PDF: LEADER
(2016)Objective
Liraglutide – To evaluate cardiovascular safety and efficacy of liraglutide in patients with type 2 diabetes at high cardiovascular risk.
Study Summary
• Stroke risk was numerically lower but not statistically significant.
Intervention
Randomized, double-blind, placebo-controlled trial. Patients with type 2 diabetes and high cardiovascular risk were randomized to receive liraglutide (up to 1.8 mg daily) or placebo, both on top of standard care, with median follow-up of 3.8 years.
Inclusion Criteria
Patients with type 2 diabetes (HbA1c ≥7%) and either established cardiovascular disease, chronic kidney disease, or at least one CV risk factor (age ≥60, albuminuria, hypertension with LVH, or dyslipidemia).
Study Design
Arms: Liraglutide vs. Placebo
Patients per Arm: Liraglutide: 4668; Placebo: 4672
Outcome
• Non-fatal stroke: 3.4% (liraglutide) vs. 3.8% (placebo); HR 0.89 (95% CI 0.72–1.11); not statistically significant.
• CV death: HR 0.78 (95% CI 0.66–0.93); P=0.007.
• All-cause death: HR 0.85 (95% CI 0.74–0.97); P=0.02.
Bottom Line
Liraglutide significantly reduced the risk of major cardiovascular events and all-cause mortality in high-risk type 2 diabetes patients, supporting its role in cardiovascular risk reduction.
Major Points
- Landmark trial establishing liraglutide (GLP-1 RA) as the first diabetes drug to demonstrate cardiovascular benefit beyond glucose lowering: 9,340 patients across 410 centers in 32 countries.
- Liraglutide reduced 3-point MACE by 13% (13.0% vs 14.9%, HR 0.87, 95% CI 0.78–0.97, P=0.01) — the first injectable GLP-1 RA superiority result for CV outcomes.
- Significant reduction in CV death (HR 0.78, P=0.007) and all-cause mortality (HR 0.85, P=0.02) — one of the few diabetes trials to show a mortality benefit.
- Nonfatal MI (HR 0.88) and nonfatal stroke (HR 0.89) showed favorable but non-significant trends — the MACE benefit was primarily driven by CV death reduction.
- Benefit observed on top of standard-of-care therapies including statins, antihypertensives, and antiplatelets — demonstrating incremental value of GLP-1 RA therapy.
- GI side effects were common (nausea 21.3%, diarrhea 13.3% vs 7.6%) but no increased risk of pancreatitis, pancreatic cancer, or thyroid cancer — allaying key safety concerns.
- Together with SUSTAIN 6 (semaglutide injectable) and PIONEER 6/SOUL (semaglutide oral), established the GLP-1 RA class as a pillar of cardiovascular risk reduction in T2DM.
- Changed ADA/EASD guidelines: GLP-1 RAs recommended as first injectable after metformin in T2DM patients with established ASCVD, independent of HbA1c level.
- 81% of patients had established CVD at baseline — results are strongest for secondary prevention; primary prevention benefit less certain.
- NNT of 53 over 3.8 years to prevent one MACE event — clinically meaningful given the also-observed mortality reduction.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 9340
- Follow-up
- Median 3.8 years
- Centers
- 410
- Countries
- 32 countries globally
Primary Outcome
Definition: Time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-point MACE)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 14.9% | 13.0% | 0.87 (0.78–0.97) | 0.01 |
Limitations & Criticisms
- Exclusion of patients with advanced CKD (eGFR <30) limits generalizability to a high-risk population that may benefit most from cardiovascular protection.
- Higher dropout rate in placebo group could bias intent-to-treat results — more placebo patients discontinued and potentially received open-label GLP-1 RAs.
- GI side effects were common (nausea 21.3%, vomiting 9.2%) and may have unblinded patients and investigators, compromising the double-blind design.
- Open-label run-in period may introduce selection bias by excluding patients with poor adherence or GI intolerance before randomization.
- MACE benefit driven primarily by CV death — nonfatal MI and stroke reductions were not individually significant, raising questions about the breadth of cardiovascular protection.
- Industry-sponsored by Novo Nordisk (liraglutide manufacturer) — potential bias in trial design, conduct, and publication strategy.
- Cannot determine whether the CV benefit is mediated by glucose lowering, weight loss, anti-inflammatory effects, or direct vascular mechanisms.
- Underrepresentation of women (35–36%) and certain ethnic groups limits generalizability.
- Daily subcutaneous injection requirement may limit real-world adherence compared to the controlled trial setting.
Citation
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375:311–322.