Liraglutide Did Not Improve Clinical Stability in High-Risk Heart Failure

ORLANDO, Fla. — Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist approved to treat diabetes, did not improve post-hospitalization clinical stability in patients with advanced heart failure (HF) and reduced left ventricular ejection fraction (LVEF), researchers reported at the American Heart Association Scientific Sessions. 

Metabolic abnormalities are associated with congestive HF, and as the heart fails, there is a downregulation of fatty acid metabolism and adenosine triphosphate (ATP) synthesis becomes more dependent on glucose, said Kenneth B. Margulies, MD, of the University of Pennsylvania in Philadelphia.

Additionally, as HF advances further, he explained, the myocardium becomes insulin-resistant, which compromises glucose utilization. At present, current HF therapies do not directly target these metabolic abnormalities. 

Because GLP-1 agonists increase insulin secretion and insulin sensitivity, thereby improving glucose uptake, the researchers hypothesized that liraglutide initiated during the post-acute HF discharge period would improve clinical stability over 180 days after hospitalization.

They based their hypothesis on preclinical and pilot studies in patients with advanced HF and reduced ejection fraction, noted Dr Margulies, who presented the data. 

The FIGHT (A Randomized Trial of Liraglutide for High-Risk Heart Failure Patients With Reduced Ejection Fraction) trial included 300 patients with prior clinical diagnosis of HF who were hospitalized for an acute HF syndrome. To qualify for inclusion, they had to have LVEF ≤40%  during the previous 3 months and had to have been hospitalized despite taking evidence-based medication for HF and at least 40 mg of furosemide daily before hospital admission.

Importantly, Dr Margulies said, both patients with diabetes and those without diabetes were included in the study. 

Patients were enrolled during the last 24 hours of their hospitalization for HF or within 2 weeks of discharge. They underwent baseline evaluation with echocardiography, the 6-minute walk test, quality-of-life questionnaire, and blood tests.

The researchers randomly assigned patients to liraglutide (n=154) or placebo (n=146), uptitrating the study drug during the first month of the trial. 

The primary end point was a global rank score, a hierarchical composite rank score in which patients were ranked on 3 tiers based on time to death, time to HF hospitalization, and time-averaged proportional change in NT-proBNP from baseline to 180 days.

Secondary end points included individual components of the primary end point as well as changes in cardiac structure or function as measured by echocardiography, quality-of-life scores, and 6-minute walk test. 

The researchers also looked at change in weight, glucose control, and markers of renal function and lipid control as tertiary end points.

Baseline features did not differ significantly between groups, although the patients tended to be older with a male-to-female predominance, noted Dr Margulies. Most had also been hospitalized during the preceding year for HF; two-thirds were NYHA III; and BMI was greater than 32. 

Also, Dr Margulies noted that, despite high levels of usage of guideline-based therapy, the average NT-proBNP level was greater than 3800 pg/mL; and average LVEF was 26%.

“Clearly, this was a population with advanced heart failure,” he said. 

For the primary end point, results revealed a nonsignificant difference in the mean global rank score between the placebo and liraglutide groups (155 vs 146; P=.309), both of which ranked near the anchor point of 150.

In terms of tiers of the primary end point, there were no significant differences in deaths between treatment groups and a nonsignificant increase in HF hospitalizations among patients treated with liraglutide. 

In a Kaplan-Meier analysis, the placebo group also appeared to fare somewhat better in terms of death or hospitalization for HF than the liraglutide group, although the difference was nonsignificant.

“I do want to highlight the hazard ratio (HR), and more importantly the 95% confidence interval,” Dr Margulies said, noting that the HR was 1.296 (95% CI, 0.92 to1.83; P=.142) for liraglutide vs placebo. “The lower limit of 0.92 suggests that, even this small study effectively excludes more than 8% favorable effect on death or heart failure hospitalization in this advanced heart failure population.” 

Overall, most of the secondary end points, including the echocardiographpically-derived end points, the 6-minute walk distance, and the quality-of-life score, did not appear to favor placebo or liraglutide.

The researchers did find a significantly greater change in cystatin C in patients who received liraglutide, which implied some worsening of renal function with the treatment.

In patients with diabetes, those treated with liraglutide lost about 5 lb over the course of the study. However, this effect was not seen in patients without diabetes, reported Dr Margulies.

Serious adverse events did not appear to be increased with liraglutide, as compared with placebo.

“Larger studies are needed to establish the safety of liraglutide or other GLP-1 agonists for diabetes management or weight loss in patients with advanced heart failure, but these findings do not exclude the potential for beneficial effects of GLP-1 agonists in patients with earlier stages of heart failure,” concluded Dr Margulies.

Reference

1. Margulies KB, Anstrom KJ, Redfield MM, et al. LBCT.01 – Failure is Not an Option: New Drugs and Systems of Care. A Randomized Trial of Liraglutide for High-Risk Heart Failure Patients with Reduced Ejection Fraction. Presented at the American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL.