{"doi":"10.1101/2024.02.05.24302354","title":"Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study","abstract":"Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.","journal":"medRxiv","year":2024,"id":485921,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":75766,"name":"Arya Aminorroaya","orcid":"0000-0003-3197-2657","position":1,"is_corresponding":false},{"id":534990,"name":"Lovedeep Singh Dhingra","orcid":"0000-0002-5664-4126","position":2,"is_corresponding":false},{"id":36635,"name":"Phyllis Thangaraj","orcid":"0000-0003-3968-1563","position":3,"is_corresponding":false},{"id":1211561,"name":"Aline Pedroso Camargos","orcid":null,"position":4,"is_corresponding":false},{"id":32100,"name":"Fan Bu","orcid":"0000-0003-3697-1477","position":5,"is_corresponding":false},{"id":299438,"name":"Xiyu Ding","orcid":"0000-0001-6852-2962","position":6,"is_corresponding":false},{"id":336581,"name":"Akihiko Nishimura","orcid":"0000-0002-6932-2513","position":7,"is_corresponding":false},{"id":1329806,"name":"Tara V Anand","orcid":null,"position":8,"is_corresponding":false},{"id":32101,"name":"Faaizah Arshad","orcid":"0000-0001-8708-2544","position":9,"is_corresponding":false},{"id":32052,"name":"Clair Blacketer","orcid":"0000-0003-2570-2124","position":10,"is_corresponding":false},{"id":1329425,"name":"Yi Chai","orcid":"0000-0002-2717-5981","position":11,"is_corresponding":false},{"id":1010367,"name":"Shounak Chattopadhyay","orcid":null,"position":12,"is_corresponding":false},{"id":314385,"name":"Michael B. 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