Heterogeneity of Treatment Effects of Glucose-lowering Drug Classes for Type 2 Diabetes: LEGEND-T2DM Network Real-World Evidence

Aims. 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). Methods. 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. Results. Pairwise differences (n=1,115 tests) between adjusted hazard ratios (HRs) showed 49 nominally significant associations (p<0.05) and one statistically significant difference after Bonferroni correction (p<4.5×10-5). 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). Conclusions. HTE among glucose-lowering drug classes by clinical and demographic subgroups may provide guidance to generate hypothesis-testing studies to inform T2D treatment decisions.