LEADER Results in Detail: Numbers, Subgroups, and Time Course

By
Published Updated Last reviewed
GLP-1 medication and metabolic health image for LEADER Results in Detail: Numbers, Subgroups, and Time Course

At a glance

Why the Primary Endpoint Matters Beyond the Headline

Before LEADER published in June 2016, no GLP-1 receptor agonist had demonstrated cardiovascular superiority in a dedicated outcomes trial. The FDA's 2008 guidance for diabetes drugs required proof of cardiovascular safety (ruling out a hazard ratio upper bound above 1.3), but LEADER went further by showing actual benefit. This distinction shifted clinical practice: liraglutide became the first GLP-1 RA to carry an indication for reducing cardiovascular events in its FDA prescribing label.

Primary Endpoint: Dissecting the 13% MACE Reduction

The three-point MACE composite occurred in 608 of 4,668 patients (13.0%) in the liraglutide group and 694 of 4,672 patients (14.9%) in the placebo group. The event rates per 100 patient-years were 3.4 and 3.9, respectively.

| Component | Liraglutide (n/rate per 100 PY) | Placebo (n/rate per 100 PY) | HR (95% CI) | |---|---|---|---| | Three-point MACE (primary) | 608 / 3.4 | 694 / 3.9 | 0.87 (0.78, 0.97) | | Cardiovascular death | 219 / 1.2 | 278 / 1.6 | 0.78 (0.66, 0.93) | | Nonfatal MI | 281 / 1.6 | 317 / 1.8 | 0.88 (0.75, 1.03) | | Nonfatal stroke | 159 / 0.9 | 177 / 1.0 | 0.89 (0.72, 1.11) |

The primary publication shows that the MACE benefit was driven most strongly by the cardiovascular death component (HR 0.78 to 95% CI 0.66 to 0.93), which reached statistical significance on its own. Nonfatal MI and nonfatal stroke trended favorably but did not individually cross the significance threshold. This pattern is unusual among cardiovascular outcomes trials, where reductions in nonfatal events (especially MI) more commonly drive the composite.

Time-Course Pattern: When Did the Curves Separate?

The Kaplan-Meier curves for the primary endpoint did not diverge immediately. Visual inspection of the published survival curves reveals three distinct phases:

Phase 1 (0 to 12 months): The curves overlapped almost entirely. Event rates were nearly identical between groups during this early period. This lag is consistent with the hypothesis that liraglutide's cardiovascular benefit stems from chronic metabolic improvements (weight loss, glycemic control, blood pressure reduction, lipid changes) rather than an acute anti-ischemic or antithrombotic mechanism.

Phase 2 (12 to 30 months): Gradual separation began. The liraglutide curve started to pull below placebo, with the gap widening progressively. By 24 months, a consistent and visible difference had emerged.

Phase 3 (30 to 60 months): The separation stabilized and persisted through end of follow-up. The benefit did not appear to accelerate or attenuate over time during this later period, suggesting a sustained rather than time-limited effect.

This time-course pattern has practical implications for treatment decisions. Clinicians should not expect rapid cardiovascular risk reduction from liraglutide in the first year. The 2019 ADA/EASD consensus report incorporated this evidence, recommending GLP-1 RAs with proven benefit for patients with established atherosclerotic cardiovascular disease regardless of baseline HbA1c.

Secondary and Exploratory Endpoints

Beyond the primary composite, LEADER pre-specified several secondary endpoints tested in a hierarchical sequence.

| Endpoint | Liraglutide | Placebo | HR (95% CI) | |---|---|---|---| | Expanded MACE (MACE + coronary revascularization, hospitalization for unstable angina, hospitalization for heart failure) | 948 (20.3%) | 1,062 (22.7%) | 0.88 (0.81, 0.96) | | All-cause mortality | 381 (8.2%) | 447 (9.6%) | 0.85 (0.74, 0.97) | | Cardiovascular death | 219 (4.7%) | 278 (6.0%) | 0.78 (0.66, 0.93) | | Nonfatal MI | 281 (6.0%) | 317 (6.8%) | 0.88 (0.75, 1.03) | | Nonfatal stroke | 159 (3.4%) | 177 (3.8%) | 0.89 (0.72, 1.11) | | Hospitalization for heart failure | 218 (4.7%) | 248 (5.3%) | 0.87 (0.73, 1.05) | | Coronary revascularization | 368 (7.9%) | 397 (8.5%) | 0.91 (0.79, 1.05) |

All-cause mortality reached significance (HR 0.85 to 95% CI 0.74 to 0.97), making LEADER one of the few diabetes drug trials to show a mortality signal. Heart failure hospitalization did not reach significance, a finding that contrasts with the SGLT2 inhibitor trials like EMPA-REG OUTCOME where heart failure reduction was a prominent benefit.

Metabolic Changes: Mediators or Markers?

The trial recorded several metabolic parameters that may partially explain the cardiovascular findings.

| Parameter | Liraglutide vs. Placebo (estimated difference at 36 months) | |---|---| | HbA1c | −0.40 percentage points | | Body weight | −2.3 kg | | Systolic blood pressure | −1.2 mmHg | | Heart rate | +3.0 bpm | | LDL cholesterol | No significant difference |

The HbA1c difference was modest and narrowed over time as investigators could intensify background therapy in both arms. Post hoc mediation analyses published subsequently suggested that HbA1c reduction explained only a fraction of the MACE benefit, pointing toward direct vascular or anti-inflammatory effects of GLP-1 receptor agonism. The heart rate increase of approximately 3 bpm was a consistent finding across GLP-1 RA trials and did not appear to translate into arrhythmic risk within the trial's follow-up window.

Subgroup Analyses: Who Benefited Most?

LEADER pre-specified subgroup analyses across 17 baseline characteristics. The primary publication's forest plot showed no statistically significant treatment-by-subgroup interactions, but several patterns merit attention.

By cardiovascular disease history: Patients with established cardiovascular disease at baseline (about 81% of participants) had a numerically larger benefit (HR 0.83) compared to those with cardiovascular risk factors only (HR 1.20). This contrast did not reach formal interaction significance (p = 0.10), but it influenced guideline recommendations to prioritize GLP-1 RAs for patients with established disease.

By baseline HbA1c: The MACE reduction appeared consistent across HbA1c categories (above and below 8.3%), suggesting the benefit was not simply a glucose-lowering effect.

By baseline BMI: The benefit did not vary significantly by BMI tertile, arguing against weight loss as the sole mediator.

By age: Patients aged 60 years and older showed consistent benefit, an important finding given that this demographic carries the highest absolute cardiovascular risk.

By renal function: Patients with eGFR <60 mL/min/1.73 m² had a numerically larger MACE reduction. This finding was later supported by the dedicated LEADER renal sub-study, which demonstrated that liraglutide slowed nephropathy progression (HR 0.78 to 95% CI 0.67 to 0.92).

Limitations the Authors Acknowledged

The LEADER investigators and subsequent commentators identified several constraints worth noting.

Enriched population. Over 80% of participants had established cardiovascular disease. Extrapolating the 13% MACE reduction to lower-risk type 2 diabetes populations requires caution, and the point estimate for the risk-factor-only subgroup did not favor liraglutide.

Concomitant therapy changes. Investigators could adjust background glucose-lowering medications throughout the trial. Fewer liraglutide-arm patients required insulin initiation or addition of other agents, which complicates attribution of the cardiovascular benefit to liraglutide alone.

Discontinuation rates. Approximately 25% of patients in the liraglutide arm and 24% in the placebo arm permanently discontinued the study drug. In the liraglutide group, gastrointestinal adverse events (nausea, vomiting, diarrhea) were the most common reason for early discontinuation.

No active comparator. The trial compared liraglutide to placebo, not to another active glucose-lowering agent. Whether the cardiovascular benefit would persist against, say, an SGLT2 inhibitor has not been tested head-to-head.

Event adjudication. All suspected cardiovascular events were adjudicated by an independent committee blinded to treatment assignment. While this is standard practice, the modest absolute risk reduction (1.9 percentage points for MACE over 3.8 years) means that small changes in adjudication could shift results.

LEADER in Context: How It Compares to Later GLP-1 CVOTs

LEADER was the first positive GLP-1 RA cardiovascular outcomes trial, but it was not the last. The SUSTAIN-6 trial (semaglutide, 2016) showed a 26% MACE reduction over just 2.1 years with a smaller sample of 3,297 patients, though that trial was powered only for noninferiority. The 2019 REWIND trial (dulaglutide) showed a 12% MACE reduction in a broader population with only 31% having established cardiovascular disease.

Taken together, these trials established a class effect for GLP-1 RAs on atherosclerotic cardiovascular events. LEADER's contribution was foundational: it provided the first proof of concept and remains the largest completed GLP-1 RA cardiovascular outcomes trial by enrollment.

Practical Takeaways for Clinicians

The LEADER data support initiating liraglutide (or another GLP-1 RA with proven benefit) in adults with type 2 diabetes and established atherosclerotic cardiovascular disease who need additional glucose lowering or cardiovascular risk reduction. The 2024 ADA Standards of Care recommend GLP-1 RAs with demonstrated cardiovascular benefit in this population independent of HbA1c level or metformin use.

Clinicians should set patient expectations: cardiovascular benefit builds over months, not weeks. The 12-to-18-month lag before curve separation means that short treatment courses are unlikely to capture the protective effect seen in the trial.

Frequently asked questions

›
›
›
›
›
›
›
›
›
›

References

  • Marso SP, Daniels GH, Tanaka-Poulsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. PubMed
  • Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. PubMed
  • Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839-848. PubMed
  • Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. PubMed
  • Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the ADA and EASD. Diabetes Care. 2018;41(12):2669-2701. PubMed
  • Victoza (liraglutide) prescribing information. FDA. AccessData