LEADER shows liraglutide cuts cardiovascular death

Results from the LEADER trial, published June 13, 2016, showed that the GLP-1 receptor agonist liraglutide reduced major cardiovascular events in people with type 2 diabetes and high cardiovascular risk, and also lowered deaths from cardiovascular causes and from any cause ^[1]. It was the first trial of a drug in this class to show that kind of survival benefit.

The trial randomly assigned 9,340 patients to liraglutide or placebo on top of standard care, in a double-blind design, and followed them for a median of 3.8 years ^[1]. The main outcome was the first occurrence of death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke ^[1].

The numbers

That main outcome happened in 608 of 4,668 patients taking liraglutide (13.0%) versus 694 of 4,672 on placebo (14.9%) — a hazard ratio of 0.87, with a 95% confidence interval of 0.78 to 0.97 ^[1]. The trial was designed first to prove liraglutide was no worse than placebo, using a margin of 1.30 for the upper edge of that confidence interval; it cleared that bar (P<0.001) and also met the tougher test of superiority (P=0.01) ^[1].

Deaths from cardiovascular causes occurred in 219 liraglutide patients (4.7%) versus 278 on placebo (6.0%), a hazard ratio of 0.78 (95% CI, 0.66 to 0.93; P=0.007) — the roughly 22% relative reduction that drew the most attention ^[1]. Death from any cause was also lower: 381 patients (8.2%) versus 447 (9.6%), hazard ratio 0.85 (95% CI, 0.74 to 0.97; P=0.02) ^[1].

The individual pieces were less dramatic. Rates of nonfatal heart attack, nonfatal stroke and hospitalization for heart failure were all lower with liraglutide, but not to a statistically significant degree ^[1]. The authors also note that no adjustments for multiple comparisons were made for the prespecified exploratory outcomes, which is a reason to read the individual secondary numbers, including the mortality findings, with some caution ^[1].

On safety, the most common adverse events that caused people to stop liraglutide were gastrointestinal — the nausea-and-vomiting profile familiar to anyone who has read about this drug class ^[1]. Pancreatitis was numerically less common in the liraglutide group, but not significantly so ^[1]. The trial was funded by Novo Nordisk and the National Institutes of Health and is registered as NCT01179048 ^[1].

Why it matters for patients

For years, diabetes drugs were judged mainly on how much they lowered blood sugar, and regulators required new ones to prove they did not increase heart risk. LEADER moved a GLP-1 drug from "does no harm to the heart" to "reduces cardiovascular events and deaths" in a high-risk population ^[1]. That reframes what these medicines are for, and it is the evidence base that later conversations about GLP-1s and heart protection are built on.

The practical translation matters, though. Over about 3.8 years, the absolute difference in the main outcome was 1.9 percentage points — 13.0% versus 14.9% ^[1]. The people studied had type 2 diabetes and high cardiovascular risk ^[1]. The trial does not tell us what happens in people without diabetes, in people taking these drugs primarily for weight, or with other molecules such as semaglutide (Ozempic, Wegovy, Rybelsus) or tirzepatide (Mounjaro, Zepbound) — none of which were tested here ^[1]. Those questions were not answered by LEADER and are not addressed in this source.

The trial also does not report how the benefit was produced. Whether it comes from blood sugar, blood pressure, weight, or a direct effect on blood vessels is not established in this report ^[1].

What happens next

The findings drew immediate commentary in the medical literature, including an editorial in the New England Journal of Medicine published July 28, 2016, and a series of letters and responses from the LEADER steering committee published November 3, 2016 ^[1]. Anyone weighing what LEADER means for their own treatment would take that up with their clinician.