Liraglutide lowered cardiovascular events and death in high-risk type 2 diabetes trial

Liraglutide, a GLP-1 receptor agonist, reduced heart attacks, strokes and cardiovascular deaths when added to standard care in people with type 2 diabetes at high cardiovascular risk, according to results of the LEADER trial published in June 2016 ^[1].

The trial randomly assigned 9,340 patients to liraglutide or placebo and followed them for a median of 3.8 years ^[1]. It was double-blind, meaning neither the patients nor their doctors knew which treatment was given ^[1]. The main outcome measured was the first occurrence of death from cardiovascular causes, a nonfatal heart attack or a nonfatal stroke ^[1].

That combined outcome occurred in 608 of 4,668 patients taking liraglutide (13.0 percent) and 694 of 4,672 taking placebo (14.9 percent) ^[1]. The hazard ratio was 0.87, with a 95 percent confidence interval of 0.78 to 0.97 ^[1]. The trial was designed to test whether liraglutide was at least as good as placebo, a test called noninferiority, and it met that bar with P<0.001; it also met the stricter test for superiority, with P=0.01 ^[1].

Death from cardiovascular causes was less common in the liraglutide group: 219 patients (4.7 percent) versus 278 (6.0 percent) on placebo, a hazard ratio of 0.78 that works out to a 22 percent relative reduction ^[1]. Death from any cause was also lower: 381 patients (8.2 percent) versus 447 (9.6 percent), hazard ratio 0.85 ^[1]. The report states that no statistical adjustment was made for multiple comparisons on these prespecified exploratory outcomes ^[1].

Rates of nonfatal heart attack, nonfatal stroke and hospitalization for heart failure were each lower with liraglutide, but the differences were not statistically significant ^[1]. The side effects most often leading patients to stop liraglutide were gastrointestinal ^[1]. Pancreatitis occurred less often in the liraglutide group, a difference the report describes as not significant ^[1]. The trial was funded by Novo Nordisk and the National Institutes of Health and registered as NCT01179048 ^[1].

Why it matters for patients

Before this trial, the cardiovascular effect of adding liraglutide to standard care in type 2 diabetes was unknown ^[1]. The results matter because they measured heart attacks, strokes and deaths, not just blood sugar numbers, in a group already at high risk of heart problems ^[1].

The size of the benefit is modest in absolute terms. The main outcome difference was 1.9 percentage points over a median of 3.8 years, meaning roughly two fewer events for every 100 people treated for that period ^[1]. The larger relative figure, a 22 percent drop in cardiovascular deaths, describes how much the risk fell compared with placebo, not how many people were spared an event ^[1].

Everyone in LEADER had type 2 diabetes and high cardiovascular risk, so the findings apply most directly to that group ^[1]. Whether similar cardiovascular protection applies to people who take GLP-1 medicines mainly for weight loss, or to people at lower heart risk, has not been reported here ^[1]. The report also does not say how much of the benefit came from blood sugar lowering rather than other effects of the drug, and it does not state whether any other GLP-1 medicine had shown a mortality benefit before this trial ^[1].

Liraglutide was given on top of each patient's existing care, so the results describe an add-on treatment rather than a replacement for other heart risk management ^[1].

What is not yet known

The published report does not include data on how long any benefit lasts after treatment stops, whether the effect holds in people without diabetes, or how liraglutide compares head-to-head with other GLP-1 medicines ^[1]. Those questions have not been answered in this trial report ^[1].