LEADER trial deep-dive: liraglutide cuts MACE 13% in type 2 diabetes (Marso 2016)
Last verified 2026-05-28 · Phase 3b/4 · Completed; primary results reported July 2016 · NCT01179048 ↗
LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was a multicenter, double-blind, placebo-controlled, event-driven phase 3b/4 trial sponsored by Novo Nordisk and co-funded by the U.S. National Institutes of Health. Investigators randomized 9,340 adults with type 2 diabetes and either established cardiovascular disease (age 50 and older) or elevated cardiovascular risk factors (age 60 and older) 1:1 to once-daily subcutaneous liraglutide titrated to 1.8 mg or matching placebo, on top of standard glycemic and cardiovascular care. The primary endpoint was a three-point major adverse cardiovascular event composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Median follow-up was 3.8 years. Results published by Marso and colleagues in the New England Journal of Medicine on July 28, 2016 reported a hazard ratio of 0.87 for the primary outcome — the first positive cardiovascular outcomes trial for any glucagon-like peptide-1 receptor agonist and the foundation for every later GLP-1 CVOT.
- Enrollment
- 9,340
- Duration
- Median follow-up 3.8 years; minimum 42 months of treatment per protocol
- Drug
- Liraglutide 1.8 mg (Victoza)
- Population
- Adults with type 2 diabetes and HbA1c at least 7.0%, either aged 50 or older with established cardiovascular, cerebrovascular, peripheral vascular, or chronic kidney disease, or aged 60 or older with at least one cardiovascular risk factor (microalbuminuria, hypertension and left-ventricular hypertrophy, left-ventricular systolic or diastolic dysfunction, or an ankle-brachial index below 0.9). Mean age 64.3 years, 64.3% male, mean HbA1c 8.7%, mean diabetes duration 12.8 years, mean BMI 32.5 kg/m², and 81.3% had established cardiovascular disease at randomization.
Primary endpoint
Three-point MACE: composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (time-to-first-event)
Treatment arm
608 of 4,668 (13.0%)
Comparator
694 of 4,672 (14.9%)
Treatment difference: Hazard ratio 0.87 (95% CI 0.78 to 0.97); P<0.001 for noninferiority, P=0.01 for superiority
13% relative reduction in three-point MACE with liraglutide vs placebo. Number needed to treat 66 over 3 years to prevent one primary outcome event. First positive cardiovascular outcomes trial for any GLP-1 receptor agonist.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Death from cardiovascular causes 22% relative reduction in cardiovascular death — formally significant under the hierarchical testing sequence and the strongest individual MACE component. | 219 of 4,668 (4.7%) | 278 of 4,672 (6.0%) | Hazard ratio 0.78 (95% CI 0.66 to 0.93); P=0.007 |
| Death from any cause (all-cause mortality) 15% relative reduction in all-cause mortality, driven primarily by the cardiovascular-death signal. | 381 of 4,668 (8.2%) | 447 of 4,672 (9.6%) | Hazard ratio 0.85 (95% CI 0.74 to 0.97); P=0.02 |
| Nonfatal myocardial infarction (component of MACE) Numerical reduction in nonfatal MI; confidence interval crossed 1.0 so not formally significant. | 281 of 4,668 (6.0%) | 317 of 4,672 (6.8%) | Hazard ratio 0.88 (95% CI 0.75 to 1.03); P=0.11 |
| Nonfatal stroke (component of MACE) No meaningful reduction in nonfatal stroke; consistent with the later SELECT pattern where stroke contributed less than MI to the MACE benefit. | 159 of 4,668 (3.4%) | 177 of 4,672 (3.8%) | Hazard ratio 0.89 (95% CI 0.72 to 1.11); P=0.30 |
| Expanded cardiovascular composite (CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or heart failure) 12% relative reduction in the broader composite that added revascularization and unstable-angina or heart-failure hospitalization to the three-point MACE. | 948 of 4,668 (20.3%) | 1,062 of 4,672 (22.7%) | Hazard ratio 0.88 (95% CI 0.81 to 0.96); P=0.005 |
| Hospitalization for heart failure Numerical reduction in heart-failure hospitalization; not statistically significant. Contrasts with the SGLT2-inhibitor class where the HF signal is much larger. | 218 of 4,668 (4.7%) | 248 of 4,672 (5.3%) | Hazard ratio 0.87 (95% CI 0.73 to 1.05); P=0.14 |
| Change in HbA1c at 36 months Modest glycemic separation; trial protocol allowed open-label glycemic rescue in both arms, narrowing the difference compared with monotherapy trials. | -0.40 percentage points lower than placebo | Reference (background-glycemic-therapy adjusted) | Estimated treatment difference -0.40 percentage points (95% CI -0.45 to -0.34); P<0.001 |
| Change in body weight at 36 months Weight reduction at the 1.8 mg dose was modest compared with the 5-7 kg loss reported at the same dose in earlier obesity-only trials, reflecting the older, sicker, polypharmacy population. | -2.3 kg vs placebo | Reference | Estimated treatment difference -2.3 kg (95% CI -2.5 to -2.0); P<0.001 |
| Composite renal outcome: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine and eGFR ≤45, end-stage renal disease, or death from renal disease (prespecified secondary endpoint, reported in detail by Mann 2017) 22% relative reduction in the kidney composite, driven primarily by a 26% reduction in new-onset persistent macroalbuminuria. Reported in the LEADER nephropathy substudy (Mann et al., NEJM 2017, PMID 28854085). | 268 of 4,668 (5.7%) | 337 of 4,672 (7.2%) | Hazard ratio 0.78 (95% CI 0.67 to 0.92); P=0.003 |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Any adverse event leading to permanent discontinuation Gastrointestinal events were the most common reason for stopping liraglutide; rates consistent with the GLP-1 class profile. | 9.5% | 7.3% |
| Nausea Most common AE; typically peaks during the first 16 weeks of dose titration, then declines. | 18.5% | 6.4% |
| Diarrhea | 16.5% | 8.9% |
| Vomiting | 9.6% | 3.7% |
| Confirmed hypoglycemia (severe or symptomatic with glucose below 56 mg/dL) Numerically fewer episodes with liraglutide despite greater HbA1c reduction; reflects glucose-dependent insulin-release mechanism. | 43.7% | 45.6% |
| Severe hypoglycemia Approximately 31% relative reduction in severe hypoglycemia with liraglutide. | 2.4% | 3.3% |
| Acute pancreatitis (adjudicated) No increased pancreatitis risk; rate numerically lower with liraglutide. | 0.4% (18 events) | 0.5% (23 events) |
| Pancreatic cancer (adjudicated) Numerical imbalance flagged in the publication; subsequent post-marketing surveillance and meta-analyses have not confirmed a causal signal. | 0.3% (13 cases) | 0.1% (5 cases) |
| Acute gallstone disease (cholelithiasis, cholecystitis, biliary colic) Modestly more common with liraglutide; consistent with rapid weight loss biology and the GLP-1 class label. | 3.1% | 1.9% |
| Neoplasms (any malignant) No significant overall cancer imbalance over a median 3.8 years of exposure. | 6.3% | 6.0% |
| Medullary thyroid carcinoma No medullary thyroid cancers in either arm despite the rodent-data boxed warning that originally accompanied the drug class. | 0 cases | 0 cases |
Subgroup analyses
- Established cardiovascular disease at baseline (81.3% of cohort): Hazard ratio for primary MACE 0.83 (95% CI 0.74 to 0.93)
Treatment effect concentrated in the secondary-prevention subgroup; the interaction with primary-prevention participants was statistically suggestive (interaction P=0.04).
- Primary-prevention cohort (age 60+ with risk factors, no prior CV event, 18.7%): Hazard ratio for primary MACE 1.20 (95% CI 0.86 to 1.67)
No benefit observed in lower-risk primary-prevention participants; supports targeting GLP-1 therapy to secondary-prevention populations for cardioprotection.
- Estimated glomerular filtration rate below 60 mL/min/1.73m² (23%): Hazard ratio for primary MACE 0.69 (95% CI 0.57 to 0.85)
Larger relative benefit in participants with reduced kidney function — a pattern echoed in later GLP-1 outcomes data.
- Age 60-66 vs 67+: Hazard ratios consistent across age strata (interaction P=0.74)
No meaningful age effect on the MACE benefit.
- Sex (male 64.3% vs female 35.7%): Hazard ratios similar between sexes (interaction P=0.83)
Benefit observed in both women and men.
Clinical significance
LEADER is the trial that opened the cardioprotective era for GLP-1 receptor agonists. Before LEADER published in July 2016, no GLP-1 had shown a positive cardiovascular outcomes result — ELIXA (lixisenatide, 2015) was neutral, and the class carried a regulatory mandate to prove cardiovascular safety rather than benefit. LEADER's 13% relative reduction in three-point MACE, anchored by a 22% reduction in cardiovascular death and a 15% reduction in all-cause mortality, made liraglutide the first member of the class to clear the superiority threshold. SUSTAIN-6 for semaglutide reported months later in September 2016 with a similar magnitude, REWIND followed with dulaglutide in 2019, and SELECT eventually extended the paradigm to obesity without diabetes in 2023. LEADER also produced the prespecified kidney-outcome substudy (Mann 2017) that established renal benefit and led the FDA to add cardiovascular risk reduction to the Victoza label in August 2017 — the first cardiovascular indication for a GLP-1 in type 2 diabetes.
Frequently asked questions
How did LEADER differ from SUSTAIN-6?
LEADER tested daily liraglutide 1.8 mg in 9,340 adults with type 2 diabetes followed a median 3.8 years, with 81% in secondary prevention. SUSTAIN-6 tested weekly semaglutide 0.5 mg or 1.0 mg in 3,297 adults with type 2 diabetes followed a median 2.1 years. LEADER was designed as a superiority trial and met it (HR 0.87 for MACE, P=0.01 for superiority). SUSTAIN-6 was designed as a noninferiority trial that produced a superiority signal (HR 0.74, P=0.02). LEADER's signal was driven primarily by cardiovascular death; SUSTAIN-6's was driven primarily by nonfatal stroke. LEADER was published in NEJM on July 28, 2016; SUSTAIN-6 followed on September 15, 2016. Both trials together established the GLP-1 cardioprotective class effect that REWIND, AMPLITUDE-O, and SELECT later confirmed.
Why does Saxenda not get used much for cardiovascular protection?
Saxenda is liraglutide 3.0 mg, FDA-approved for chronic weight management, not type 2 diabetes. The LEADER cardiovascular trial used the 1.8 mg dose — the diabetes label — and enrolled only adults with type 2 diabetes. The FDA cardiovascular indication that came out of LEADER in August 2017 was added to the Victoza (1.8 mg, diabetes) label, not to Saxenda. There is no completed cardiovascular outcomes trial of the 3.0 mg dose for cardioprotection in obesity, so prescribers and payers do not have a regulatory basis to use Saxenda for MACE reduction. Patients seeking GLP-1 cardioprotection in the obesity-without-diabetes population are now directed to semaglutide 2.4 mg (Wegovy) after the SELECT trial in 2023.
What about Victoza for cardioprotection in type 2 diabetes today?
Victoza retains an FDA-approved indication to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, added to the label in August 2017 directly on the basis of LEADER. In practice, prescribing has shifted toward weekly GLP-1 receptor agonists — semaglutide (Ozempic) and dulaglutide (Trulicity) — because once-weekly dosing improves adherence and these agents have their own positive cardiovascular trials (SUSTAIN-6 and REWIND respectively). Victoza is still used where daily dosing is preferred, where weekly options are not covered, or in pediatric type 2 diabetes (Victoza was approved for ages 10 and older in 2019). The liraglutide molecule lost patent protection in 2024, and authorized generics have begun to appear, which may stabilize its niche.
Does the LEADER signal apply to higher-dose liraglutide such as Saxenda 3.0 mg?
There is no completed cardiovascular outcomes trial of liraglutide 3.0 mg, so the LEADER signal cannot be assumed to extend to the higher dose. The 1.8 mg dose tested in LEADER and the 3.0 mg dose used in Saxenda involve the same molecule but different exposure, different titration schedules, and different populations (diabetes in LEADER, obesity without diabetes for Saxenda). The conservative regulatory interpretation, reflected on both U.S. labels, is that the Victoza cardiovascular indication does not transfer to Saxenda. The closest analog for high-dose GLP-1 cardioprotection in adults without diabetes is the SELECT trial of semaglutide 2.4 mg, which showed a 20% MACE reduction — but SELECT was a different drug and dose, not a higher-dose liraglutide trial.
Why has liraglutide not been studied in obesity-only patients without diabetes for MACE?
By the time the field had the resources and clinical equipoise to run a large cardiovascular outcomes trial in adults with obesity but without diabetes, semaglutide had eclipsed liraglutide in both efficacy and pipeline priority. Novo Nordisk chose to invest the obesity-CVOT effort in semaglutide 2.4 mg, which became the SELECT trial that reported in 2023. Running a parallel cardiovascular trial of liraglutide 3.0 mg in the same population would have required several thousand participants and roughly four years at substantial cost, with limited commercial upside given that weekly semaglutide had already demonstrated larger weight loss and was on track to do so in cardiovascular outcomes as well. The result is that the GLP-1 cardioprotective indication in obesity without diabetes belongs to semaglutide, while liraglutide's MACE evidence remains anchored to the type 2 diabetes population enrolled in LEADER.
How robust was the kidney-outcome signal from LEADER?
The prespecified secondary renal endpoint reported in the primary LEADER paper showed a hazard ratio of 0.78 (95% CI 0.67 to 0.92) for the composite of new-onset persistent macroalbuminuria, doubling of serum creatinine with eGFR at or below 45, end-stage kidney disease, or death from renal causes. The dedicated nephropathy substudy by Mann and colleagues, published in NEJM in 2017 (PMID 28854085), confirmed that the signal was driven primarily by a 26% reduction in new-onset persistent macroalbuminuria, with smaller, nonsignificant signals on the harder kidney endpoints. The result was hypothesis-generating rather than definitive on hard renal outcomes — the larger FLOW trial of semaglutide in diabetic kidney disease (reported in 2024) was needed to establish a confirmed GLP-1 renal-protection signal.
References
- 1.Marso SP, Daniels GH, Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016. PMID: 27295427.
- 2.Mann JFE, Ørsted DD, Brown-Frandsen K, et al.; LEADER Steering Committee and Investigators. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017. PMID: 28854085.
- 3.Novo Nordisk A/S. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results — A Long Term Evaluation (LEADER). ClinicalTrials.gov, NCT01179048. 2016. https://clinicaltrials.gov/study/NCT01179048
- 4.U.S. Food and Drug Administration. Victoza Prescribing Information Update: Indication to Reduce Risk of Major Adverse Cardiovascular Events in Adults with Type 2 Diabetes and Established Cardiovascular Disease. FDA Label Update, August 2017. 2017. https://www.fda.gov/drugs/drug-safety-and-availability/victoza-liraglutide-injection-drug-safety-communication-fda-approves-changes-prescribing-information