The gynecologic tumor risk related to GLP-1 receptor agonists and SGLT2 inhibitors use: a network meta-analysis of 91 randomized controlled trials

Ping-Tao Tseng; Bing-Yan Zeng; Chih-Wei Hsu; Cheuk-Kwan Sun; Mein-Woei Suen; Andre F Carvalho; Brendon Stubbs; Yen-Wen Chen; Tien-Yu Chen; Wei-Te Lei; Po-Huang Chen; Jiann-Jy Chen; Yow-Ling Shiue; Bing-Syuan Zeng; Kuan-Pin Su; Chih-Sung Liang

doi:10.1186/s13045-025-01750-x

The gynecologic tumor risk related to GLP-1 receptor agonists and SGLT2 inhibitors use: a network meta-analysis of 91 randomized controlled trials

J Hematol Oncol. 2025 Nov 27;18(1):109. doi: 10.1186/s13045-025-01750-x.

Authors

Ping-Tao Tseng^#^{1

2

3

4}, Bing-Yan Zeng^#^{5

6}, Chih-Wei Hsu^#⁷, Cheuk-Kwan Sun^#^{8

9}, Mein-Woei Suen^#^{10

11

12

13}, Andre F Carvalho^#¹⁴, Brendon Stubbs^{15

16}, Yen-Wen Chen¹⁷, Tien-Yu Chen^{18

19}, Wei-Te Lei^{20

21}, Po-Huang Chen²², Jiann-Jy Chen¹⁷, Yow-Ling Shiue^#^{23

24}, Bing-Syuan Zeng^#²⁵, Kuan-Pin Su^#^{26

27

28}, Chih-Sung Liang^#^{29

30}

Affiliations

¹ Institute of Precision Medicine, National Sun Yat-sen University, 70 Lienhai Rd, Kaohsiung City, 80424, Taiwan. ducktseng@gmail.com.
² Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. ducktseng@gmail.com.
³ Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan. ducktseng@gmail.com.
⁴ Prospect Clinic for Otorhinolaryngology & Neurology, No. 252, Nanzixin Road, Nanzi District, Kaohsiung City, 81166, Taiwan. ducktseng@gmail.com.
⁵ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁶ Department of Internal Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan.
⁷ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁸ Department of Emergency Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan.
⁹ School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.
¹⁰ Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
¹¹ Gender Equality Education and Research Center, Asia University, Taichung, Taiwan.
¹² Department of Medical Research, Asia University Hospital, Asia University, Taichung, Taiwan.
¹³ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
¹⁴ Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.
¹⁵ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁶ Department of Sport, University of Vienna, Vienna, Austria.
¹⁷ Prospect Clinic for Otorhinolaryngology & Neurology, No. 252, Nanzixin Road, Nanzi District, Kaohsiung City, 81166, Taiwan.
¹⁸ Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan.
¹⁹ Department of Psychiatry, College of Medicine, National Defense Medical University, Taipei, Taiwan.
²⁰ Division of Pediatric Allergy, Immunology, and Rheumatology, Department of Pediatrics, Hsinchu Municipal MacKay Children's Hospital, Hsinchu City, Taiwan.
²¹ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
²² Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital; School of Medicine, National Defense Medical University, Taipei, Taiwan.
²³ Institute of Precision Medicine, National Sun Yat-sen University, 70 Lienhai Rd, Kaohsiung City, 80424, Taiwan. shirley@imst.nsysu.edu.tw.
²⁴ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. shirley@imst.nsysu.edu.tw.
²⁵ Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, No.21, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung, 82445, Taiwan. b95401072@ntu.edu.tw.
²⁶ Office of Research and Development, Asia University, Taichung, Taiwan. cobolsu@gmail.com.
²⁷ College of Medicine, China Medical University, Taichung, Taiwan. cobolsu@gmail.com.
²⁸ An-Nan Hospital, China Medical University, Tainan, Taiwan. cobolsu@gmail.com.
²⁹ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical University, No. 60, Xinmin Road, Beitou District, Taipei City, 112003, Taiwan. lcsyfw@gmail.com.
³⁰ Department of Psychiatry, National Defense Medical University, Taipei, Taiwan. lcsyfw@gmail.com.

^# Contributed equally.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: PROSPERO CRD420251003016: The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB E202516007).

Keywords: GLP-1 receptor agonist; Gynecologic; Malignant; Network meta-analysis; SGLT2 inhibitor; Tirzepatide; Tumor; Uterine.

Publication types

Network Meta-Analysis

MeSH terms

Female
Genital Neoplasms, Female* / chemically induced
Genital Neoplasms, Female* / epidemiology
Glucagon-Like Peptide-1 Receptor Agonists*
Humans
Randomized Controlled Trials as Topic
Risk Factors
Sodium-Glucose Transporter 2 Inhibitors* / adverse effects
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Sodium-Glucose Transporter 2 Inhibitors
Glucagon-Like Peptide-1 Receptor Agonists