Objectives

To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure.

Background

Heart failure was the leading cause of hospitalization in the United States with more than 4 million admissions per year from 2003–2009. Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). As heart failure progresses, these abnormalities become more pronounced and are observed in both patients with and without type 2 diabetes. At this time of this study, there was no heart failure therapy that targeted these metabolic abnormalities; however, in earlier clinical studies, glucagon-like peptide 1 (GLP-1) agonists showed cardioprotective effects in patients with advanced heart failure, irrespective of type 2 diabetes status. Glucagon-like peptide 1 is an endogenous incretin hormone that improves insulin sensitivity with minimal risk of hypoglycemia. This study was created to determine if use of GLP-1 agonists improved clinical stability in recently hospitalized patients with acute heart failure and reduced LVEF.

Participants

Participants, aged 18 years or older, were required to have an established diagnosis of heart failure and a LVEF of 40% or lower during the preceding 3 months. Additional inclusion criteria included: (1) a recent (within 14 days) hospitalization for an acute heart failure syndrome despite already receiving evidence-based therapies and (2) a preadmission oral diuretic dose of at least 40 mg of furosemide or an equivalent.

Key exclusion criteria were (1) recent acute coronary syndrome or coronary intervention, (2) known intolerance of GLP-1 agonist therapy, and (3) severe renal, hepatic, or pulmonary disease. Subjects with and without type 2 diabetes were enrolled in the trial, however, subjects with type 1 diabetes were excluded from participation.

In total, 300 patients were randomized. Of these, 154 were randomized to the treatment arm and 146 were randomized to the placebo arm.

Design

Participants were identified by hospital admission records and were enrolled during either the last 24 hours of his or her hospitalization for heart failure or the 2-week interval after the hospitalization. Baseline evaluations were conducted, which included echocardiographic measures, the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire (KCCQ), and blood tests.

After the baseline evaluation, patients were randomized in a 1:1 ratio to receive either the GLP-1 agonist liraglutide or placebo as a daily subcutaneous injection. The protocol involved titration of study drug dosage as tolerated every 14 days from 0.6 mg/d to 1.2 mg/d to 1.8 mg/d during the first 30 days of the trial (as tolerated). Follow-up testing was performed at 30-, 90-, and 180-day study visits.

The primary end point was a global rank score in which all participants, 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 (NT-proBNP) level from baseline to 180 days.

Conclusions

The GLP-1 agonist liraglutide did not improve post-hospitalization clinical stability in patients with advanced heart failure and reduced LVEF. There was no significant between-group difference in the global rank scores and furthermore, there were no significant differences detected in any of the secondary endpoints.

Margulies KB, Hernandez AF, Redfield MM, et al. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016;316(5):500-508. doi:10.1001/jama.2016.10260

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