LEADER

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Marso SP, et al. "Liraglutide and cardiovascular outcomes in type 2 diabetes". The New England Journal of Medicine. 2016. 375(4):311-322.
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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.[1] Diabetes is a major independent risk factor for cardiovascular disease. Several large scale glucose-lowering medication trials including PROactive (2005), EXAMINE (2013),[2] SAVOR-TIMI 53 (2013),[3] TECOS (2015), and ELIXA (2015)[4] 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)[5] 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.[6] 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 antagonist 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.[7] 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, liraglutide joins empaglifozin and metformin as the only glucose lowering agents to demonstrate CVD event reduction in patients with T2DM, despite a modest reduction in Hgb A1c.

Guidelines

As of September 2016, no guidelines have been published that reflect the results of this trial.

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.[8]

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[8] and in the design publication.[9] 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:[8]
    • 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.[8]

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.[8]

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[10]
  • No use of DPP-4 inhibitors as add-on to metformin, which was considered standard of care during this trial[11]
  • Primary composite outcome was purely driven by non-North American countries, especially in Europe.

Funding

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

Further Reading

  1. Wild S et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004. 27:1047-53.
  2. White WB et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 2013. 369:1327-35.
  3. Scirica BM et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 2013. 369:1317-26.
  4. Pfeffer MA et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N. Engl. J. Med. 2015. 373:2247-57.
  5. Hong J et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013. 36:1304-11.
  6. Beglinger C & Degen L Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY?. Physiol. Behav. 2006. 89:460-4.
  7. Jensen TM et al. Is there a link between liraglutide and pancreatitis? A post hoc review of pooled and patient-level data from completed liraglutide type 2 diabetes clinical trials. Diabetes Care 2015. 38:1058-66.
  8. 8.0 8.1 8.2 8.3 8.4 Supplementary appendix
  9. Marso SP et al. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Am. Heart J. 2013. 166:823-30.e5.
  10. Colhoun HM et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004. 364:685-96.
  11. American Diabetes Association Standards of medical care in diabetes--2014. Diabetes Care 2014. 37 Suppl 1:S14-80.