New England Journal of Medicine JULY 28, 2016

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Steven P. Marso, Gilbert H. Daniels, Kirstine Brown-Frandsen, et al.

Bottom Line

In patients with type 2 diabetes and high cardiovascular risk, the GLP-1 receptor agonist liraglutide significantly reduced the risk of major adverse cardiovascular events and all-cause mortality compared to placebo.

Key Findings

1. The primary composite outcome (CV death, nonfatal MI, or nonfatal stroke) occurred in 13.0% of the liraglutide group versus 14.9% of the placebo group (HR 0.87; 95% CI, 0.78 to 0.97; P=0.01 for superiority) [1.7].

2. Fewer patients died from cardiovascular causes in the liraglutide group (4.7%) than in the placebo group (6.0%) (HR 0.78; 95% CI, 0.66 to 0.93; P=0.007).

3. The rate of death from any cause was lower in the liraglutide group (8.2%) than in the placebo group (9.6%) (HR 0.85; 95% CI, 0.74 to 0.97; P=0.02).

4. The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were numerically, but not significantly, lower in the liraglutide group.

5. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events, while the incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.

Study Design

Design

RCT

Double-Blind

Sample

9,340

Patients

Duration

3.8 yr

Median

Setting

Multicenter, global

Population Adults with type 2 diabetes (HbA1c ≥7.0%) and high cardiovascular risk (age ≥50 with established CVD/CKD, or age ≥60 with ≥1 CV risk factor)

Intervention Liraglutide 1.8 mg (or maximum tolerated dose) administered subcutaneously once daily, added to standard care

Comparator Matching placebo administered subcutaneously once daily, added to standard care

Outcome Time to first occurrence of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-point MACE)

Study Limitations

• The study population was selected for high baseline cardiovascular risk, limiting the generalizability of the findings to lower-risk populations with type 2 diabetes [1.5].

• Follow-up was relatively short (median 3.8 years), leaving long-term cardiovascular and safety outcomes unknown.

• Because it was a cardiovascular outcomes trial, the prespecified primary outcome adjustments did not extend to all exploratory endpoints, increasing the risk of type I errors for secondary outcomes.

• The inclusion of patients already on standard-of-care cardiovascular medications may obscure the precise mechanistic benefit contributed independently by liraglutide.

Clinical Significance

LEADER was a landmark trial establishing the cardiovascular benefits of the GLP-1 receptor agonist liraglutide in patients with type 2 diabetes at high cardiovascular risk. Alongside the EMPA-REG OUTCOME trial for SGLT2 inhibitors, it initiated a paradigm shift in diabetes management, proving that specific glucose-lowering therapies could directly reduce cardiovascular mortality and overall morbidity rather than simply controlling glycemic levels safely.

Historical Context

Following the rosiglitazone controversy in 2007, the FDA mandated cardiovascular safety trials for all new type 2 diabetes drugs to rule out excess cardiovascular risk (non-inferiority). Prior trials of DPP-4 inhibitors and early GLP-1 agonists (like lixisenatide in ELIXA) demonstrated cardiovascular safety but no superiority in event reduction. LEADER, reporting shortly after the groundbreaking EMPA-REG OUTCOME trial, was the first trial of a GLP-1 receptor agonist to demonstrate superiority in reducing major adverse cardiovascular events and mortality, confirming that the cardiovascular benefits observed in modern diabetes medications were not limited to a single drug class.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of liraglutide, and how might its physiological effects explain the reduction in cardiovascular events seen in the LEADER trial?

Key Response

Liraglutide is a GLP-1 receptor agonist. It stimulates glucose-dependent insulin release, suppresses glucagon, slows gastric emptying, and promotes satiety. Beyond glycemic control, it lowers body weight, improves lipid profiles, and reduces blood pressure. It may also have direct endothelial and anti-atherosclerotic effects, all of which likely contribute to the reduction in major adverse cardiovascular events observed in the trial.

Resident

A 65-year-old patient with type 2 diabetes and a history of myocardial infarction is on maximum tolerated metformin, but their A1c remains at 7.8%. Based on the LEADER trial, why should a GLP-1 receptor agonist like liraglutide be prioritized as the next add-on therapy over a sulfonylurea or DPP-4 inhibitor?

Key Response

The LEADER trial demonstrated that liraglutide significantly reduces the risk of MACE and all-cause mortality in patients with T2DM and established cardiovascular disease. Sulfonylureas carry hypoglycemia and weight gain risks without proven CV benefit, and DPP-4 inhibitors are generally neutral regarding CV outcomes. Thus, liraglutide offers a disease-modifying mortality benefit beyond mere glycemic control.

Fellow

In the LEADER trial, the cardiovascular benefits of liraglutide became apparent only after 12 to 18 months of treatment, contrasting with the early divergence of event curves seen in SGLT2 inhibitor trials like EMPA-REG OUTCOME. What differing pathophysiological mechanisms do these distinct temporal patterns suggest?

Key Response

The delayed benefit of liraglutide suggests a primarily anti-atherosclerotic mechanism, such as plaque stabilization, reduction in vascular inflammation, and gradual weight and blood pressure reduction, which takes time to translate into reduced clinical events. In contrast, the early benefit of SGLT2 inhibitors points to rapid hemodynamic effects, such as reduced preload and afterload, osmotic diuresis, and immediate improvements in ventricular loading, which rapidly prevent heart failure exacerbations.

Attending

The LEADER trial showed a mortality benefit for liraglutide, but a significant portion of patients were not on optimal baseline medical therapy, such as high-intensity statins or SGLT2 inhibitors, by modern standards. How does this affect the interpretation of the drug's absolute benefit in a contemporary practice where background risk-factor modification is much more aggressive?

Key Response

If baseline therapy in the trial was suboptimal, the absolute risk reduction of liraglutide might be exaggerated compared to what would be seen in a fully optimized modern patient. However, current consensus and subsequent real-world data support its use, viewing GLP-1RAs as providing an independent, additive, and synergistic cardiovascular benefit on top of modern guideline-directed medical therapy, though the absolute number needed to treat may be higher today.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The LEADER trial was originally designed as a non-inferiority trial to meet FDA safety requirements for diabetes drugs, but transitioned to a superiority analysis when non-inferiority was met. What are the statistical implications of testing for superiority in a non-inferiority framework, and how does a hierarchical testing strategy preserve the study's alpha level?

Key Response

A hierarchical, or closed, testing procedure allows researchers to test for non-inferiority first. If the upper bound of the 95 percent confidence interval for the hazard ratio is below the non-inferiority margin, they can proceed to test for superiority without inflating the family-wise Type I error rate. This approach maximizes the utility of large cardiovascular outcomes trials but requires strict pre-specification in the statistical analysis plan to prevent alpha spending issues.

Journal Editor

The LEADER trial reported a significant reduction in time to first occurrence of MACE. However, the differential discontinuation of the study drug, with more gastrointestinal side effects in the liraglutide group, was notable. How might informative censoring and differential dropouts bias the intention-to-treat analysis of cardiovascular outcomes in this context?

Key Response

If patients who discontinue liraglutide due to GI side effects also have different baseline cardiovascular risks, known as informative censoring, the analysis might be biased. While an intention-to-treat analysis is generally conservative for superiority trials, substantial differential dropouts can dilute the observable treatment effect, biasing the result toward the null. A rigorous peer review would demand robust sensitivity analyses, such as per-protocol or on-treatment analyses, to confirm that early discontinuations did not artificially distort the MACE outcomes.

Guideline Committee

Based on the LEADER trial and subsequent cardiovascular outcome trials, how should current ADA and ACC guidelines recommend the sequencing of GLP-1 receptor agonists versus SGLT2 inhibitors in patients with type 2 diabetes who have established atherosclerotic cardiovascular disease versus those with predominantly heart failure?

Key Response

Current ADA guidelines elevate both GLP-1RAs with proven CV benefit, such as liraglutide, and SGLT2 inhibitors to first-line or add-on therapies independent of A1c in high-risk patients. If ASCVD predominates, a GLP-1RA or SGLT2i with proven benefit is recommended with a Level A strength of evidence, heavily supported by LEADER. If heart failure or CKD predominates, an SGLT2i is preferred due to robust data on reducing HF hospitalizations. LEADER secured the Class I recommendation for GLP-1RAs specifically for the ASCVD-predominant phenotype.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin 10mg or 25mg daily

Population

T2DM patients with established cardiovascular disease

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced the risk of 3-point MACE by 14 percent and cardiovascular death by 38 percent compared to placebo.

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide 0.5mg or 1.0mg weekly

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Semaglutide significantly reduced the risk of the primary composite outcome by 26 percent, driven largely by a significant decrease in nonfatal stroke.

2019

REWIND Trial

n = 9,901 · Lancet

Tested

Dulaglutide 1.5mg weekly

Population

T2DM patients with CV risk factors or previous CV events

Comparator

Placebo

Endpoint

3-point MACE

Key result: Dulaglutide significantly reduced the risk of 3-point MACE by 12 percent across a broad population including primary and secondary prevention cohorts.

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