FDA committee supports expanded CV indication for liraglutide in adults with type 2 diabetes

An FDA advisory panel on Tuesday voted 17 to 2 in favor of an expanded indication for the GLP-1 receptor agonist liraglutide, supporting language in the prescribing information that the drug can reduce cardiovascular risk in patients with type 2 diabetes.

The decision follows an analysis of primary and secondary endpoints in the LEADER trial, a randomized, double blind, placebo-controlled study conducted at 410 sites in 32 countries. The trial showed that, over a mean 3.8 years, liraglutide (Victoza, Novo Nordisk) reduced the risk for 3-point major adverse cardiac events by 13%, for all-cause death by 15% and for CV death by 22% vs. placebo, while reducing HbA1c and body weight. The FDA requires that all diabetes drugs undergo testing for CV outcomes.

But debate over recommending the expanded indication hinged in part on a subgroup analysis that showed primarily CV-neutral outcomes in U.S. patients when compared with non-U.S. patients, and some panel members noted that the drug did not demonstrate CV benefit in low-risk groups.

“The overall primary trial results are very robust and substantiated, and the cardiovascular mortality is the biggest contributor to that, which is obviously a very important finding,” Marvin A. Konstam, MD, chief physician executive at the CardioVascular Center and professor of medicine at Tufts University School of Medicine in Boston, said following his vote in favor of an expanded indication. “I am concerned about the U.S. population [subgroup], but, at the end of the day, it’s a subgroup, and I just can’t overrate that to diminish the overall finding.”

In explaining his “no” vote, Carmen J. Allegra, MD, chief of hematology and oncology at the University of Florida, said he was “concerned and swayed” by the subgroup analysis.

“The U.S. target population is a pretty darn important population for us to consider, and we saw a significant interaction with outcomes vs. the other regions by the FDA’s analysis,” Allegra said. “We really didn’t see evidence for superiority in the U.S. population, yet, in other parts of the world, even with smaller populations included in the trial, we still saw superiority.”

“The fact is that we just don’t see good evidence [in the U.S.]... and it’s a single trial,” Allegra said. “I suppose if the labeling is clear about this concern of efficacy in the U.S., then I guess I’d be reasonably content with that, but I don’t think it’s fair to make a blanket approval here.”

The panel also voted unanimously in support of claims that LEADER established that the use of liraglutide in patients with type 2 diabetes is not associated with unacceptably high CV risk.

“Even the subgroups showed no unacceptably high [CV] risk,” Peter Wilson, MD, chairperson of EMDAC, said in comments explaining his vote.

LEADER design, results

In LEADER, researchers analyzed data from 9,340 patients aged at least 50 years with poorly controlled type 2 diabetes (HbA1c 7% or greater) and established CVD or chronic renal failure, or were aged at least 60 years and had risk factors for CVD. Researchers randomly assigned patients daily liraglutide therapy, beginning at 1.2 mg and increasing to 1.8 mg based on tolerance (n = 4,668), or placebo injection (n = 4,672).

Over a mean follow-up period of 3.8 years, fewer patients in the liraglutide group experienced a primary CV outcome event vs. those assigned placebo (13% vs. 14.9%), for an HR of 0.87 (95% CI, 0.78-0.97) and a 1.9% absolute risk reduction. Fewer patients in the liraglutide group died from CV causes (4.7% vs. 6%), for an HR of 0.78 (95% CI, 0.66-0.93). In addition, rate of death from any cause was lower in the liraglutide group vs. placebo (8.2% vs. 9.6%), for an HR of 0.85 (95% CI, 0.74-0.97).

The CV results were a surprise to investigators when first presented in June 2016, as the trial was fundamentally designed to assess CV safety.

“The results of LEADER are most remarkable because, except for glycemic control, these cardiovascular events were well implemented with high fidelity in both arms of the study,” John Buse, MD, PhD, chief of the division of endocrinology at University of North Carolina School of Medicine in Chapel Hill and a lead investigator in LEADER, said while speaking on behalf of Novo Nordisk. “Even on top of risk management, liraglutide reduced the risk of cardiovascular events.”

“The LEADER data allows clinicians to change the conversation about diabetes care from one of lowering glucose and wanting to reduce the risk over decades, to a conversation about reducing death, heart attacks and strokes over 3 to 5 years,” Buse said. “Now we can talk to patients about major, life changing endpoints that they care about within practical time frames.”

Questionable U.S. benefit

In FDA presentations during the meeting, however, clinical reviewers raised concerns regarding subgroup analysis that compared U.S. and non-U.S. adults, showing CV-neutral outcomes in U.S. adults, which make up about 25% of the trial population.

Speaking during the open public comment portion of the meeting, Sammy Almashat, MD, MPH, a research associate with Public Citizen Health Research, noted that in LEADER, the overall reduction in risk for major adverse CV events was due to outcomes at clinical sites outside of the United States.

“The fact remains that Victoza had no cardiovascular or mortality benefit for Americans,” Almashat said. “The absence of any evidence for a benefit in favor of Victoza on MACE, cardiovascular death or overall death raises serious doubts about the real-world effectiveness of Victoza for reducing cardiovascular risk in U.S. diabetes patients.”

Voting in favor of an expanded indication “seems not to be rational,” Almashat said.

Despite concerns, several clinicians spoke skeptically about subgroup analyses, or spoke of the benefits observed in patients who were prescribed liraglutide. Richard E. Pratley, MD, senior investigator at the Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, said liraglutide was an important new clinical tool for patients with type 2 diabetes at high CV risk.

“As a clinician, I have a lot of confidence in the results of the LEADER study,” said Pratley, who was also an investigator with the LEADER trial. “We have now entered a totally new era in diabetes management. We have these cardiovascular outcomes trials that in some cases, demonstrate a cardiovascular benefit, and, in some cases, they don’t. The LEADER study was a large, robust trial ... I strongly urge you to consider revising the label for liraglutide to take into account this new and important evidence.”

Vincent Cole , Sr., a Philadelphia resident with type 2 diabetes who participated in the LEADER trial at Thomas Jefferson University, spoke about his experience in the trial and his concerns, which initially included the length of the study and fear of using an injectable drug.

Over the course of the trial, Cole’s HbA1c fell from 9% to 7%, he said; he also lost 20 lbs and improved his adherence to all medications. He said his wife administered his injections.

“If I were asked if I feel like I benefitted from the liraglutide study, I would say, yes,” Cole said. “If I were asked would I take it again, I would say yes, though, hopefully, in an oral form. I believe I was fortunate in being able to participate in this trial.”

The panel’s recommendations are nonbinding, although the FDA often follows its suggestions. – by Regina Schaffer

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