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Original Investigation |

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

Kenneth B. Margulies, MD1; Adrian F. Hernandez, MD, MHS2; Margaret M. Redfield, MD3; Michael M. Givertz, MD4; Guilherme H. Oliveira, MD5; Robert Cole, MD6; Douglas L. Mann, MD7; David J. Whellan, MD, MHS8; Michael S. Kiernan, MD, MS9; G. Michael Felker, MD, MHS10; Steven E. McNulty, MS2; Kevin J. Anstrom, PhD2; Monica R. Shah, MD, MSH11; Eugene Braunwald, MD4; Thomas P. Cappola, MD, ScM1 ; for the NHLBI Heart Failure Clinical Research Network
[+] Author Affiliations
1Perelman School of Medicine, University of Pennsylvania, Philadelphia
2Duke Clinical Research Institute, Durham, North Carolina
3Mayo Clinic, Rochester, Minnesota
4Brigham and Women’s Hospital, Boston, Massachusetts
5University Hospitals, Case Medical Center, Cleveland, Ohio
6Emory University, Atlanta, Georgia
7Washington University School of Medicine, St Louis, Missouri
8Thomas Jefferson University, Philadelphia, Pennsylvania
9Tufts University, Boston, Massachusetts
10Duke University School of Medicine and Duke Heart Center, Durham, North Carolina
11National Heart, Lung, and Blood Institute, Bethesda, Maryland
JAMA. 2016;316(5):500-508. doi:10.1001/jama.2016.10260.
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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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Figure 1.
Patient Flow Diagram for the Functional Impact of GLP-1 for Heart Failure Treatment Study

Data on patients screened for eligibility were not available. Secondary end points were analyzed with multiple imputation techniques when data were unavailable for the end point.

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Figure 2.
Components of the Primary End Point

HR indicates hazard ratio. A and B, y-axis scale in blue indicates range from 0% to 16%. The median duration of follow-up was 179 days (IQR, 157-182 days) in the liraglutide group and 178 days (IQR, 150-183 days) in the placebo group. In part C, the box plots were formed by the 25th and 75th percentiles and the line within the box is the median; the error bars indicate the 95% CIs and the data markers indicate the means.

aWithout missing data.

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Figure 3.
Prespecified Subgroup Analysis of Patients Who Died or Experienced Rehospitalization for Heart Failure by Type 2 Diabetes Status

HR indicates hazard ratio. The median duration of follow-up was 179 days (interquartile range, 157-182 days) in the liraglutide group and 178 days (interquartile range, 150-183 days) in the placebo group.

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