Effects of liraglutide on cardiovascular outcomes in type 2 diabetes patients with and without baseline metformin use: post hoc analyses of the LEADER trial
Open accessAbstract
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) reduce cardiovascular (CV) events among patients with type 2 diabetes and high CV risk. Because consensus professional society recommendations endorse metformin as the first-line medication for type 2 diabetes, the CV efficacy of GLP-1RAs has primarily been studied with background metformin therapy (1). However, the European Society of Cardiology now recommends GLP-1RAs as a first-line type 2 diabetes treatment for patients at high CV risk (2). These discordant recommendations raise the question of how background metformin might influence the CV benefits of GLP-1RAs. Using data from the LEADER trial, we sought to answer this question by exploring possible heterogeneity in the CV efficacy of liraglutide related to baseline metformin treatment (3). The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (NCT01179048, ClinicalTrials.gov) has been described elsewhere (3). Patients with type 2 diabetes and high CV risk underwent double-blind randomization to daily liraglutide versus placebo in addition to existing care. Each patient contributed data from randomization until censoring. The primary outcome was time from randomization to first occurrence of a composite of CV death, myocardial infarction, or stroke. Prespecified secondary outcomes included an expanded composite (primary plus coronary revascularization or hospitalization for unstable angina or heart failure), the composite components, and all-cause death. All outcomes were centrally adjudicated. Metformin treatment was identified at the baseline trial visit and each visit thereafter. Within each baseline metformin treatment subgroup, effect estimates for liraglutide versus placebo (hazard ratio [HR], 95% CI) were derived using Cox proportional hazards regression models; multivariable adjustment for baseline demographic and clinical factors was performed. Inverse probability for treatment weighting (IPTW) was used to account for imbalances in covariates between baseline metformin treatment subgroups (4). For multivariable analyses with IPTW, heterogeneity in the association between baseline metformin …
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The benefits of GLP-1 RA and SGLT2i for cardiovascular and renal outcomes are independent of metformin use.
“Notably, the benefi ts of GLP-1 RA and SGLT2i for cardiovascular and renal outcomes have been found to be independent of metformin use, and thus these agents should be considered in people with established or high risk of CVD, HF, or CKD, independent of metformin use (173 -175).”
From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [173]
In the discussion and conclusion, the paper reports no clear evidence that baseline metformin use changes liraglutide’s cardiovascular efficacy, though a sensitivity analysis found a significant interaction. It also reports cardiovascular benefits of empagliflozin irrespective of baseline metformin use. These passages support the cardiovascular part of the claim, but do not establish metformin-independent renal benefits or the claim for GLP-1 RAs and SGLT2 inhibitors as whole classes. (LLM, conf=0.88)
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- Authors
- Crowley, M. J., McGuire, D. K., Alexopoulos, A.-S., Jensen, T. J., Rasmussen, S., Saevereid, H. A., Verma, S., & Buse, J. B.
- Affiliations
- Duke University (US)
- The University of Texas Southwestern Medical Center (US)
- Novo Nordisk (Denmark) (DK)
- St. Michael's Hospital (CA)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Crowley, Matthew J.
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2020-07-09
- Volume
- 43
- Issue
- 9
- Pages
- e108-e110
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC7440910
- OpenAlex
- W3042095004
- Cited by
- 47
- References
- 8
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 14 · 2021: 12 · 2020: 5
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Health Services Research and Development (CIN 13-410)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007012)
- National Center for Advancing Translational Sciences (UL1TR002489)
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- liraglutide, metformin, type 2 diabetes, cardiovascular outcomes, GLP-1 receptor agonists, LEADER trial, cardiovascular risk, first-line therapy, cardiovascular mortality, myocardial infarction, stroke, heart failure, coronary revascularization, treatment effect heterogeneity
- MeSH terms
- Liraglutide, Adult, Aged, Cardiovascular Diseases, Cardiovascular System, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Drug Therapy, Combination, Female, Hospitalization, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Prognosis, Retrospective Studies, Prevalence, Randomized Controlled Trials as Topic, Treatment Outcome
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