ArticleJournal of the American College of Cardiology2024
Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.
Abstract readComparative StudyMulticenter Study
In one paragraph
Article in Journal of the American College of Cardiology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 2 of them syntheses that pooled it.
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32citing papers in PubMed, 2 pooled it
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Who cites it
32 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- SGLT2 versus DPP-4 inhibitors in type 2 diabetes: a meta-analysis of outcomes.Frontiers in endocrinology · 2026Pooled it
- Effects of Tirzepatide in Type 2 Diabetes: Individual Variation and Relationship to Cardiometabolic Outcomes.Journal of the American College of Cardiology · 2025 · on this mapPooled it
- Semaglutide and Neovascular Age-Related Macular Degeneration among Adults with Type 2 Diabetes: An Observational Health Data Sciences and Informatics Network Study.Ophthalmology · 2026Observational
- Class effect beyond glucose: Implications of the LEGEND-T2DM findings for cardiovascular outcomes.Journal of diabetes investigation · 2026Article
- Congenital heart disease in pregnancy and severe maternal morbidity: a distributed data network study.Pregnancy (Hoboken, N.J.) · 2026Article
- PDA (Privacy-Preserving Distributed Algorithms) in action: ten principles for high-quality multi-site clinical evidence generation.Journal of the American Medical Informatics Association : JAMIA · 2026Article
- From study design to executable code: automating target trial emulation with large language models.JAMIA open · 2026Article
- Heterogeneity of Treatment Effects Across Nine Glucose-Lowering Drug Classes in Type 2 Diabetes: Extension of the LEGEND-T2DM Network Study.Diabetes, obesity & metabolism · 2026Observational
- Comparative Cardiovascular Effectiveness of Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Diabetes Mellitus.Journal of the American College of Cardiology · 2026Article
- Global approaches to infectious disease surveillance and modeling.Nature medicine · 2026Review
- Trust in Observational Research.Journal of the American College of Cardiology · 2026Article
- Real-world evidence for comparative safety of second-line antihyperglycemic agents in older adults with type 2 diabetes.Nature communications · 2026Article
- Artificial Intelligence-enhanced Electrocardiography for Heart Failure Screening and Risk Stratification.Current heart failure reports · 2026Review
- GLP-1 receptor agonists or SGLT2-inhibitors? Evaluation of a personalized treatment algorithm for individuals with type 2 diabetes: a registry-based cohort study.Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association · 2026Observational
- Hypertensive Disorders of Pregnancy and Premature Cardiovascular Disease in a Diverse Cohort of Young US Women.Circulation · 2026Article
- A real-world evaluation of longitudinal healthcare expenses in a health system registry of type-2 diabetes mellitus and cardiovascular disease enabled by the 21st century cures act.American journal of preventive cardiology · 2026Article
- Heterogeneity of Treatment Effects Across Nine Glucose-Lowering Drug Classes in Type 2 Diabetes: Extension of the LEGEND-T2DM Network Study.medRxiv : the preprint server for health sciences · 2026Article
- Glucagon-like peptide-1 receptor agonist versus other anti-diabetic agents on patients with prostate cancer undergoing androgen-deprivation therapy.Frontiers in urology · 2026Article
- AldehydeFrontiers in medicine · 2026Article
- CYP2C19 intermediate and poor metabolizer statuses may be associated with coronary atherosclerosis among patients with type 2 diabetes mellitus.Frontiers in medicine · 2026Article
Corrections and comments
- Update of
Authors and funding
54 authors.
Rohan KheraSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA; Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, Connecticut, USA; Section of Health Informatics, Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA. Electronic address: rohan.khera@yale.edu.
Arya AminorroayaSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
Lovedeep Singh DhingraSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
Phyllis M ThangarajSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
Aline Pedroso CamargosSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
Fan BuDepartment of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Xiyu DingDepartment of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Akihiko NishimuraDepartment of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Tara V AnandDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Faaizah ArshadDepartment of Biostatistics, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, California, USA.
Clair BlacketerObservational Health Data Analytics, Janssen Research and Development, Titusville, New Jersey, USA.
Yi ChaiDepartment of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Shounak ChattopadhyayDepartment of Biostatistics, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, California, USA.
Michael CookDepartment of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
David A DorrDepartment of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, USA.
Talita Duarte-SallesFundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Barcelona, Spain; Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Scott L DuVallVeterans Affairs Informatics and Computing Infrastructure, U.S. Department of Veterans Affairs, Salt Lake City, Utah, USA; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Thomas FalconerDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Tina E FrenchTennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, Tennessee, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Elizabeth E HanchrowTennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, Tennessee, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Guneet KaurDivision of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, United Kingdom.
Wallis C Y LauResearch Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom; Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, United Kingdom; Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Laboratory of Data Discovery for Health, Hong Kong Science Park, Hong Kong, China.
Jing LiData Transformation, Analytics, and Artificial Intelligence, Real World Solutions, IQVIA, Durham, North Carolina, USA.
Kelly LiDepartment of Biostatistics, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, California, USA.
Yuntian LiuSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA; Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, Connecticut, USA.
Yuan LuSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
Kenneth K C ManResearch Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom; Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, United Kingdom; Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Laboratory of Data Discovery for Health, Hong Kong Science Park, Hong Kong, China.
Michael E MathenyTennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, Tennessee, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Nestoras MathioudakisDivision of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jody-Ann McLeggonDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Michael F McLemoreTennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, Tennessee, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Evan MintyFaculty of Medicine, O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada.
Daniel R MoralesDivision of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, United Kingdom.
Paul NagyDivision of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Anna OstropoletsObservational Health Data Analytics, Janssen Research and Development, Titusville, New Jersey, USA.
Andrea PistilloFundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Barcelona, Spain.
Thanh-Phuc PhanSchool of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Nicole PrattQuality Use of Medicines and Pharmacy Research Centre, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
Carlen ReyesFundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Barcelona, Spain.
Lauren RichterDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Joseph S RossCenter for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, Connecticut, USA; Section of General Medicine and National Clinician Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Elise RuanDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Sarah L SeagerData Transformation, Analytics, and Artificial Intelligence, Real World Solutions, IQVIA, London, United Kingdom.
Katherine R SimonTennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, Tennessee, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Benjamin ViernesVeterans Affairs Informatics and Computing Infrastructure, U.S. Department of Veterans Affairs, Salt Lake City, Utah, USA; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Jianxiao YangDepartment of Computational Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.
Can YinData Transformation, Analytics, and Artificial Intelligence, Real World Solutions, IQVIA, Shanghai, China.
Seng Chan YouDepartment of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea; Institute for Innovation in Digital Healthcare, Yonsei University College of Medicine, Seoul, South Korea.
Jin J ZhouDepartment of Biostatistics, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.
Patrick B RyanDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Martijn J SchuemieEpidemiology, Office of the Chief Medical Officer, Johnson & Johnson, Titusville, New Jersey, USA.
Harlan M KrumholzSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA; Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, Connecticut, USA; Section of Cardiovascular Medicine, Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut, USA.
George HripcsakDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Marc A SuchardDepartment of Biostatistics, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, California, USA; Veterans Affairs Informatics and Computing Infrastructure, U.S. Department of Veterans Affairs, Salt Lake City, Utah, USA; Department of Biomathematics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA. Electronic address: msuchard@ucla.edu.
Funding
DISCOVERING AND APPLYING KNOWLEDGE IN CLINICAL DATABASESR01LM006910 · NLM · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI HRIPCSAK, GEORGE M · 2000 to 2023
$10.6MGenomics, GPUs, and Next Generation Computational StatisticsR01HG006139 · NHGRI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SOBEL, ERIC · 2011 to 2023
$5.1MReal-world Evidence to Inform Decisions for Hypertension Treatment EscalationR01HL169954 · NHLBI · YALE UNIVERSITY · PI Yuan Lu · 2023 to 2026
$2.6MTranslating Personalized Inference from Randomized Clinical Trials to Real-World Cardiovascular CareR01HL167858 · NHLBI · YALE UNIVERSITY · PI Rohan Khera · 2024 to 2026
$2.3MTraining in Implementation Science Research and MethodsT32HL155000 · NHLBI · YALE UNIVERSITY · PI SPIEGELMAN, DONNA L, VELAZQUEZ, ERIC J · 2021 to 2025
$2.2MLeveraging Physician Networks to Improve Care and Outcomes for Low-Income PopulationsR01HL144644 · NHLBI · YALE UNIVERSITY · PI NDUMELE, CHIMA · 2019 to 2021
$1.6MEvaluating and Improving Utilization of Evidence-Based Medical Therapy in Patients with Heart Failure using Automated Tools in the Electronic Health RecordK23HL153775 · NHLBI · YALE UNIVERSITY · PI KHERA, ROHAN · 2021 to 2025
$918kAHRQ HHS R01 HS022882AHRQ HHS R01 HS025164FDA HHS U01 FD005938NHGRI NIH HHS R01 HG006139NHLBI NIH HHS K23 HL153775NHLBI NIH HHS R01 HL144644NHLBI NIH HHS R01 HL167858NHLBI NIH HHS R01 HL169954NHLBI NIH HHS T32 HL155000NLM NIH HHS R01 LM006910Wellcome Trust
Abstract
backgroundSodium-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.
objectivesThe 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.
methodsAcross 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.
resultsOver 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]).
conclusionsIn 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.
Indexed as
Cardiovascular DiseasesDiabetes Mellitus, Type 2Hypoglycemic AgentsSodium-Glucose Transporter 2 InhibitorsAgedDipeptidyl-Peptidase IV InhibitorsFemaleGlucagon-Like Peptide-1 Receptor AgonistsHumansMaleMiddle AgedSulfonylurea CompoundsTreatment OutcomeDipeptidyl-Peptidase IV InhibitorsGlucagon-Like Peptide-1 Receptor AgonistsHypoglycemic AgentsSodium-Glucose Transporter 2 InhibitorsSulfonylurea Compoundscardiovascular diseasescomparative effectiveness researchglucagon-like peptide-1 receptor agonistshypoglycemic agentssodium-glucose transporter 2 inhibitorstype 2 diabetes mellitus
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