Heterogeneity of treatment effects of glucose-lowering drug classes for type 2 diabetes: LEGEND-T2DM network real-world evidence
Date
2025
Authors
Dávila-García, D.M.
Falconer, T.
Pratt, N.
Natarajan, K.
Hripcsak, G.
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Journal article
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Journal of Diabetes and its Complications, 2025; 39(9)
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<h4>Aims</h4>To assess heterogeneity of treatment effects (HTE) of glucose-lowering drug classes by clinical (cardiovascular [CV] risk, renal impairment) and demographic (age, sex) subgroups in adults with type 2 diabetes mellitus (T2D).<h4>Methods</h4>The LEGEND-T2DM network identified 4,746,939 adults with T2D on metformin monotherapy who initiated one of four glucose-lowering drug classes: glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylureas. HTE was assessed between glucose-lowering drug classes by clinical (low CV risk vs. higher CV risk; without renal impairment vs. renal impairment) and demographic (lower vs. middle vs. older age; male vs. female) subgroups. Outcomes included MACE (primary), acute myocardial infarction, stroke, sudden cardiac death and safety endpoints.<h4>Results</h4>Pairwise differences (n = 1115 tests) between adjusted hazard ratios (HRs) showed 49 nominally significant associations (p < 0.05) and one statistically significant difference after Bonferroni correction (p < 4.5 × 10<sup>-5</sup>). Among older subjects (vs. younger), those taking GLP-1 RA (vs. sulfonylureas) had statistically significant difference in risk of hypoglycemia (HRs: lower age, 0.53 ± 0.14 vs. older age, 0.20 ± 0.05, p < 0.001).<h4>Conclusions</h4>HTE among glucose-lowering drug classes by clinical and demographic subgroups may provide guidance to generate hypothesis-testing studies to inform T2D treatment decisions.
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Data source: Supplementary data, https://doi.org/10.1016/j.jdiacomp.2025.109114
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Copyright 2025 The Authors. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)