NEW ORLEANS — Patients with type 2 diabetes and a history of cardiovascular disease assigned Victoza therapy saw reduced risk for cardiovascular death, nonfatal myocardial infarction and stroke vs. those assigned a placebo, according to an analysis of the LEADER trial results presented at the American Diabetes Association Scientific Sessions.
Results from the Liraglutide Effect and Action in Diabetes — Evaluation of Cardiovascular Outcome Results (LEADER) trial, conducted at 410 sites in 32 countries, showed that, over a mean of 3.8 years, the glucagon-like peptide 1 receptor agonist Victoza (liraglutide, Novo Nordisk), reduced 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.
John B. Buse
The CV results were a surprise to investigators, who predicted liraglutide’s CV benefit would be noninferior to placebo.
“When we started this trial, it was fundamentally designed to assess cardiovascular safety,” John Buse, MD, PhD, the Verne S. Caviness distinguished professor and chief, division of endocrinology at University of North Carolina School of Medicine in Chapel Hill, said during a press conference. “It was beyond our expectations that we would be able to demonstrate cardiovascular efficacy.”
In a double blind, randomized controlled trial, researchers analyzed data from 9,340 patients aged at least 50 years with poorly controlled type 2 diabetes (HbA1c of 7% or greater) who were taking any combination of oral antidiabetic therapy and/or basal or premixed insulin, or were drug naïve. Participants had 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). Participant characteristics were similar across groups (mean age, 64 years; 64% men; mean diabetes duration, 13 years; mean HbA1c, 8.7%; mean BMI, 32.5 kg/m²); 73% had prior CVD. Researchers assessed patients at 1, 3 and 6 months, then every 6 months for up to 5 years.
Primary outcome was the time to first occurrence of 3-point major adverse cardiac event (CV death, nonfatal MI or nonfatal stroke); secondary outcomes included time to first occurrence of expanded composite CV outcome, which included coronary revascularization, unstable angina or hospitalization for heart failure, as well as all-cause death and each individual component of CV outcome.
Patients were treated to a target HbA1c of 7% or less (individualized depending on patient), target blood pressure of 130/80 mm Hg, target LDL cholesterol of less than 100 mg/dL (or less than 70 mg/dL in patients with prior CV events) and aspirin therapy for patients with prior CV events.
Over a mean follow-up period of 3.8 years, fewer patients in the liraglutide group experienced a primary CV outcome 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.
“If you look at the Kaplan Meier curve, there’s early separation [between groups] that becomes very apparent by 12 months, and the lines continue to diverge over time, suggesting a sustained benefit for liraglutide therapy in this population,” Steven Marso, MD, medical director of interventional cardiology and professor of medicine at University of Texas Southwestern Medical Center in Dallas, said during a press conference.
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).
Patients assigned liraglutide also experienced fewer myocardial infarctions vs. placebo (6.3% vs. 7.3%) for a 14% relative risk reduction, Marso said. There was also a “remarkable consistency of benefit” for stroke, Marso said, with patients in the liraglutide group experiencing a 14% relative risk reduction (3.4% vs. 3.8%). Hospitalization for heart failure was also lower in the liraglutide group, with a rate of 4.7% vs. 5.3%.
“If you step back ... what’s striking is the consistency in the relative risk reduction in all the major cardiovascular endpoints that we measured in LEADER,” Marso said.
Over the study period, patients assigned liraglutide also experienced a greater reduction in HbA1c (estimated treatment difference, –0.4%; 95% CI, –0.45 to –0.34), body weight (ETD = –2.3 kg; 95% CI, –2.5 to –2) and what Zinman called a “small, but significant and maintained” reduction in systolic blood pressure (ETD = 1.2 mm Hg; 95% CI, 1.9-0.5), and diastolic blood pressure (ETD = 0.6 mm Hg; 95% CI, 0.2-1). There was a sustained increase in pulse of approximately 3 beats per minute in the liraglutide group, according to researchers.
Looking at microvascular complications, researchers also found that patients in the liraglutide group experienced a 22% reduction in renal events (HR = 0.78; 95% CI, 0.67-0.92) and an increase in adverse eye events (HR = 1.15; 95% CI, 0.87-1.52).
Among liraglutide patients, 1.5% more experienced any adverse event vs. placebo patients, with most attributed to nausea. There was no between-group statistical significance for serious adverse events.
“Pancreatitis was the big concern with this class,” Buse said, adding there were numerically fewer cases of pancreatitis with liraglutide vs. placebo; two cases of chronic pancreatitis occurred in placebo patients. Acute gallstone disease, too, has been previously reported with liraglutide, and Buse noted there was a “statistically significant imbalance” between groups (3.1% vs. 1.9%).
Importance of glucose management
Following the presentation, Buse said that the results put the importance of glucose management into greater perspective.
“I think, after ACCORD, in some communities, particularly in the cardiology community, there was a sense that managing glucose wasn’t that important,” Buse told Endocrine Today. “I think this trial, part along with the EMPA-REG trial, puts it in a different perspective. The kind of benefits in EMPA-REG and in LEADER are like the benefits that are seen for the most important CV drugs. So, it changes the conversation, which is arguably the most important thing about the patient and colleague interaction.”
The mechanism behind the CV benefits of liraglutide are “hard to pin down,” Buse said, but he speculated that the effects may have to do with endothelium-derived relaxing factor on blood vessels or plaque stability.
“If I had to guess, ground zero for the liraglutide effect, it’s the endothelium and plaque stability,” Buse said.
Speaking after the presentation, Matthew Riddle, MD, professor of medicine at Oregon Health and Science University, called the trial “well designed and well executed with encouraging and even exciting results.”
“I think what you have heard today is a big deal,” Riddle said. “We are now entering the era where treatment of hyperglycemia and other metabolic abnormalities of diabetes can have short-term as well as what we believe to be long-term favorable effects on cardiovascular outcomes.”
LEADER results were published online in the New England Journal of Medicine. – by Regina Schaffer
Marso SP, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1603827. Presented at: American Diabetes Association Scientific Sessions; June 10-14, 2016; New Orleans.
Disclosure: Novo Nordisk and the National Institutes of Health supported this study. Please see the full study for the authors’ relevant financial disclosures.