Liraglutide No Match for Heart Failure in Early Round of FIGHT

Marlene Busko

November 10, 2015

ORLANDO, FL— The glucagonlike peptide-1 (GLP-1) receptor agonist liraglutide (Victoza, Novo Nordisk) did not improve clinical stability at 6 months in 300 patients with advanced heart failure (HF) and reduced ejection fraction in the Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT) trial[1].

The patients had been randomized to receive daily subcutaneous injections of the antidiabetic drug liraglutide or placebo after they had been hospitalized for acute HF. There were no significant differences in the main 6-month outcomes: 12% of patients in the liraglutide group vs 11% of patients in the placebo group died, and 34% of patients in the treatment group vs 28% of patients in the placebo group were rehospitalized for HF.

Thus "the GLP-1 agonist liraglutide does not appear to improve posthospitalization clinical stability in patients with advanced HF," said Kenneth B Margulies, MD (University of Pennsylvania, Philadelphia), presenting the findings in a press conference prior to a late-breaking clinical-trial session here at the American Heart Association (AHA) 2015 Scientific Sessions. However, these findings do not exclude the potential for beneficial effects of GLP-1 agonists in patients with earlier stages of HF, he added.

Among the subgroup of patients with diabetes, liraglutide "did what it was expected to do": decrease weight and improve glycemic control.

"The findings suggest that liraglutide should not be used in heart-failure patients [who don't have] diabetes, [and] in diabetics, liraglutide should not be used in patients with advanced heart failure for the purpose of improving heart-failure outcomes," Margulies told heartwire from Medscape.

Promising Pilot Study

In HF, fatty-acid use and glucose uptake are impaired. Researchers speculated that GLP-1 agonists, which increase glucose uptake by increasing insulin secretion and insulin sensitivity, might be useful to treat patients with HF.

In fact, in a small pilot study of 12 patients with advanced HF, 5 weeks of therapy including a continuous infusion of recombinant GLP-1 improved LVEF, exercise, and quality of life compared with historical controls.

Dr Kenneth Margulies

Building on this, Margulies and colleagues hypothesized that patients who had been hospitalized with acute HF and then received sustained therapy with liraglutide from their time of discharge from the hospital would have better survival and less rehospitalization 6 months later.

FIGHT enrolled 63 women and 277 men with HF who were hospitalized for an acute HF syndrome, had an LVEF ≤40%, and had been on evidence-based medication for HF.

The patients had a mean age of 60, and 22% were female. On average, they had been diagnosed with HF 8 years ago, and close to 90% had been hospitalized with HF at least once in the year before the index hospitalization. Only 60% had type 2 diabetes.

The patients had an average BMI above 32, and most were NYHA class 3 (66%) or class 2 (30%).

"Despite high rates of disease-modifying therapy for HF, the average NT-proBNP level was over 3800 and the average LVEF was 26%, so this was clearly a population with advanced HF," said Dr Margulies.

The patients were randomized to placebo (n=146) or liraglutide (n=154).

Negative Trial

There was no significant difference in global rank score (where a score of 150 indicated no treatment effect and a higher score indicated a more favorable response): patients in the placebo group had a score of 155 and patients in the liraglutide group had a score of 146 (P=0.309).

Compared with patients who received placebo, the hazard ratio for the composite outcome of death or rehospitalization for HF in patients who received liraglutide was 1.296 (95% CI 0.92–1.83, P=0.142). The 0.92 at the low end of the confidence interval means that at most, 8% of patients with advanced HF who receive liraglutide would have a benefit of a lower risk of death or HF hospitalization, Dr Margulies explained.

Most secondary end points, including the echocardiographically derived end points, the 6-min-walk distance, and the quality-of-life score were similar with placebo or liraglutide. However, the change in cystatin C was significantly greater in liraglutide-treated subjects, suggesting that these patients had some worsening of renal function.

On the other hand, diabetic patients treated with liraglutide lost 5 more pounds and their HbA1c levels decreased, compared with diabetic patients who received placebo. These changes were not seen with nondiabetic patients.

"For clinicians, the major issue is whether liraglutide and other GLP-1 agonists are safe in diabetics with advanced heart failure, and our study does not provide a definitive answer at this point," Dr Margulies said.

The researchers are conducting additional subgroup analyses of the diabetic patients in FIGHT, which should help clarify this.

In addition, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long-Term Evaluation (LEADER) study of about 9000 patients "will provide much more information about safety across the full spectrum of heart-failure patients, [although] I don't think it will have much to say about the advanced HF patients that we studied," according to Margulies.

In a discussion following the presentation, Prof John McMurray (University of Glasgow, Scotland) said, "I think it is crucially important that we are doing trials looking at overlap between diabetes, dyslipidemia, and heart failure, because it is so common in these patients." There has been a lot of interest, initially with detrimental findings with thiazolidinedione class of drugs (which includes rosiglitazone), he noted, and it is important not to rush in and overinterpret initial studies. "I think [Dr Margulies] was absolutely right in his cautious interpretation of the findings."

Margulies reports receiving research grants from Juventis Therapeutics, Celladon, Thoratec, and Innolign Biomedical. He is a consultant/on the advisory board for Novo Nordisk (unpaid), Janssen, Merck, Pfizer, Ridgetop Research, and AstraZeneca. Disclosures for the coauthors are listed in the abstract.

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