Divergent Risks of Hematologic Malignancies Associated with GLP-1 Receptor Agonists and SGLT2 Inhibitors: Preliminary...

Although glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have gained attention for their broad therapeutic effects, their influence on hematologic malignancy remains underexplored. Given the high mortality associated with hematologic cancers, clarifying the impact of these agents on such malignancies is essential.

This pilot network meta-analysis (NMA) aimed to assess the comparative risk of hematologic malignancies-including lymphoma, leukemia, and myeloma-associated with various GLP-1 receptor agonists and SGLT2 inhibitors.

Following Cochrane-recommended confirmatory methods, we systematically searched multiple databases for randomized controlled trials (RCTs) published through 4 December 2024. The primary outcome was the incidence of overall hematologic malignancies. A frequentist random-effects NMA via the netmeta package was conducted, with additional validation through Bayesian NMA for solely sensitivity analyses.

Fifty-five RCTs (n = 200,606) were analyzed. Dulaglutide showed a significantly higher risk of overall hematologic malignancy [odds ratio (OR) = 2.18, 95% confidence interval (95%CI) = 1.14-4.19). In contrast, tirzepatide was linked to a significantly reduced risk (OR = 0.14, 95%CI = 0.03-0.60), especially for lymphoma. No statistically significant associations were identified for SGLT2 inhibitors (i.e., 95%CI across 1.0).

Our preliminary findings reveal distinct and agent-specific effects of GLP-1 receptor agonists on hematologic malignancy risk. While dulaglutide may elevate the risk, tirzepatide appears protective, particularly against lymphoma. These results call for further long-term mechanistic studies to clarify causality and underlying pathways.