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 ≥7.0%) who were either age ≥50 with ≥1 established cardiovascular coexisting condition (coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease stage ≥3, or NYHA class II–III heart failure) OR age ≥60 with ≥1 CV risk factor (microalbuminuria/proteinuria, hypertension with LVH, LV systolic or diastolic dysfunction, or ankle-brachial index <0.9).
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, 95% CI 0.75–1.03, P=0.11) and nonfatal stroke (HR 0.89, 95% CI 0.72–1.11, P=0.30) 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 events were the most common cause of permanent discontinuation (nausea 1.6% vs 0.4%, vomiting 0.7% vs <0.1%, diarrhea 0.6% vs 0.1%; all P<0.001). Acute pancreatitis was similar (0.4% vs 0.5%, P=0.44). Acute gallstone disease was more frequent with liraglutide (3.1% vs 1.9%, P<0.001). No episodes of medullary thyroid carcinoma occurred in the liraglutide group.
- 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.
- 72.4% (6764/9340) had established cardiovascular disease and 81.3% (7598/9340) had established CVD, CKD stage ≥3, or both — the trial was overwhelmingly a secondary prevention population.
- NNT of 66 over 3 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
- No benefit and possibly harm was seen in the primary-prevention subgroup (age ≥60 with risk factors only): HR 1.20 (0.86–1.67), interaction P=0.04 — cardiovascular benefit was concentrated in patients with established CVD.
- Permanent discontinuation for adverse events was higher with liraglutide (9.5% vs 7.3%, P<0.001), driven by GI events — a real-world tolerability limit that may bias per-protocol estimates.
- GI side effects were common causes of discontinuation (nausea, vomiting, diarrhea all P<0.001) and may have unblinded patients and investigators, compromising the double-blind design.
- Open-label placebo 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, though NIH also contributed funding.
- Cannot determine whether the CV benefit is mediated by glucose lowering, weight loss, anti-inflammatory effects, or direct vascular mechanisms.
- Numerical excess of pancreatic carcinoma (13 vs 5, P=0.06) and acute gallstone disease (P<0.001) with liraglutide represent residual safety signals despite reassuring pancreatitis rates.
- 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.