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Large-scale evidence generation and evaluation across a network of databases for type 2 diabetes mellitus (LEGEND-T2DM): a protocol for a series of multinational, real-world comparative cardiovascular effectiveness and safety studies

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Khera, Rohan, Schuemie, Martijn J, Lu, Yuan, Ostropolets, Anna, Chen, RuiJun, Hripcsak, George, Ryan, Patrick B, Krumholz, Harlan M +1 more·2022·BMJ Open
DOI 10.1136/bmjopen-2021-057977PMC PMC9185490

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Abstract

Introduction: Therapeutic options for type 2 diabetes mellitus (T2DM) have expanded over the last decade with the emergence of cardioprotective novel agents, but without such data for older drugs, leaving a critical gap in our understanding of the relative effects of T2DM agents on cardiovascular risk. Methods and analysis: The large-scale evidence generations across a network of databases for T2DM (LEGEND-T2DM) initiative is a series of systematic, large-scale, multinational, real-world comparative cardiovascular effectiveness and safety studies of all four major second-line anti-hyperglycaemic agents, including sodium–glucose co-transporter-2 inhibitor, glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor and sulfonylureas. LEGEND-T2DM will leverage the Observational Health Data Sciences and Informatics (OHDSI) community that provides access to a global network of administrative claims and electronic health record data sources, representing 190 million patients in the USA and about 50 million internationally. LEGEND-T2DM will identify all adult, patients with T2DM who newly initiate a traditionally second-line T2DM agent. Using an active comparator, new-user cohort design, LEGEND-T2DM will execute all pairwise class-versus-class and drug-versus-drug comparisons in each data source, producing extensive study diagnostics that assess reliability and generalisability through cohort balance and equipoise to examine the relative risk of cardiovascular and safety outcomes. The primary cardiovascular outcomes include a composite of major adverse cardiovascular events and a series of safety outcomes. The study will pursue data-driven, large-scale propensity adjustment for measured confounding, a large set of negative control outcome experiments to address unmeasured and systematic bias. Ethics and dissemination: The study ensures data safety through a federated analytic approach and follows research best practices, including prespecification and full disclosure of results. LEGEND-T2DM is dedicated to open science and transparency and will publicly share all analytic code from reproducible cohort definitions through turn-key software, enabling other research groups to leverage our methods, data and results to verify and extend our findings.

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  • The OHDSI network and its open-source analytic tools have been previously used to generate reliable evidence in medicine, including ophthalmology.

    “The OHDSI network and its open-source analytic tools have been previously used to generate reliable evidence in medicine, including ophthalmology.”

    From Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy (2025) · cites this paper as [7]

    The Data sources section describes OHDSI network studies, and Transparent and re-usable research tools describes its rigorously tested open-source tools. The paper also refers to prior LEGEND hypertension work in Research methods > Analysis. It does not report or identify an ophthalmology application, so that part of the claim is unsupported (page numbers unavailable in our copy). (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • GLP-1RAs offer well-documented benefits in reducing cardiovascular and kidney complications.

    “GLP-1RAs, approved by the US Food and Drug Administration (FDA) for type 2 diabetes (T2D) treatment in 2017, offer well-documented benefits in reducing cardiovascular and kidney complications.”

    From Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy (2025) · cites this paper as [7]

    The Rationale and background section says trials found that many GLP-1 receptor agonists and SGLT2 inhibitors reduced major adverse cardiovascular events, supporting the cardiovascular part of the claim. Our copy does not state that GLP-1 receptor agonists reduce kidney complications; Research methods > Outcomes lists renal outcomes to be studied, not an established kidney benefit. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Khera, R., Schuemie, M. J., Lu, Y., Ostropolets, A., Chen, R., Hripcsak, G., Ryan, P. B., Krumholz, H. M., & Suchard, M. A.
Affiliations
  • Yale New Haven Hospital (US)
  • University of California, Los Angeles (US)
  • Columbia University Irving Medical Center (US)
  • NewYork–Presbyterian Hospital (US)
  • United States Department of Veterans Affairs (US)
Corresponding author
Suchard, Marc A
ORCID
Venue
BMJ Open
Publisher
BMJ
Published
2022-06
Volume
12
Issue
6
Pages
e057977
ISSN
2044-6055 (ISSN-L)
DOI
10.1136/bmjopen-2021-057977
PMC
PMC9185490
OpenAlex
W4281735080
Cited by
37
References
13
Citations by year
2026: 7 · 2025: 15 · 2024: 8 · 2023: 5 · 2022: 1 · 2021: 1
FWCI
5.37
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ Open (publishedVersion, cc-by-nc)
  • medRxiv (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. National Library of Medicine (R01LM006910)
  • National Heart, Lung, and Blood Institute (K23HL153775)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
type 2 diabetes, cardiovascular risk, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas, major adverse cardiovascular events, drug safety, real-world evidence, observational health data, OHDSI, propensity score adjustment, negative control outcomes, federated analysis, open science
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Adult, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Sulfonylurea Compounds, Reproducibility of Results, Dipeptidyl-Peptidase IV Inhibitors

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