A big analysis of 91 trials found that the highest dose of tirzepatide (15 mg per week) more than doubled the chance of getting a gynecologic tumor, especially inside the uterus, compared to not using the drug. Even the lower 5 mg dose showed a similar jump in uterine tumor risk. No other GLP‑1 or SGLT2 drugs showed this problem.

Concerns have emerged regarding the oncogenic potential of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors, particularly in relation to gynecologic malignancies. To date, no consensus has been reached on regimen-specific risks. This network meta-analysis (NMA) evaluated and compared the incidence of gynecologic tumors associated with various GLP-1 receptor agonists and SGLT2 inhibitors. Following a Cochrane-recommended confirmatory approach, we conducted a frequentist-based NMA using data from randomized controlled trials (RCTs) including female participants. Systematic searches of major databases were conducted through March 3, 2025. The primary outcome was the incidence of gynecologic tumors; drop-out rates served as an acceptability endpoint. Bayesian sensitivity analyses were conducted for validation. This NMA included 91 RCTs comprising 224,986 participants (89,558 females). Only high-dose tirzepatide (15mg/week) was associated with significantly increased overall gynecologic tumor risk compared to controls [odds ratio (OR) = 2.37, 95% confidence interval (CI): 1.04-5.39; absolute risk difference= 0.57%; number needed to harm = 176]. Site-specific analysis noticed that both high-dose tirzepatide (15mg/week) (OR = 4.65, 95% CI: 1.28-16.94) and low-dose tirzepatide (5mg/week) (OR = 4.61, 95% CI: 1.07-19.90) were associated with a significantly elevated risk of intra-uterus tumor. No other regimen demonstrated a significant elevation in risk. Tirzepatide appears to be associated with gynecologic tumor risk, particularly intra-uterus neoplasms. Given that these agents are frequently prescribed to individuals with predisposing risk factors, personalized risk-benefit evaluation is warranted. However, more data are needed to confirm whether this association is causal and not due to chance/bias or not. Besides, longitudinal research is essential to elucidate underlying mechanisms and guide clinical decision-making.  PROSPERO CRD420251003016: The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB E202516007).