%0 Preprint
%T Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.
%A Khera R
%A Aminorroaya A
%A Dhingra LS
%A Thangaraj PM
%A Camargos AP
%A Bu F
%A Ding X
%A Nishimura A
%A Anand TV
%A Arshad F
%A Blacketer C
%A Chai Y
%A Chattopadhyay S
%A Cook M
%A Dorr DA
%A Duarte-Salles T
%A DuVall SL
%A Falconer T
%A French TE
%A Hanchrow EE
%A Kaur G
%A Lau WC
%A Li J
%A Li K
%A Liu Y
%A Lu Y
%A Man KK
%A Matheny ME
%A Mathioudakis N
%A McLeggon JA
%A McLemore MF
%A Minty E
%A Morales DR
%A Nagy P
%A Ostropolets A
%A Pistillo A
%A Phan TP
%A Pratt N
%A Reyes C
%A Richter L
%A Ross J
%A Ruan E
%A Seager SL
%A Simon KR
%A Viernes B
%A Yang J
%A Yin C
%A You SC
%A Zhou JJ
%A Ryan PB
%A Schuemie MJ
%A Krumholz HM
%A Hripcsak G
%A Suchard MA
%J medRxiv
%V 0
%N 0
%D 2024 Feb 8
%M 38370787
暂无%R 10.1101/2024.02.05.24302354
%X <B>UNASSIGNED: </B>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.<BR><B>UNASSIGNED: </B>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.<BR><B>UNASSIGNED: </B>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]).<BR><B>UNASSIGNED: </B>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.<BR><B>UNASSIGNED: </B>National Institutes of Health, United States Department of Veterans Affairs.