Liraglutide Reduces Cardiovascular Events and Mortality in Type 2 Diabetes Mellitus Independently of Baseline Low-Density Lipoprotein Cholesterol Levels and Statin Use: Results From the LEADER Trial
Open accessAbstract
liraglutide T he causal relationship between low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular events has been well established.1 In people with type 2 diabetes mellitus, LDL-C lowering with statins is strongly endorsed by clinical practice guidelines, with suggested LDL-C target levels including <100 mg/dL for high-risk patients, <70 mg/dL for very high-risk patients, 2-4 and ≤55 mg/dL in patients with cardiovascular disease at extreme risk. 2 Because LDL-C is a dominant pathophysiological mechanism of atherogenesis, questions pertain to whether newer antiatherosclerotic and cardiovascular protective therapies exhibit efficacy, even in the setting of low LDL-C.In this post hoc analysis of the LEADER trial, we evaluated the efficacy of liraglutide on cardiovascular outcomes and mortality across the spectrum of baseline LDL-C and statin use. 5 LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; https://www.clinicaltrials.gov;unique identifier: NCT01179048) was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk (median follow-up, 3.8 years).5 The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (major adverse cardiovascular events [MACEs]).The key secondary outcome (expanded MACEs) also included coronary revascularization, hospitalization for unstable angina, and hospitalization for heart failure.The ethics committee or institutional review board at each center approved the trial protocol.Patients provided informed consent.Cardiovascular outcomes were prospectively adjudicated by an independent, blinded event adjudication committee.Tests for trends in risk of first MACE and cardiovascular death across the 3 baseline LDL-C groups were performed with the Cochran-Armitage test for trend applied in a logistic regression adjusted for prior cardiovascular disease.The treatment effect of liraglutide versus placebo on cardiovascular outcomes by LDL-C level <50, 50 to 70, and >70 mg/dL and statin use at baseline was estimated with Cox regression with treatment, groups by LDL-C level, and the interactions of both as factors and further adjusted for baseline cardiovascular risk factors (sex, region, smoking history, prior cardiovascular disease, antidiabetes medications, age, diabetes duration, and estimated glomerular filtration rate).5 In LEADER, 9187 patients had baseline LDL-C measured: 926 (10.1%), 2021 (22.0%), and 6240 (67.9%) had LDL-C <50, 50 to 70, or >70 mg/dL, respectively.Baseline demographics and risk factors were well balanced across LDL-C levels, except that the highest LDL-C group had a higher proportion of women, a lower incidence of prior myocardial infarction or stroke, and a lower rate of statin use compared with the other 2 groups.Mean LDL-C in the 3 groups was 38.7 (SD, 7.7), 61.9 (SD, 3.9), and 108.3 (SD, 30.9) mg/dL, respectively.At baseline, 72% were on a statin, with an additional 10% having statin added during the course of the study (9% in the liraglutide and 11% in the placebo group).
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Current evidence suggests that newer diabetes treatments and lipid lowering have complementary benefits.
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- Authors
- Verma, S., Leiter, L. A., Mazer, C. D., Bain, S. C., Buse, J., Marso, S., Nauck, M., Zinman, B., Bosch-Traberg, H., Rasmussen, S., Michelsen, M. M., Bhatt, D. L., & The LEADER Publication Committee on behalf of the LEADER Trial Investigators
- Affiliations
- St. Michael's Hospital (CA)
- Swansea University (GB)
- University of North Carolina at Chapel Hill (US)
- HCA Midwest Division (US)
- St. Josef-Hospital (DE)
- Mount Sinai Hospital (CA)
- Novo Nordisk A/S, Søborg, Denmark (H.B.-T., S.R., M.M.M.).
- Novo Nordisk (Denmark) (DK)
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Circulation
- Published
- 2018-10-09
- Volume
- 138
- Issue
- 15
- Pages
- 1605-1607
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2899521789
- Cited by
- 35
- References
- 5
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 7 · 2019: 10 · 2018: 1
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 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 › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- liraglutide, type 2 diabetes, LDL cholesterol, statin use, major adverse cardiovascular events, cardiovascular mortality, GLP-1 receptor agonists, atherosclerosis, LEADER trial, cardiovascular risk stratification, LDL-C target levels, coronary revascularization, heart failure hospitalization, myocardial infarction, stroke, high cardiovascular risk patients
- MeSH terms
- Liraglutide, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Cholesterol, LDL, Risk Factors, Time Factors, Multicenter Studies as Topic, Biomarkers, Randomized Controlled Trials as Topic, Treatment Outcome, Risk Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Dyslipidemias
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