Agent-specific, histopathology-stratified hematologic malignancy risk among dpp-4 inhibitors, glp-1 receptor agonists, and SGLT2 inhibitors: a network meta-analysis of 270,471 participants.
- 2026-04-09
- Journal of hematology & oncology 19(1)
- Pao-Yen Lin
- Bing-Syuan Zeng
- Jiann-Jy Chen
- Bing-Yan Zeng
- Mein-Woei Suen
- Chao-Ming Hung
- Chih-Wei Hsu
- Brendon Stubbs
- Yen-Wen Chen
- Tien-Yu Chen
- Wei-Te Lei
- Shih-Pin Hsu
- Yow-Ling Shiue
- Kuan-Pin Su
- Cheng-Ta Li
- Hung-Yu Wang
- Ping-Tao Tseng
- Chih-Sung Liang
- PubMed: 41957612
- DOI: 10.1186/s13045-026-01788-5
Study Design
- Type
- Meta-Analysis
- Sample size
- n = 471
- Population
- 270,471 participants from 75 RCTs
- Methods
- Frequentist-based network meta-analysis (NMA) of randomized controlled trials (RCTs) following Cochrane guidance for adverse-event synthesis; Bayesian models used as sensitivity analyses
Dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely prescribed for their cardiometabolic benefits, yet their hematologic oncologic safety remains uncertain. Because hematologic malignancies are highly lethal and biologically heterogeneous, delineating drug-specific risks across histopathologic subtypes is clinically crucial. This histopathology-stratified network meta-analysis (NMA) evaluated and compared the hematologic malignancy risks associated with individual agents from these drug classes. Following Cochrane guidance for adverse-event synthesis, we conducted this frequentist-based NMA of randomized controlled trials (RCTs). The primary endpoint was incident hematologic malignancy, categorized a priori into leukemia (acute and chronic forms), lymphoma (Hodgkin and non-Hodgkin), and myeloma/plasma cell neoplasms. Bayesian models were used as sensitivity analyses. Seventy-five RCTs including 270,471 participants were eligible. Dulaglutide was associated with a significantly increased risk of overall hematologic malignancy (RR = 2.17, 95% CIs = 1.14–4.17). In contrast, tirzepatide (RR = 0.22, 95% CIs = 0.06–0.78) and linagliptin (RR = 0.51, 95% CIs = 0.27–0.95) were linked to a reduced overall risk. In histopathology-specific analyses, tirzepatide showed a significant protective association against non-Hodgkin’s lymphoma, whereas no agent demonstrated clear signals for leukemia or myeloma. In this histopathology-focused NMA, dulaglutide emerged as the only agent with a significantly elevated overall hematologic malignancy risk, whereas tirzepatide and linagliptin exhibited protective profiles. The lymphoma-specific benefit observed for tirzepatide underscores the value of histologic subclassification when evaluating oncologic safety of antidiabetic therapies and calls for targeted mechanistic and long-term outcome studies. TRIAL REGISTRATION: PROSPERO CRD420251151419. The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical University (TSGHIRB E202516007).