LEADER

Published

Marso SP, et al. "Liraglutide and cardiovascular outcomes in type 2 diabetes". The New England Journal of Medicine. 2016. 375(4):311-322.
PubMed • Full text • PDF

Clinical Question

Among patients with T2DM at increased risk for CV events, does daily liraglutide reduce CV mortality, nonfatal MI, or nonfatal strokes when compared to placebo?

Bottom Line

Among patients with T2DM at increased risk for CVD, liraglutide was associated with a reduction in CV events when compared to placebo.

Major Points

The global prevalence of diabetes is expected to rise from an estimated 2.8% (171 million) to 4.4% (366 million) in 2030. Diabetes is a major independent risk factor for cardiovascular disease. Several large scale glucose-lowering medication trials including PROactive (2005), EXAMINE (2013), SAVOR-TIMI 53 (2013), TECOS (2015), and ELIXA (2015) and the Look AHEAD lifestyle intervention trial (2013) have disappointingly failed to show a significant reduction in CV events. UKPDS 34 (1998) and SPREAD-DIMCAD (2013) showed reduction in CVD events with metformin. Similarly, the 2015 EMPA-REG OUTCOME found a CVD benefit with empaglifozin, an SGLT-2 inhibitor.

Glucagon-like peptide-1 (GLP-1) is one 'satiety peptide' known to stimulate insulin release in the context of elevated blood glucose levels, reduce prandial glucagon, and delay gastric emptying. Liraglutide is an FDA-approved, injectable, long-acting GLP-1 receptor agonist that lowers blood sugar, reduces BP, and promotes weight loss. While the ELIXA trial did not find benefit for CVD endpoint reduction with use of the GLP-1 agonist lixisenatide among diabetics with recent ACS, whether liraglutide is protective against CVD in at-risk diabetics without recent ACS was unknown.

Published in 2016, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial randomized 9,340 patients with type 2 diabetes and high CV risk to receive liraglutide or placebo. With a median follow-up of 3.8 years, liraglutide was associated with a significant reduction in CV mortality, nonfatal MI, or nonfatal stroke (13.0% vs. 14.9%, P<0.001) as well as a reduction in all-cause mortality (8.2% vs. 9.6%, P=0.02). GLP-1 and DPP-4 inhibitors as a class carry warnings for increased incidence of pancreatitis. In this trial, the incidence of pancreatitis was similar between groups but there was a slightly higher incidence of acute cholecystitis with liraglutide.

With this trial, GLP-1 agonists join SGLT-2 inhibitors and metformin as the only glucose lowering agents to demonstrate CVD event reduction in patients with T2DM, despite a modest reduction in Hgb A1c. Of note, also published in 2016, SUSTAIN-6 similarly found benefit for CVD events with the GLP-1 agonist semaglutide.

Guidelines

2019 ESC and EASD Guidelines on diabetes, pre-diabetes, and cardiovascular disease

• GLP-1 receptor agonists are recommended in patients with T2DM with or at high risk of CVD to reduce CV events (COR I, LOE A)
• Liraglutide is recommended in patients with T2DM and CVD to reduce the risk of death (COR I, LOE B)
• Liraglutide and semaglutide should be considered in DM treatment if eGFR >30 mL/min/1.73m²) as they are associated with a lower risk of renal endpoints (COR IIa, LOE B)

2019 ADA Standards of Medical Care in Diabetes

• In patients with T2DM and atherosclerotic CV disease, SGLT-2 inhibitors or GLP-1 receptor agonists are recommended. (LOE A)
• Consider SGLT-2 inhibitor or GLP-1 receptor agonist in patients with T2DM and CKD. It has shown to reduce risk of CKD progression, CV events or both. (LOE C)

Design

• Multicenter, randomized, placebo-controlled trial
• N=9,340
  • Liraglutide (n=4,668)
  • Placebo (n=4,672)
• Setting: 410 sites in 32 countries
• Enrollment: 2010-2012
• Median follow-up: 3.8 years
• Analysis: Intention-to-treat
• Primary outcome: First occurrence of CV mortality, nonfatal MI, or non-fatal stroke

Population

Full details are on page 39 of the supplementary appendix.

Inclusion Criteria

• T2DM and Hgb A1c ≥7.0%
  • If age ≥50 years, has ≥1 of the following:
    • Cardiovascular, cerebrovascular, or peripheral vascular disease
    • CKD with eGFR <60 mL/min/1.73m², but not on HD
    • HF with NYHA class II-III symptoms
  • If age ≥60 years, has risk factors for vascular disease (microalbuminuria/proteinuria, HTN with LVH, systolic or diastolic LV dysfunction, or ABI <0.9)

Exclusion Criteria

• T1DM
• Use of GLP-1 receptor agonist, DPP-4 inhibitor, or pramlintide (an amylin analogue) within the 3 months prior to screening
• Use of insulin except long-acting agents (including NPH) in prior 3 months
• Intensification of treatment to prevent acute complications of diabetes in the last 3 months
• ACS or cerebrovascular event in prior 14 days
• ESRD, ESLD, or HF with NYHA class IV symptoms
• Prior or anticipated organ transplantation
• Family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma
• History of non-familial medullary thyroid carcinoma
• Malignant neoplasm in prior 5 years

Baseline Characteristics

On page 62 of supplementary appendix and in the design publication. From the liraglutide group except italicized results, which are among all participants as described in the design publication.

• Demographics: Age 64 years, 64% male, White race 78%, Black race 8.3%, Asian race 10%, Hispanic/Latino 12%
• Location: Europe 35%, N. America 30%, Asia 8%, other 27%
• Health data: BMI 32 kg/m², weight 92 kg, BP 136/77 mm Hg
• Diabetes characteristics: Duration of disease 13 years, Hgb A1c 8.7%
• PMH: HF with NYHA class I-III symptoms 18%, other:
  • Established CVD (among age ≥50 years): Any 82%, MI 31%, stroke or TIA 16%, prior revascularization 39%, >50% stenosis of coronary/carotid/lower extremity artery 25%, symptomatic CHD 9%, known asymptomatic CHD 27%, CKD with eGFR <60 mL/min/1.73m² 25%
  • CVD risk factors (among age ≥60 years): Any 18%, microalbuminuria/proteinuria 11%, HTN with LVH 5%, systolic or diastolic LV dysfunction 4%, ABI <0.9 2%
  • Renal impairment (eGFR): None (≥90) 35%, mild (60-89) 41%, moderate (30-59) 21%, severe (<30) 2%
• Medications: Metformin 76%, SU 51%, TZD 6%, long-acting insulin 24%, B-blocker 57%, CCB 33%, ACE-inhibitor 52%, ARBs 32%, loop diuretics 18%, thiazides 18%, aldosterone antagonists 5%, statin 73%, antiplatelet 69% (ASA 64%)

Interventions

• After a run-in phase with placebo injections (106 dropped for run-in failures), participants were randomized to a group:
  • Liraglutide 1.8 mg (or maximum tolerated dose) subcutaneous daily injection
  • Placebo as a subcutaneous injection
• Both groups received standard of care detailed on Table S1 on page 60 of the supplementary appendix:
  • Medication intensification to achieve A1c ≤7.0% when appropriate
    • Add-on medications were TZDs, SUs, alpha glucosidase inhibitors
      • DPP-4 and incretin medications were not allowed
  • Lifestyle modifications
  • Target BP 130/80 mm Hg, first-line antihypertensives were ACE-inhibitors and ARBs
  • Target LDL <100 mg/dL, statins were recommended for all patients
  • Antiplatelets (preferentially ASA) for patients with prior CV events

Outcomes

Presented as liraglutide vs. placebo.

Primary Outcomes

First occurrence of CV mortality, nonfatal MI, or non-fatal stroke

13.0% vs. 14.9% (HR 0.87; 95% CI 0.78-0.97; P=0.01; NNT=53)

Secondary Outcomes

CV mortality, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or HF

20.3% vs. 22.7% (HR 0.88; 95% CI 0.81-0.96; P=0.005; NNT=42)

Mortality

All-cause: 8.2% vs. 9.6% (HR 0.85; 95% CI 0.74-0.97; P=0.02; NNT=71)

CV: 4.7% vs. 6.0% (HR 0.78; 95% CI 0.66-0.93; P=0.007; NNT=77)

Non-CV: 3.5% vs. 3.6% (HR 0.95; 95% CI 0.77-1.18; P=0.66)

Coronary revascularization

8.7% vs. 9.4% (HR 0.91; 95% CI 0.80-1.04; P=0.18)

Hospitalizations

Unstable angina: 2.6% vs. 2.7% (HR 0.98; 95% CI 0.76-1.26; P=0.87)

HF: 4.7% vs. 5.3% (HR 0.87; 95% CI 0.73-1.05; P=0.14)

Microvascular event

7.6% vs. 8.9% (HR 0.84; 95% CI 0.73-0.97; P=0.02; NNT=77)

Retinopathy: 2.3% vs. 2.0% (HR 1.15; 95% CI 0.87-1.52; P=0.33)

Nephropathy: 5.7% vs. 7.2% (HR 0.78; 95% CI 0.67-0.92; P=0.003; NNT=67)

Additional Outcomes

For the following, full details are on Table S4 on pages 64-65 of the supplementary appendix.

New medications introduced during the trial

Statin: 8.1% vs. 9.6% (P=0.01)

Metformin: 5.4% vs. 6.4% (P=0.03)

SUs: 7.6% vs. 10.8% (P<0.001)

Alpha-glucosidase inhibitors: 1.8% vs. 3.1% (P<0.001)

TZDs: 2.1% vs. 3.4% (P<0.001)

DPP-4 inhibitors: 3.2% vs. 3.6% (P=0.24)

GLP-1 receptor antagonists: 1.9% vs. 3.0% (P<0.001)

SGLT-2 inhibitors: 2.1% vs. 2.8% (P=0.046)

Glinides: 1.8% vs. 2.9% (P<0.001)

For the following, see details on Figure S5 on page 53 of the supplementary appendix.

Hgb A1c

Neither group achieved a mean A1c ≤7% at the end of the trial. At 36 months, the liraglutide group had a mean A1c -0.40% lower than the placebo group (95% CI -0.45 to -0.34%).

Body weight at the end of the trial

Lower by about 3 kg in the liraglutide group

BP at the end of the trial

Similar in both groups

Post-hoc Analyses

These were not prespecified except where noted. We consider these to be exploratory analyses and NNTs are not presented. —WJC Editors

MI

6.3% vs. 7.3% (HR 0.86; 95% CI 0.73-1.00; P=0.046)

Fatal: 0.4% vs 0.6% (HR 0.60; 95% CI 0.33-1.10; P=0.10)

Nonfatal: 6.0% vs. 6.8% (HR 0.88; 95% CI 0.75-1.03; P=0.11)

Above was prespecified

Silent: 1.3% vs. 1.6% (95% CI 0.86; 95% CI 0.61-1.20; P=0.37)

Stroke

3.7% vs. 4.3% (HR 0.86; 95% CI 0.71-1.06; P=0.16)

Fatal: 0.3% vs. 0.5% (HR 0.64; 95% CI 0.34-1.19; P=0.16)

Nonfatal: 3.4% vs. 3.8% (HR 0.89; 95% CI 0.72-1.11; P=0.30)

Above was prespecified

TIA

1.0% vs. 1.3% (HR 0.79; 95% CI 0.54-1.16; P=0.23)

Subgroup Analysis

Sex, age, geographic region, race, ethnic group, BMI, HbA1c, duration of DM, CVD risk, presence of HF, DM therapy, and renal function were included in the prespecified subgroup analysis. For the primary composite outcome, HRs and P-values for interaction were significant for the following subgroups.

Risk of CVD

≥50 y and established CVD: HR 0.83

≥60 y and risk factors for CVD: HR 1.20

P-value for interaction: 0.04

Renal function

GFR <60: HR 0.69

GFR ≥60: HR 0.94

P-value for interaction 0.01

Adverse Events

Statistically significant AEs are presented. See Table 2 on page 320 for a complete list of adverse events.

Any

62.3% vs. 60.8% (P=0.12)

Serious

32.2% vs. 32.8% (P=0.51)

Severe hypoglycemia (<56 mg/dL)

2.4% vs. 3.3% (P=0.02; NNH=111)

Acute gallstone disease

3.1% vs. 1.9% (P<0.001; NNH=83)

Injection site reaction

0.7% vs. 0.3% (P=0.002; NNH=250)

Criticisms

• Neither group achieved an A1c ≤7.0%
• SU use increased CVD endpoints in UKPDS 34 and more participants in the LEADER placebo arm were treated by SUs, potentially increased CVD outcomes
  • More individuals in the placebo arm were started on statins, which would have reduced risk of CVD in this group, as demonstrated in CARDS
• No use of DPP-4 inhibitors as add-on to metformin, which was considered standard of care during this trial

Funding

• Private: Novo Nordisk, the makers of Victoza and Saxenda (the brand names of liraglutide)
• Public: NIH