Diabetes Drug Liraglutide Falls Short in Advanced Heart Failure

Larry Hand

August 02, 2016

PHILADELPHIA, PA — Patients with advanced heart failure did not benefit from taking the glucagonlike peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) in terms of posthospitalization clinical stability in a recent clinical trial[1].

However, the drug may still be beneficial in patients with pre- or less severe heart failure, according to researchers.

"Our study had, in a sense, two goals. One goal was to see, completely independent of diabetes, whether liraglutide helps heart failure in people who already have a pretty advanced degree of heart failure," Dr Kenneth B Margulies (University of Pennsylvania Perelman School of Medicine, Philadelphia) told heartwire from Medscape in a telephone interview.

"On that we have a pretty definitive answer: no. We were hoping for improvement in heart failure, and we didn't get that at all," he said.

Margulies and colleagues conducted a double-blind placebo-controlled phase 2 randomized trial involving 300 patients (median age 61, 79% male, 59% with type 2 diabetes) with established heart failure and reduced left ventricular ejection fraction (LVEF) at 24 US sites between August 2013 and March 2015. Of all patients, 271 completed the study.

The researchers randomized patients to receive either liraglutide (up to 1.8 mg/day) or placebo via daily subcutaneous injection for up to 180 days, assessing for a primary end point of a global rank score, with all patients ranked across three 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. At baseline, median LVEF was 25% and median NT-proBNP level was 2049 pg/mL.

The researchers found that liraglutide, compared with placebo, had no significant effect on the number of deaths or rehospitalizations for heart failure. Global rank scores came to 146 for the liraglutide group and 156 for the placebo group.

Change in NT-proBNP level in those who were alive and not rehospitalized for heart failure came to 1.52 in the liraglutide group and 1.44 in the placebo group, which were not significantly different.

Investigators reported 16 hyperglycemic events for the liraglutide group and 27 for the placebo group, while hypoglycemic events were "infrequent."

Safety was the second goal of the study, Margulies said. "Because we didn't only do diabetics and because it wasn't really powered for outcomes, we didn't really get a positive signal to say it's unsafe," he said. "What we did see is a trend toward worrying about starting it in people who already have advanced heart failure. I'd be careful starting it in someone who already has heart failure because the signals are worrisome about that, and especially since there are other diabetes drugs that one might choose."

The new results differ from a study published in early 2015 in which researchers found potential benefit from GLP-1 agonists against heart failure among patients with diabetes[2]. But the studies are much different methodologically, said senior study author Dr David Lanfear (Henry Ford Health System, Detroit, MI).

"There are numerous possible reasons for the differences," he told heartwire in a telephone interview, including the earlier study being retrospective and observational and examining only patients with diabetes (nearly all without a history of heart failure). In contrast, the current study was prospective and included only established heart-failure patients, "who were, by design, much higher risk," he added.

However, Margulies pointed out that in a new study in the New England Journal of Medicine[3] researchers found that liraglutide had reduced the risk of the first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke among patients with type 2 diabetes.

"In earlier heart failure, the death, stroke, and MI outcome was reduced by liraglutide," Margulies said of the study.

"If [patients] already have advanced heart failure, you definitely shouldn't use [liraglutide] for the sake of their heart failure and you probably shouldn't use it if there are better choices for diabetes control," he advised. "In earlier phases where they're already on the drug, there's nothing about our study that says you couldn't use it."

Heart-failure patients who were already on liraglutide were excluded from and not evaluated by the new study, Margulies said.

More studies of all diabetes drugs are needed and are under way, he said, "to see what they do to the critical organ function over time—whether it's kidney function, heart function, vascular function. Lowering glucose is part of the story, but it's not enough. Some of the things that lower blood glucose sometimes give us adverse signals in these important organ functions."

The research was grant from the National Heart, Lung, and Blood Institute (NHLBI). The study drug and matching placebo injections were supplied by Novo Nordisk. Margulies reported receiving grants from Juventis Therapeutics, Celladon, Thoratec, Innolign Biomedical, and Merck Sharp and Dohme and serving as a consultant for Janssen Pharmaceuticals, Merck Sharp and Dohme, Pfizer, and Ridgetop Research. Disclosures for the coauthors are listed in the article.

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