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While average treatment effects are established for many drug classes, responses may vary by clinical and demographic factors. Here, we evaluated whether major glucose\u2010lowering drug classes exhibit heterogeneous treatment effects (HTE) across key patient characteristics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>This large\u2010scale observational cohort study was replicated in six data\u2010sources across the Observational Health Data Sciences and Informatics network. New\u2010user, active\u2010comparator cohorts were constructed for patients with T2DM initiating one of the nine antihyperglycemic drug classes. Large\u2010scale propensity score adjustment, empirical calibration using negative controls, and random\u2010effects meta\u2010analysis were used to estimate calibrated hazard ratios (HRs). HTE was assessed by comparing differences in log HRs across clinical and demographic subgroups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nominal signals of HTE were observed in the hyperlipidemia, hypertension, obesity, and sex subgroups: Biguanides (vs. DPP\u20104 inhibitors) were associated with lower risk of acute myocardial infarction in hyperlipidemia and heart failure hospitalization in obesity. SGLT\u20102 inhibitors (vs. GLP\u20101 receptor agonists) were associated with reduced stroke risk only in non\u2010obese patients. Sex\u2010specific patterns included higher risk of diarrhoea with GLP\u20101 receptor agonists and lower risk of stroke with SGLT\u20102 inhibitors (both vs. DPP\u20104 inhibitors) in women. None of the signals demonstrated statistical significance after multiple testing correction. Several subgroups (e.g., diabetic ketoacidosis and retinopathy) did not meet diagnostic criteria for clinical reliability and were not evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This hypothesis\u2010generating study identified limited signals of HTE. These findings are exploratory and require cautious interpretation and validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.70918","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:51:37Z","timestamp":1780537897000},"page":"7321-7341","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Heterogeneity of Treatment Effects Across Nine Glucose\u2010Lowering Drug Classes in Type 2 Diabetes: Extension of the\n                    <scp>LEGEND<\/scp>\n                    \u2010\n                    <scp>T2DM<\/scp>\n                    Network Study"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7907-2335","authenticated-orcid":false,"given":"Hsin Yi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics Columbia University Irving Medical Center  New York New York 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