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Evevident
Original paper
2016NEJMEndocrinology/Metabolism

LEADER

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

RCTDiabetes / CV outcomes

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Overview

Liraglutide reduced major adverse cardiovascular events and mortality in high-risk T2DM.

Clinical takeaway

LEADER established GLP-1 receptor agonists as outcome-improving agents in T2DM with high cardiovascular risk, beyond A1c lowering.

Key result

Three-point MACE was reduced with liraglutide (HR 0.87; 95% CI 0.78-0.97).

Practice impact

GLP-1 receptor agonists became preferred agents for T2DM with ASCVD or high ASCVD risk.

Evidence

Study design

Randomized, double-blind, placebo-controlled cardiovascular outcomes trial.

Enrollment

9,340

Follow-up

Median 3.8 years.

Geography

Multinational

Clinical question

Does liraglutide improve cardiovascular outcomes in high-risk type 2 diabetes?

Population

  • Patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk.

Intervention

Liraglutide up to 1.8 mg subcutaneously daily.

Comparator

Placebo, both added to standard care.

Primary outcome

Three-point MACE: CV death, nonfatal MI, or nonfatal stroke.

Liraglutide reduced major adverse cardiovascular events compared with placebo in high-risk type 2 diabetes.

Hazard ratio / 0.87 / CI 95% CI 0.78-0.97 / p=0.01

Key results

  • Primary MACE: 13.0% with liraglutide vs 14.9% with placebo; HR 0.87; 95% CI 0.78-0.97; p=0.01 for superiority.
  • Cardiovascular death: 4.7% vs 6.0%; HR 0.78; 95% CI 0.66-0.93; p=0.007.
  • All-cause mortality: 8.2% vs 9.6%; HR 0.85; 95% CI 0.74-0.97.
  • Gastrointestinal adverse events were the most common reason for discontinuing liraglutide.

Harms

  • Gastrointestinal adverse events (nausea, vomiting, diarrhea) were more common and were the leading cause of discontinuation.
  • Acute gallstone disease was more frequent with liraglutide.
  • Acute pancreatitis was numerically, but not significantly, less frequent with liraglutide.

Clinical Use

When to cite

  • When discussing GLP-1 receptor agonists with cardiovascular outcome benefit in high-risk type 2 diabetes.

Practice impact

  • GLP-1 receptor agonists became preferred agents for T2DM with ASCVD or high ASCVD risk.

Applicability

  • Most applicable to patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk.

Limitations

  • Enrolled a high-risk population, so absolute benefit may be smaller in lower-risk patients.
  • Tested daily injectable liraglutide; cardiovascular benefit is not a uniform class effect across all GLP-1 receptor agonists.
  • Median follow-up under 4 years limits inference about very long-term effects.

Common misinterpretations

  • Do not assume every GLP-1 receptor agonist reduces MACE; lixisenatide (ELIXA) was neutral, so benefit is agent-specific.
  • The cardiovascular benefit is largely independent of the modest A1c difference and should not be attributed to glucose lowering alone.

Related evidence

EMPA-REG OUTCOME - Same DiseaseSELECT - Same Drug Class

Citation

Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827

In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.