Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of 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 clinical trials.
Objectives: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM.
Methods: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis.
Results: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]).
Conclusions: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.
Competing Interests: Funding Support and Author Disclosures This study was partially funded through National Institutes of Health grants R01 HL167858, K23 HL153775, R01 LM006910, R01 HG006139, and R01 HL169954 and the U.S. Department of Veterans Affairs under the research priority to “Put VA Data to Work for Veterans” (VA ORD 22-D4V). The funders had no role in the design and conduct of the protocol; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Khera is an associate editor at JAMA; and has received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (awards R01 HL167858 and K23 HL153775) and the Doris Duke Charitable Foundation (award 2022060); has received research support, through Yale University, from Bristol Myers Squibb, Novo Nordisk, and BridgeBio; is a coinventor of U.S. provisional patent applications WO2023230345A1, US20220336048A1, 63/346,610, 63/428,569, 63/484,426, 63/508,315, 63/580,137, 63/606,203, 63/619,241, and 63/562,335, unrelated to the present work; and is a cofounder of Evidence2Health and Ensight-AI, precision health platforms to improve evidence-based cardiovascular care and cardiovascular diagnostics. Dr DuVall has received grants from Alnylam Pharmaceuticals, AstraZeneca Pharmaceuticals, Biodesix, Celgene, Cerner Enviza, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis International, and Parexel International through the University of Utah or the Western Institute for Veteran Research (outside the submitted work). Dr Man has received support from the C.W. Maplethorpe Fellowship, the National Institute of Health Research, European Commission Framework Horizon 2020, the Hong Kong Research Grant Council, and the Innovation and Technology Commission of the Hong Kong Special Administration Region Government outside the submitted work). Dr Morales is supported by a Wellcome Trust Clinical Research Fellowship (214588/Z/18/Z). In the past 3 years, Dr Krumholz has received expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, the Arnold and Porter Law Firm, and the Martin/Baughman Law Firm; is a cofounder of Refactor Health, HugoHealth, and Ensight-AI; and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare and Medicaid Services and, through Yale University, from Johnson & Johnson. Dr You is chief technology officer of PHI Digital Healthcare. Dr Ross has received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (grant U01 FD005938), from the Agency for Healthcare Research and Quality (grant R01 HS022882), and from Arnold Ventures; has received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology and from the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants R01 HS025164 and R01 HL144644); and was an expert witness at the request of the relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled September 2022. Dr Thangaraj is a coinventor on provisional patent 63/606,203, unrelated to the present work, and is funded by grant 5T32 HL155000-03. Ms Blacketer, Dr Ostropolets, and Dr Ryan are employees of Johnson & Johnson. Dr Schuemie is an employee and shareholder of Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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