FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Liraglutide is associated with a decreased risk of cardiovascular events, compared with placebo, in individuals with type 2 diabetes, according to results from the randomized, placebo-controlled, double-blind LEADER trial.
In the 9,340 patients with type 2 diabetes in LEADER, those treated with the glucagonlike peptide–1 (GLP-1) analogue liraglutide had a 13% lower risk of a composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke over a median follow-up of 3.8 years (hazard ratio, 0.87; 95% confidence interval, 0.78-0.97; P less than .001 for noninferiority; P = .01 for superiority).
This significant reduction in the primary outcome in LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) makes liraglutide (Victoza) the second antihyperglycemic drug to be shown to reduce cardiovascular outcomes since the Food and Drug Administration mandated that all such agents be tested in such a way in 2008. The first was the sodium-glucose cotransporter–2 inhibitor empagliflozin, which reduced the risk of the composite endpoint of hospitalization for heart failure or death due to cardiovascular disease by 34% in the EMPA-REG OUTCOME trial ( N Engl J Med. 2015;373:2117-28 ).
In LEADER, the rate of death from cardiovascular causes was 22% lower in the liraglutide group than in the placebo group (95% CI, 0.66-0.93; P = .007). However, the lower incidences of nonfatal MI, stroke, and hospitalization for heart failure in the liraglutide group did not reach statistical significance.
The participants in LEADER all had a hemoglobin A1c level of 7.0%, and were either aged over 50 with at least one cardiovascular condition such as coronary heart disease, or aged over 60 with at least one cardiovascular risk factor such as hypertension or microalbuminuria.
The participants, who were recruited from 410 sites in 32 countries, were randomized to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to equivalent placebo, in addition to standard care ( N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827 ).
“Although glycemic control is associated with reductions in the risk of microvascular complications, the macrovascular benefits of glycemic control are less certain,” wrote Dr. Steven P. Marso of the University of Texas Southwestern Medical Center, Dallas, and his coauthors.
“Furthermore, concern has been raised about the cardiovascular safety of antihyperglycemic therapies, [and] consequently, regulatory authorities have mandated cardiovascular safety assessments of new diabetes treatments.”
The study did see a significant interaction between liraglutide and renal function. Patients who had an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m2 showed more benefits from the liraglutide in terms of the primary outcomes than did those with an eGFR of at least 60 mL/min.
Individuals aged over 50 years with established cardiovascular disease also showed greater benefits in reductions in the primary outcome from liraglutide than did patients aged over 60 years with cardiovascular risk factors.
The authors commented that their findings contrast with those of the Lixisenatide in Acute Coronary Syndrome (ELIXA) trial using the shorter-acting and structurally dissimilar GLP-1 receptor agonist lixisenatide. This trial failed to show any cardiovascular benefit of the drug in patients with diabetes and a recent acute coronary syndrome, as did several other trials looking at cardiovascular outcomes in high-risk patients with type 2 diabetes treated with drugs including insulin, thiazolidinediones, and dipeptidyl peptidase–4 inhibitors.
“Our trial had greater statistical power and included patients with a higher baseline glycated hemoglobin level than did most previous studies,” the authors wrote. “However, no obvious single explanation in terms of either the study designs or the included populations is apparent to explain the divergent findings across this body of medical literature.
The study also examined the incidence of adverse events, finding a nonsignificantly higher overall rate of benign or malignant neoplasms with liraglutide, compared with placebo. However, there was a trend toward an increased risk of pancreatic cancer in those taking liraglutide, which approached statistical significance.
“There has been considerable interest in a potential association between the use of GLP-1 receptor agonists and pancreatitis and pancreatic cancer, although there is no consistent preclinical, pharmacovigilance, or epidemiologic evidence to date,” the authors commented.
The study was supported by Novo Nordisk and the National Institutes of Health. Several authors declared grants, consultancies and funding from the pharmaceutical industry, including from Novo Nordisk. Several authors are employees of Novo Nordisk, are on steering committees, and/or own shares in the company.
