NEW ORLEANS — New data from the LEADER trial demonstrate that liraglutide (Victoza®, Novo Nordisk) lowers the rate of a composite end point of first occurrence of death from cardiovascular (CV) causes, nonfatal myocardial infarction (MI), or nonfatal stroke in patients with type 2 diabetes when compared with placebo.
“As the study was designed to only demonstrate that the drug was safe, we were a little surprised at the higher bar of showing that the drug was effective at reducing the risk of heart attack, stroke, and death as well as evidence of kidney disease,” John B. Buse, MD, PhD, of the University of North Carolina School of Medicine, Chapel Hill, told Endocrinology Advisor.
Dr Buse and fellow researchers from the LEADER trial presented their findings at the American Diabetes Association (ADA) 76th Scientific Sessions.
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Dr Buse explained that the primary aim of the double blind trial was to evaluate the CV safety of liraglutide, as part of the mandate of the Food and Drug Administration (FDA). In all, 9340 patients with type 2 diabetes and high CV risk were randomly assigned to either liraglutide (n=4668) or placebo (n=4672).
First occurrence of death from CV causes, nonfatal MI, or nonfatal stroke served as the primary composite outcome in the time-to-event analysis. Researchers hypothesized that liraglutide would be noninferior to placebo in the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval (CI) of the hazard ratio (HR), according to study methodology.
Liraglutide Superior in Primary Outcome, Mortality
During follow-up (median, 3.8 years), fewer patients experienced the primary outcome in the liraglutide arm than in the placebo arm (13% vs 14.9%; HR=0.87; 95% CI, 0.78-0.97; noninferiority, P<.001; superiority, P=.01).1 The CV mortality rate was lower in the liraglutide group (4.7% vs 6%; HR=0.78; 95% CI, 0.66-0.93; P=.007), as was the all-cause mortality rate (8.2% vs 9.6%; HR=0.85; 95% CI, 0.74-0.97; P=.02).1
Numerical, but not statistically significant, differences in favor of liraglutide were reported in rates of nonfatal MI, nonfatal stroke, heart failure hospitalization, and incidence of pancreatitis.
During a press conference, Bernard Zinman, MD, study investigator with Mount Sinai Hospital, Toronto, also discussed the microvascular outcomes observed in the trial.
“There is a significant reduction of 22% in the development of the renal outcomes with liraglutide compared to placebo,” Dr Zinman said. “With respect to eye events, there is no significant difference [between groups].”
Furthermore, gastrointestinal events were the most frequent adverse events leading to the discontinuation of the study drug.
“The conversation in diabetes care is changing from ‘Let’s work to get your blood sugar controlled’ to ‘We can work to prevent heart attacks, strokes, and death,’” Dr Buse said. “That is a very different message that I hope will inspire doctors, patients, and payers to change their focus in diabetes care.”
Looking ‘Beyond Metformin’
At the press conference, Robert H. Eckel, MD, session moderator from the University of Colorado, Aurora, explained that the majority of clinicians currently agree that under most circumstances, metformin is the drug of choice for patients with type 2 diabetes.
“Now, with EMPA-REG published a year ago and ultimately now LEADER, we have to think beyond metformin in terms of what that second drug of choice might be,” he said.
Dr Eckel added that one of the questions that often comes up in the LEADER and EMPA-REG trials is whether the observed effect is the result of a class effect or the molecule.
“Ultimately, validation of studies like this are incredibly important and studies are ongoing with other [sodium glucose cotransporter-2] inhibitors to see whether or not we can validate EMPA-REG,” he said. “In LEADER, we already have a hint that there is another drug in this class that appears to be beneficial.”
Disclosures: LEADER was funded by Novo Nordisk and grants from the National Institutes of Health. Dr Buse’s is a consultant and stock/shareholder for PhaseBio; has received research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GI Dynamics, Intarcia, J&J, Lexicon, Medtronic, Novo Nordisk, Orexigen, Sanofi, Scion NeuroStim, Takeda, and Theracos; and is an advisor under contract between employer and company for Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, Elycylex, F. Hoffman LaRoche, GI Dynamics, Lexicon, Merck, Metavention, Novo Nordisk, Orexigen, Quest, Takeda, and vTv Therapeutics. Dr Zinman is a consultant for and has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi, and has received grant support from Boehringer Ingelhiem, Novo Nordisk, and AstraZeneca.
Sources
- Marso SP, Daniels GH, Brown-Frandsen KB, et al; for the LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;doi:10.1056/nejmoa1603827.
- 3-CT-SY24 – Results of the Liraglutide Effect and Action in Diabetes—Evaluation of Cardiovascular Outcome Results (LEADER) Trial. Presented at: ADA 76th Scientific Sessions; June 10-14, 2016; New Orleans, LA.
This article originally appeared on Endocrinology Advisor
