{"doi":"10.1101/2025.06.02.25328066","title":"Heterogeneity of Treatment Effects of Glucose-lowering Drug Classes for Type 2 Diabetes: LEGEND-T2DM Network Real-World Evidence","abstract":"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.","journal":"medRxiv","year":2025,"id":567537,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":0.0,"corpus_rank":10256,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.7267,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":266935,"name":"Thomas Falconer","orcid":"0000-0001-6904-1394","position":1,"is_corresponding":false},{"id":266933,"name":"Nicole Pratt","orcid":"0000-0001-8730-8910","position":2,"is_corresponding":false},{"id":32076,"name":"Karthik Natarajan","orcid":"0000-0002-9066-9431","position":3,"is_corresponding":false},{"id":2010,"name":"George Hripcsak","orcid":"0000-0003-2664-7614","position":4,"is_corresponding":false},{"id":1471556,"name":"David M. Davila-Garcia","orcid":"0000-0002-9951-2270","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:44.340853Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}