A packed session greeted the highly anticipated results of the LEADER trial, which found that the GLP-1 receptor agonist liraglutide has cardiovascular benefits in high-risk patients with diabetes.
The type 2 diabetes therapy liraglutide (Victoza) reduces the risk of cardiovascular (CV) death by 22%, cuts the risk of death from any cause by 15%, and reduces major CV events by 13%, according to results from the LEADER trial1 presented Monday at the 76th Scientific Sessions of the American Diabetes Association (ADA) in New Orleans, Louisiana.
Liraglutide thus becomes the first glucagon-like peptide-1 (GLP-1) receptor agonist and the second major type 2 diabetes (T2D) therapy, after the SGLT2 inhibitor empagliflozin, to go beyond CV safety and offer actual benefits, something that Yale Professor of Medicine Silvio E. Inzucchi, MD, dubbed the “holy grail” last year at ADA, during the session on another GLP-1 receptor agonist, lixisenatide.
(The initial CV results on empagliflozin were presented in September 2015 in the EMPA-REG OUTCOME trial, and more findings will be presented at ADA Tuesday.)
Steven Marso, MD, of the University of Texas Southwestern Medical Center and lead author of the study, said during a press briefing ahead of Monday’s presentation that the reduction of CV mortality is clearly the major benefit identified in the study, beyond liraglutide’s primary purpose of lowering blood sugar and providing modest weight loss benefits.
The dose of liraglutide in this study, 1.8 mg, is approved by FDA for treating T2D and marketed as Victoza; Novo Nordisk later received approval for a 3 mg formulation to treat obesity, which is marketed as Saxenda.
Novo Nordisk launched the Liraglutide Effect and Action in Diabetes of Cardiovascular Outcomes Results (LEADER) in 2010 to meet FDA requirements for post-marketing CV analysis of new diabetes and obesity therapies, which arose in the wake of the uproar over rosiglitazone.
During the press briefing, John B. Buse, MD, PhD, professor of medicine at the University of North Carolina, said researchers didn’t go in expecting these results. “When we started this trial, it was fundamentally designed to assess cardiovascular safety,” he said. Buse is also senior author on the study, which was simultaneously published in the New England Journal of Medicine.1
Methods and Results
LEADER was a double-blind trial that randomized 9340 patients with T2D and high CV risk to receive either 1.8 mg of liraglutide or placebo. The primary composite was a time-to-event analysis of a first occurrence: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.
Admitted patients fell into 2 groups: those at least 50 years old with established CVD or chronic kidney disease, or those at least 60 years old who had at least 2 risk factors. The 2 groups were very well matched: both groups had about two-thirds men, average age 64, with a body mass index (BMI) of 32.5. The patients had an average glycated hemoglobin (A1C) of 8.7%, in part because the investigators did not put an upper limit on participants. Average duration of disease was 12.9 years for placebo and 12.8 years for the liraglutide arm.
Patients were followed for a median of 3.8 years. Significantly fewer patients taking liraglutide had a primary outcome (609 out of 4668, or 13.0%) than in the placebo group (694 of 4672, or 14.9%). Death from any cause was also lower in the liraglutide group (381 patients, or 8.2%) vs placebo (447 patients, or 9.6%). Rates of nonfatal heart attack, nonfatal stroke and hospitalization for heart failure were also lower in the liraglutide group. Pancreatitis, which is also a concern to FDA with diabetes and obesity drugs, was actually lower in the liraglutide group. The most common complaint among the liraglutide patients was gastrointestinal issues. Researchers reported that the outcomes were consistent across subgroups.
Class Effect or Molecule?
Robert Eckel, MD, of the University of Colorado, who moderated the press briefing, said that in T2D, “Most of us agree that metformin is the drug of choice. With EMPA-REG published a year ago, we have to think beyond metformin to what that second drug might be.”
For patients with poorly controlled T2D, insulin provides a possibly, but it has risks, as well—notably hypoglycemia, Eckel said. Having other options that also provide a CV benefit may be appealing, given the high rate of cardiovascular mortality in diabetes. The potential added benefit of weight loss also has some appeal, he said, but more studies are needed.
“The benefit for cardiovascular death [in liraglutide] is very similar to what statins do,” Eckel said, without adding the obvious: statins have been on the market for decades and are cheap, compared with liraglutide.
The other big question in cardiovascular outcomes trials Eckel said, “Is this a class effect, or is this the molecule?”
After EMPA-REG, which Buse said, "rocked the diabetes world," there was speculation that the benefits might apply to the entire sodium glucose co-transporter-2 inhibitor class, but at the American Heart Association meeting last November, Inzucchi warned reporters not to assume, because researchers who did so in the past had been burned.
When it comes to the GLP-1 class, however, LEADER shows there is clear differentiation between liraglutide and lixisenatide, which was shown in the ELIXA trial to be safe, but not to offer any CV benefit.
Buse said the 2 drugs are not the same, and the populations studied were also different. Lixisenatide is short-acting, which he said in the session may offer some post-prandial benefits in glucose control. “Lixisenatide does not provide 24-hour coverage. Liraglutide provides 24-hour coverage,” he said.
Novo Nordisk Chief Medical Officer for North America, Todd Hobbs, MD, said the results should set liraglutide apart in the GLP-1 market and also provide a positive outlook for the combination therapy of isulin degludec, now sold as Tresiba, and liraglutide, which is pending before the FDA. Both individual therapies now have safety results that beat competitors, and Hobbs said the results for the dual therapy are outstanding.
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes [published online June 13, 2016]. N Engl J Med. 2016; doi: 10.1056/NEJMoa603827