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Abstract <p>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.</p> Trial registration <p>PROSPERO CRD420251151419. The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical University (TSGHIRB E202516007).</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • 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

摘要

Abstract

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).