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Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial
Open accessAbstract
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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In the citing paper
“in earlier smaller studies with liraglutide in patients with HF with reduced left ventricular ejection fraction, the GLP-1RA was associated with increased incidence of serious cardiac events (rhythm disorders, worsening of HF)”
From Safety of Semaglutide (2021) · cites this paper as [102]
Experimental — accuracy not yet measuredIn the citing paper
“Vildagliptin, not tested in a CVOT, had no significant effect on LVEF but led to an increase in LV volumes in a small trial.551”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [551]
In the citing paper
“Vildagliptin, not tested in a CVOT, had no significant effect on LVEF but led to an increase in LV volumes in a small trial.551”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [551]
In the citing paper
“Furthermore, 2 small randomized clinical trials of liraglutide in patients with HF with reduced EF, 1 of which enrolled patients with recent HF hospitalization, suggested potential harm of liraglutide, although neither trial found statistically significant differences.36,37”
From Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review (2020) · cites this paper as [36]
In the citing paper
“In a placebo-controlled FIGHT trial, of patients with HFrEF, with and without T2DM (41%), liraglutide was not associated with an improvement in the composite primary endpoint of death, rehospitalization and NT-proBNP change.181”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [181]
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Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504720 · Cited by 12,315
Effect of carvedilol on survival in severe chronic heart failure
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Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes
Green, J. B., Bethel, M. A., Armstrong, P. W., Buse, J. B., Engel, S. S., Garg, J., Josse, R., Kaufman, K. D., Koglin, J., Korn, S., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1501352 · Cited by 2,577
Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome
Pfeffer, M. A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H. C., Køber, L. V., Lawson, F. C., Ping, L., Wei, X., Lewis, E. F., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1509225 · Cited by 2,409
Effect of carvedilol on survival in severe chronic heart failure
Packer, M., Coats, A. J. S., & Fowler, M. B. (2001) · ACC Current Journal Review · doi:10.1016/s1062-1458(01)00477-9 · Cited by 1,651
Anand, I. S., Fisher, L. D., Chiang, Y., Latini, R., Masson, S., Maggioni, A. P., Glazer, R. D., Tognoni, G., & Cohn, J. N. (2003) · Circulation · doi:10.1161/01.cir.0000054164.99881.00 · Cited by 857
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Scirica, B. M., Braunwald, E., Raz, I., Cavender, M. A., Morrow, D. A., Jarolim, P., Udell, J. A., Mosenzon, O., Im, K., Umez-Eronini, A. A., et al. (2014) · Circulation · doi:10.1161/circulationaha.114.010389 · Cited by 725
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
(2016) · New England Journal of Medicine · doi:10.1056/nejmc1600827 · Cited by 700
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Ye, X., Wu, Q., Li, L., Huang, M., & Wang, S. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1955431
Functional Implications of GLP-1RA Use Beyond Obesity in Aging Adults
Mascone, S. E., Prior, S. J., & Addison, O. R. (2026) · Current Geriatrics Reports · doi:10.1007/s13670-026-00467-0
Krongauz, D. L., Kohn, S., Zulti, A., Schlesinger, Y., Godneva, A., Talmor‐Barkan, Y., & Segal, E. (2026) · medRxiv · doi:10.64898/2026.10.18.26365823
Nzobokela, J., Choolwe, S. C., & Masenga, S. K. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1987811
Jang, R., Jang, M., Ruan, X., Jin, C., & Kim, W. (2026) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-026-04199-0
Saleem, M. F., Mansoor, A., Shahid, E., Lohana, M., Ghafoor, M. S., Khan, M. U., Abbas, F. M., Hirpara, H., Khalid, A., Hassan, F., et al. (2026) · Monaldi Archives for Chest Disease · doi:10.4081/monaldi.2026.3980
Metadata
- 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
- 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
- bronze
- doi.org
- 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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