LEADER
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
Year of Publication: 2016
Authors: Steven P. Marso, Gilles R. Driessen, Søren E. Buse, et al.
Journal: New England Journal of Medicine
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.
PDF: Clinical Question
Does liraglutide reduce major cardiovascular events in patients with type 2 diabetes at high cardiovascular risk compared with placebo?
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.
Design
Study Type: Multicenter, randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind
Enrollment Period: September 2010 to April 2015
Follow-up Duration: Median 3.8 years
Centers: 410
Countries: 32 countries globally
Sample Size: 9340
Analysis: Time-to-event analysis using Cox proportional hazards model
Inclusion Criteria
- Adults with type 2 diabetes (HbA1c ≥7.0%)
- Age ≥50 years with established cardiovascular disease, or age ≥60 years with CV risk factors
Exclusion Criteria
- Type 1 diabetes
- Personal/family history of medullary thyroid carcinoma or MEN2
- eGFR <30 ml/min/1.73 m²
- Recent MI or stroke (<14 days)
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age (mean) | 64.2 | 64.3 |
| Female (%) | 36% | 35% |
| HbA1c (%) | 8.7 | 8.7 |
| BMI (kg/m²) | 32.5 | 32.5 |
| eGFR (ml/min/1.73m²) | 80.6 | 80.9 |
| History of CV disease | 81.3% | 81.1% |
| Insulin use (%) | 44% | 43% |
Arms
| Field | Liraglutide | Control |
|---|---|---|
| Intervention | 1.8 mg liraglutide daily subcutaneous injection (or max tolerated dose) | Matching placebo injection |
| Duration | Median 3.8 years | Median 3.8 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-point MACE) | Primary | 14.9% | 13.0% | 0.87 | 0.01 |
| Death from cardiovascular causes | Secondary | 6.0% | 4.7% | 0.78 | 0.007 |
| All-cause mortality | Secondary | 8.2% | 6.0% | 0.85 | 0.02 |
| Nonfatal MI | Secondary | 6.8% | 6.0% | 0.88 | NS |
| Nonfatal stroke | Secondary | 3.4% | 3.1% | 0.89 | NS |
| Nausea | Adverse | 21.3% (liraglutide) vs 8.6% (placebo) | |||
| Vomiting | Adverse | 9.2% vs 3.5% | |||
| Diarrhea | Adverse | 13.3% vs 7.6% | |||
| Pancreatitis | Adverse | Low and similar between groups | |||
| Thyroid cancer | Adverse | Rare; no significant increase |
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.
Funding
Novo Nordisk
Based on: LEADER (New England Journal of Medicine, 2016)
Authors: Steven P. Marso, Gilles R. Driessen, Søren E. Buse, et al.
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.
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