Liraglutide Doesn't Lower LVEF in HF but Does Increase Heart Rate, Says LIVE Trial

Deborah Brauser

May 24, 2016

FLORENCE, ITALY — A new study agrees with recent research that the glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) has no clinical benefit for patients with heart failure (HF), but it adds to the literature by noting some serious treatment-related CV events.

Last fall, results from the FIGHT trial showed no significant differences in 6-month outcomes, including mortality and rehospitalization, between the antidiabetic drug and placebo in 300 patients with acute HF and reduced ejection fraction (HFrEF). However, as expected, weight decreased and glycemic control improved in the subgroup with diabetes.

The newly reported LIVE trial enrolled 241 patients with chronic HFrEF at five centers in Denmark. After 24 weeks of treatment, there were no significant differences between the liraglutide and placebo groups for the primary end point of change in LVEF—whether the patients did or did not have comorbid diabetes[1].

More troubling, there was a significant increase in heart rate for those receiving liraglutide vs placebo (P<0.001) and more serious adverse cardiac events (12 vs three, respectively, P=0.04).

Dr Henrik Wiggers

Principal investigator Dr Henrik Wiggers (Aarhus University Hospital, Denmark) told heartwire from Medscape that even a moderately elevated resting heart rate can have a negative effect on HF and that that may explain the increased adverse events they found in their study.

"Although I must stress that this was a secondary end point, if a patient like this came to me to discuss getting a GLP-1 analogue, I would hesitate," added Dr Anders Jorsal (Aarhus University Hospital), who presented the findings during a late-breaking-trial session here at the European Cardiology Society (ESC) Heart Failure 2016 Congress.

Official discussant Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France) called LIVE's results disappointing and the adverse events worrisome. "At the moment, liraglutide may not be the drug of choice for heart failure and diabetes."

"We Expected Better"

Dr Anders Jorsal

"We currently don't know how to treat diabetes in heart failure and so wanted to study whether liraglutide could improve LVEF," said Jorsal.

He added that some pilot studies and experimental data "have been very promising" for this treatment and have shown LVEF improvements for HF patients with and without type 2 diabetes mellitus, which made them hopeful.

"We really expected better for our patients," he said.

In the study, 122 of the patients were randomly assigned to liraglutide and 119 to placebo (89% men and mean age 65 years in each group). In addition, 32% and 29% of the groups, respectively, had type 2 diabetes.

Inclusion criteria for this study included LVEF <45% and an NYHA classification of 1–3. All participants underwent 3D contrast echocardiography to measure LVEF changes from baseline, as well as blood-pressure measurements and a 6-minute-walk test, and they filled out the Minnesota Living with Heart Failure (MLHF) questionnaire.

Surprising Results

At 6 months, the liraglutide-receiving group had a 0.8% change in LVEF vs a 1.5% change in the placebo group (P=0.24). "And there were no between-group differences in other measures of systolic function," reported Jorsal.

Weight loss was significantly greater in the liraglutide vs placebo groups (-2.2 kg vs 0.1 kg, respectively; P<0.001), HbA1c level was significantly reduced (-5.1 mmol/mol vs 3.2 mmol/mol, P<0.001), and the 6-minute-walk test was significantly improved (P=0.04).

However, heart rate was increased by 6 beats per minute in the liraglutide patients vs a decrease of 1 beat in the placebo patients (P<0.001). In addition, there were four vs two reports of atrial fibrillation, respectively, three vs zero reports of ACS, three vs one nonfatal VTs, one vs zero fatal VTs, and one vs zero worsening of heart failure.

"This study wasn't actually powered to detect any clinical-end-point differences. So we were surprised by this," said Wiggers. "We now need larger studies to confirm these serious clinical effects."

He noted that the ongoing, 9000-person strong Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Results (LEADER) trial, which announced top-line results in March, has excited many people in the field. "But only a minority of its patients had heart failure at baseline, and the type of heart failure is probably unknown." Although it'll be interesting to see what LEADER shows when its full results are released, "it might not be enough," he said.

Caution for Now

After the presentation, discussant Komajda said that the clinical implications of both the LIVE and FIGHT trials are that there is no evidence of clinical benefit in cardiac function with liraglutide and that CV safety in diabetes with HF or LV dysfunction "remains an open question."

Session moderator Dr Frank Ruschitzka (University of Zurich, Switzerland) called diabetes and HF "vicious twins" and noted that the ESC's Heart Failure Association has just opened a new committee focused on the joint conditions.

He later told heartwire that the LIVE trial was intriguing and shed some light on important topics, "including some important safety signals" for arrhythmic events. "It's a small study, so I don't want to overplay these results. But safety should come first."

Although he's looking forward to upcoming outcomes studies, Ruschitzka said that at present he would not treat a patient of this type with this kind of drug. And that won't change "until I see the final analysis [from ongoing large trials] presented and published."

LIVE was sponsored in part by Novo Nordisk. Jorsal, Wiggers, and Ruschitzka reported no relevant financial relationships.

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