non-obesity-associated cancers such as lung (RR 0.72) and prostate (RR 0.82) cancers. Substantial heterogeneity across pooled estimates was noted, attributed to differences in study design, populations, and comparator agents. Proposed mechanisms underlying these associations include indirect effects of GLP-1RAs on weight and fat loss, modulation of pro-inflammatory pathways, and potential behavioral influences such as reductions in alcohol and nicotine consumption. Despite reliance on observational data and inherent limitations such as residual confounding and heterogeneity, the findings underscore the potential of GLP-1RAs in cancer risk reduction, warranting confirmation in randomized controlled trials and further investigation into their role beyond metabolic indications. [2]
A 2024 systematic review and meta-analysis rigorously evaluated the risk of gastrointestinal cancers associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) by analyzing 90 randomized controlled trials (RCTs) encompassing 124,791 participants. The included trials had a minimum treatment duration of 24 weeks and a mean follow-up period of 3.1 years, with some extending to five years or more. The RCTs compared GLP-1 RAs—both pure and dual agonists—to placebo or active controls across diverse populations, predominantly patients with type 2 diabetes mellitus (T2DM) and overweight/obese individuals . Meta-analytical results demonstrated no significant association between GLP-1 RA treatment and the incidence of any gastrointestinal cancer, yielding a pooled risk ratio (RR) of 0.99 (95% CI 0.86 to 1.13) with zero heterogeneity (I² = 0%). This null effect persisted across subgroup analyses restricted to placebo-controlled trials, studies with follow-up durations of one year, two years, and five years, as well as high-dose GLP-1 RA regimens. Site-specific analyses encompassing biliary tract, colorectal, gallbladder, gastric, hepatic, esophageal, pancreatic, and small intestine cancers similarly revealed no statistically significant increased or decreased risk, with RRs all hovering around unity and confidence intervals excluding meaningful risk changes. Further stratification by GLP-1 RA type (pure versus dual agonists), route of administration (subcutaneous versus oral), and treatment indication (T2DM versus weight loss) failed to identify differential cancer risks. The study’s robust methodology, extensive participant pool, and lengthy follow-up reinforce the finding that GLP-1 RAs do not elevate gastrointestinal cancer risk, providing reassuring evidence for clinicians prescribing these agents in metabolic disorders. [3]
A 2023 systematic review and meta-analysis evaluated the cancer risk profile of semaglutide across 37 randomized controlled trials (representing 33,398 patients) and 19 real-world studies (representing 13,330 patients). Pancreatic cancer occurred at an increased odds with semaglutide vs placebo (odds ratio [OR] 0.25, 95% confidence interval [CI] 0.03 to 2.24; p= 0.21), whereas all neoplasms occurred at an OR 0.95 (95% CI 0.62 to 1.45; p= 0.82). When semaglutide was compared vs active controls, pancreatic cancer and all neoplasms were still observed at no significantly increased odds (OR 0.40, 95% CI 0.09 to 1.87, p= 0.26; and OR 0.91, 95% CI 0.44 to 1.89, p= 0.79; respectively). Real-world data with follow-up ranging from 30 weeks through 18 months revealed limited malignancy signals (1 pancreatic cancer case and 1 B-cell lymphoma case). Despite the non-significant findings, the included randomized trials were limited by high risk of “other” bias, especially industry bias, necessitating longer-term follow-up and surveillance data to truly capture the scale of harm associated with GLP1 receptor agonist use and cancer development beyond thyroid C-cell carcinoma. [4]
Most recently, a 2024 population-based cohort study investigated the risk of GLP-1RA exposure in adult patients with type 2 diabetes mellitus (T2DM) and risk of pancreatic cancer. Utilizing data from a cumulative follow-up of 3,290,439 person-years of 543,595 adult patients (age 21 to 89), 33,377 patients (6.1%) were found to have used GLP-1RAs and 106,849 (19.7%) used basal insulin. The estimated hazard ratio for pancreatic cancer associated with use of GLP-1RAs compared to basal insulin in year 5 to 7 after initiation of therapy was 0.50 (95% CI 0.15 to 1.71). These data do not support increased incidence of pancreatic cancer over 7 years related to initiating treatment with GLP-1RAs. The authors still suggest monitoring for risk beyond 7 years. Risk associated with individual GLP-1RAs was not identified. [5]
A 2025 systematic review and meta-analysis evaluated pancreatitis and pancreatic cancer risk among GLP-1 receptor agonists, pooling data from 62 randomized, controlled trials representing 66,232 patients. Evaluated agents included dulaglutide, exenatide, liraglutide, semaglutide, beinaglutide, retatrutide, and tirzepatide, with subgroup analyses stratified by background antidiabetic medication use; mean follow-up duration was 43.5 weeks. GLP-1 receptor agonist use showed no significant overall association with pancreatic cancer (RR 1.30, 95% CI 0.86 to 1.97, p= 0.22, I²= 0%). Subgroup analysis verified this lack of significant association in patients without background antidiabetic medication use (RR 0.81, 95% CI 0.43 to 1.55, p= 0.53); however, a significant increase in cancer risk was noted when stratified by use of background antidiabetic medications (RR 1.85, 95% CI 1.05–3.26, p=0.03, I²=0%), yet this observation was in the setting of few studies with very few number of events. In trials with ≥24-week follow-up period, pancreatic cancer risk remained nonsignificant (RR 1.28, 95% CI 0.84 to 1.96, p= 0.25, I²= 25%). The authors were not able to provide conclusive evidence linking GLP-1 receptor agonist use to increased overall pancreatic cancer risk. [6]
Another 2025 meta-analysis synthesized data from 50 randomized controlled trials encompassing over 102,000 patients to evaluate the oncogenic risk associated with glucagon-like peptide-1 receptor agonists (GLP-1 RA) compared to various comparators in diabetes and obesity treatment. Trials included had durations of at least 52 weeks and involved diverse populations with type 2 diabetes or obesity, using different GLP-1 RA agents such as liraglutide, semaglutide, dulaglutide, exenatide, and lixisenatide. Incidence of overall cancers and specific malignancies, particularly obesity-associated cancers (uterine, esophageal, thyroid, colorectal, among others), were extracted primarily from serious adverse event reports. Subgroup analyses considered variables including trial duration, GLP-1 RA molecule, and treatment indication (obesity versus diabetes), with rigorous risk of bias assessments and statistical heterogeneity evaluations. The meta-analysis revealed no significant difference in overall cancer risk between GLP-1 RA and comparator groups (MH-OR 1.05, 95% CI 0.98–1.13), with consistency across molecules and populations. Notably, a significant reduction in uterine cancer incidence emerged in obese subjects receiving GLP-1 RA (MH-OR 0.24, 95% CI 0.06–0.94), although this effect was not seen in diabetic cohorts. Conversely, a modest but statistically significant increased risk of thyroid cancer was observed among GLP-1 RA recipients (MH-OR 1.55, 95% CI 1.05–2.27), particularly in longer-term trials, raising concerns about potential oncogenic risk requiring further targeted investigation. Additionally, colorectal cancer incidence was slightly elevated in the GLP-1 RA arm (MH-OR 1.27, 95% CI 1.03–1.57), predominantly in shorter-duration studies, a phenomenon possibly attributable to detection bias stemming from gastrointestinal side effects prompting increased diagnostic scrutiny. No significant associations were identified for other obesity-related malignancies or cancers without established obesity links. These findings underscore a generally neutral oncologic safety profile for GLP-1 RA but highlight the need for ongoing vigilance regarding thyroid cancer risk and the interpretation of colorectal cancer signals in clinical contexts. [7]