Multinational Patterns of Second-line Anti-hyperglycemic Drug Initiation Across Cardiovascular Risk Groups: A Federated Pharmacoepidemiologic Evaluation in LEGEND-T2DM

Objectives To assess the uptake of second-line antihyperglycemic agents among patients with type-2 diabetes mellitus (T2DM) receiving metformin. Design Serial cross-sectional study (2011-2021). Setting Ten US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network. Participants 4.8 million patients with T2DM receiving metformin. Main Outcomes Measures Calendar-year trends in the proportional initiation of second-line antihyperglycemic agents, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), dipeptidyl peptidase-4 inhibitors, and sulfonylureas, for each database. We also evaluated the relative drug class-level uptake across cardiovascular risk groups. Results We identified 4.6 million patients with T2DM in US databases, 61,382 from Spain, 32,442 from Germany, 25,173 from the UK, 13,270 from France, 5,580 from Scotland, 4,614 from Hong Kong, and 2,322 from Australia. During 2011-2021, the combined proportional initiation of cardioprotective antihyperglycemic agents, GLP-1 RAs and SGLT2is, increased across all data sources, with the combined initiation of these drugs as second-line agents in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of GLP-1 RAs and SGLT2is increased more significantly among populations without cardiovascular disease compared to those with established cardiovascular disease, without any data source providing evidence of a greater increase in their uptake in the populations with cardiovascular disease. Conclusions Despite the increase in overall uptake of cardioprotective antihyperglycemic agents as second-line treatment for T2DM, their uptake was lower in patients with cardiovascular disease over the last decade. A strategy to ensure medication use concordant with guideline recommendations is essential to improve outcomes of patients with T2DM.