Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study
Authors: Khera Rohan , Aminorroaya Arya , Dhingra Lovedeep Singh , Thangaraj Phyllis M , Camargos Aline Pedroso , Bu Fan , Ding Xiyu , Nishimura Akihiko , Anand Tara V , Arshad Faaizah , Blacketer Clair , Chai Yi , Chattopadhyay Shounak , Cook Michael , Dorr David A , Duarte-Salles Talita , DuVall Scott L , Falconer Thomas , French Tina E , Hanchrow Elizabeth E , Kaur Guneet , Lau Wallis CY , Li Jing , Li Kelly , Liu Yuntian , Lu Yuan , Man Kenneth KC , Matheny Michael E , Mathioudakis Nestoras , McLeggon Jody-Ann , McLemore Michael F , Minty Evan , Morales Daniel R , Nagy Paul , Ostropolets Anna , Pistillo Andrea , Phan Thanh-Phuc , Pratt Nicole , Reyes Carlen , Richter Lauren , Ross Joseph , Ruan Elise , Seager Sarah L , Simon Katherine R , Viernes Benjamin , Yang Jianxiao , Yin Can , You Seng Chan , Zhou Jin J , Ryan Patrick B , Schuemie Martijn J , Krumholz Harlan M , Hripcsak George , Suchard Marc A 
Published: February 2024

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