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Cited by 706Heart Failure Treatment and ManagementDiabetes Treatment and ManagementCardiovascular Function and Risk Factors

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Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial

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Margulies, Kenneth B., Hernandez, Adrian F., Redfield, Margaret M., Givertz, Michael M., Oliveira, Guilherme H., Cole, Robert, Mann, Douglas L., Whellan, David J., Kiernan, Michael S., Felker, G. Michael, McNulty, Steven E., Anstrom, Kevin J., Shah, Monica R., Braunwald, Eugene, Cappola, Thomas P., for the NHLBI Heart Failure Clinical Research Network·2016·JAMA
DOI 10.1001/jama.2016.10260PMC PMC5021525
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Abstract

IMPORTANCE: Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status. OBJECTIVE: To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure. DESIGN, SETTING, AND PARTICIPANTS: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites. INTERVENTIONS: The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days. MAIN OUTCOMES AND MEASURES: The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events. RESULTS: Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%-33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054-4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57-2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89-1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively). CONCLUSIONS AND RELEVANCE: Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01800968.

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Authors
Margulies, K. B., Hernandez, A. F., Redfield, M. M., Givertz, M. M., Oliveira, G. H., Cole, R., Mann, D. L., Whellan, D. J., Kiernan, M. S., Felker, G. M., McNulty, S. E., Anstrom, K. J., Shah, M. R., Braunwald, E., Cappola, T. P., & for the NHLBI Heart Failure Clinical Research Network
Affiliations
  • University of Pennsylvania (US)
  • Duke University (US)
  • Mayo Clinic (US)
  • Brigham and Women's Hospital (US)
  • University Hospitals of Cleveland (US)
  • Emory University (US)
  • Washington University in St. Louis (US)
  • Thomas Jefferson University (US)
  • Tufts University (US)
  • National Heart, Lung, and Blood Institute (US)
  • Brigham and Women’s Hospital, Boston, Massachusetts
Corresponding author
Margulies, Kenneth B.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2016-08-02
Volume
316
Issue
5
Pages
500
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2016.10260
PMC
PMC5021525
OpenAlex
W2505843168
Cited by
706
References
24
Citations by year
2026: 85 · 2025: 99 · 2024: 75 · 2023: 58 · 2022: 46 · 2021: 50 · 2020: 77 · 2019: 68 · 2018: 78 · 2017: 56 · 2016: 13
FWCI
59.02
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (U10HL110297, U10HL110342, U10HL084904, U10HL110262, U01HL084861, U10HL110309, U10HL110336, U10HL110302, U10HL110337, U10HL110312, U10HL110338)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
liraglutide, GLP-1 receptor agonists, advanced heart failure, reduced left ventricular ejection fraction, clinical stability, heart failure readmission, mortality, NT-proBNP, myocardial metabolism, type 2 diabetes, cardiac structure and function, 6-minute walk distance, quality of life, subcutaneous injection, cardioprotection
MeSH terms
Liraglutide, Aged, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Heart Failure, Humans, Hypoglycemic Agents, Male, Middle Aged, Patient Readmission, Quality of Life, Stroke Volume, United States, Odds Ratio, Treatment Outcome, Ventricular Dysfunction, Left, Glucagon-Like Peptide 1

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