Endocrinology · 2016
LEADER
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
In 2008, the FDA issued guidance requiring all manufacturers of new glucose-lowering drugs to demonstrate cardiovascular safety before and after approval. The requirement followed evidence that rosiglitazone, a widely used thiazolidinedione, increased myocardial infarction risk. What regulators asked for was non-inferiority, not superiority. The assumption embedded in the requirement was that newer agents would at best do no harm. The GLP-1 receptor agonist class, which had been introduced for its incretin-based glucose lowering and modest weight loss, had not been expected to improve cardiovascular outcomes.
LEADER enrolled 9,340 adults with type 2 diabetes and high cardiovascular risk across 410 sites in 32 countries. Participants were randomized to once-daily subcutaneous liraglutide 1.8 mg or matching placebo and followed for a median of 3.8 years. Steven Marso of the HCA Midwest Health Heart and Vascular Institute was the first author, and John Buse of the University of North Carolina served as a senior investigator. The primary endpoint, a three-point MACE composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, was reduced by 13% in the liraglutide arm. Cardiovascular death alone fell by 22%.
The trial achieved superiority, not just non-inferiority, separating it clearly from the neutral results of saxagliptin in SAVOR-TIMI 53 and alogliptin in EXAMINE. An earlier GLP-1 trial, ELIXA with lixisenatide, had been neutral, making LEADER's positive result class-specific rather than universal. The benefit signal for liraglutide appeared driven primarily by the atherosclerotic component, cardiovascular death and MI, rather than heart failure hospitalization, a contrast with EMPA-REG OUTCOME published the same year.
Debate about mechanism centered on whether liraglutide's benefit reflected direct cardiac effects, the drug's anti-inflammatory properties, weight loss, blood pressure reduction, or favorable effects on lipids and renal function. The drug produced modest but consistent reductions in systolic pressure, HbA1c, body weight, and albuminuria across the trial population. Parsing which of those effects drove the mortality reduction proved difficult, as liraglutide affected all of them simultaneously.
The American Diabetes Association responded by revising its Standards of Medical Care algorithm in subsequent years, listing liraglutide and other agents with proven cardiovascular benefit as preferred second-line therapy for patients with established atherosclerotic cardiovascular disease, independent of their glucose-lowering effect. That positioning, based on outcomes data rather than HbA1c reduction, represented a change in how diabetes medications were categorized and selected. Later trials of semaglutide, dulaglutide, and albiglutide extended the cardiovascular benefit further across the GLP-1 class, though results were not uniform.
Key People
- Steven Marso — First author; designed and ran the LEADER outcomes trial
- John Buse — Senior investigator; helped translate results into guideline recommendations
- Lasse Kober — Co-investigator; contributed to cardiovascular endpoint adjudication
- Michael Nauck — GLP-1 pharmacology expert; contributed to mechanistic interpretation
N Engl J Med. 2016;375(4):311-322.
Related landmarks
- 2015 · EMPA-REG OUTCOME (Endocrinology)
- 2021 · STEP 1 (Semaglutide for Obesity) (Endocrinology)
- 2022 · SURMOUNT-1 (Tirzepatide for Obesity) (Endocrinology)
- 2023 · SELECT (Semaglutide Cardiovascular Outcomes in Obesity) (Endocrinology)