LEADER - Liraglutide in diabetes with high CV risk

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Liraglutide and cardiovascular outcomes in type 2 diabetes. NEJM 2016;375:311-22.

Bottom line: In patients with T2DM & high CV risk (~4%/year), liraglutide reduced the risk of death, MI or stroke (NNT ~50) over ~4 years versus placebo.

Notes:

  • Liraglutide's efficacy is not clearly due to its antihyperglycemic effect, but it should likely be considered as a 3rd-line agent (after metformin & empagliflozin) for patients with T2DM above their individualized A1c target;

  • Small trials raise concern for CV safety of liraglutide in HFrEF. I will personally avoid using this drug (or any GLP-1 agonist) in HFrEF until better data shows that it's safe.

 

Patients (n=9340)

  • Included
    • Type 2 diabetes (T2DM) with A1c 7% or more
    • Either
      • Age 50 y/o or greater +
        • CAD (no ACS <14 days of enrolment)
        • Cerebrovascular disease (no stroke/TIA <14 days of enrolment)
        • Peripheral vascular disease
        • HF NYHA functional class 2-3
        • CKD stage 3-5
      • Age 60 y/o or greater +
        • Micro- or macroalbuminuria
        • HTN + LVH
        • LV systolic or diastolic dysfunction
        • ABI <0.9
  • Baseline characteristics
    • Age 64 y
    • Male 64%
    • Diabetes duration ~13 y
    • PMHx
      • MI 30%
      • Stroke/TIA 16%
      • Prior revascularization 39%
      • Symptomatic CAD 9%, documented asymptomatic cardiac ischemia 26%
      • HF 14%
      • >60 y/o with micro/macroalbuminuria (11%), HTN+LVH (5%), ABI<0.9 (<3%)
    • Clinical variables
      • Wt 92 kg
      • BMI 32.5
      • BP 136/77
    • Labs
      • A1c 8.7%
      • eGFR 30-59 (21%), <30 (<3%)

 

Interventions

  • I: Liraglutide (started at 0.6 mg subcutaneously daily, uptitrated as tolerated to 1.8 mg)
    • Median dose 1.78 mg/d
  • C: Placebo
  • Patients in both groups received standard-of-care therapy to lower BP (<130/80), glucose (A1c <7%) & lipids (statin for all patients; LDL-C <2.6 mmol/L if no ASCVD, <1.8 mmol/L if ASCVD)
    • Patients in liraglutide generally had a negligibly fewer initiation medications for these risk factors during trial (e.g. statins initiated in 11% on placebo vs 9.4% on liraglutide), except for insulin initiation (started in 43% on placebo vs 29% on liraglutide)
  • Median duration of therapy 3.5 years

 

Results @ median 3.8 years

  • Composite renal outcome: 15% vs 19%, HR 0.78 (0.67-0.92)
    • Death due to renal disease: 0.4% vs 0.3%, HR 1.59, (0.52-4.87)
    • Dialysis start: 3.1% vs 3.4%, HR 0.87 (0.61-1.24)
    • Persistent doubling of SCr: 4.9% vs 5.5%, HR 0.89 (0.67-1.19)
    • New-onset persistent macroalbuminuria: 0.9% vs 12.1%, HR 0.74 (0.60-0.91) - the least important component of the composite renal outcome, & the only one driving the significant difference
  • Safety
    • Serious adverse events: Liraglutide 49.7%, placebo 50.4%
    • Any adverse event: 62.3% vs 60.8% (p=0.12)
    • Severe hypoglycemia: 2.4% vs 3.3% (p=0.02)
    • Acute gallstone disease (cholecystitis or cholelithiasis): 3.1% vs 1.9% (p<0.001)
    • Acute pancreatitis: 0.4% vs 0.5%
    • Pancreatic carcinoma: 0.3% vs 0.1% (p=0.06)
  • Surrogates
    • @ 3 months: Liraglutide ~7.2%, placebo ~8.2%; difference decreased over time (A1c 0.4% lower with liraglutide on average through trial)
    • Wt 2.3 kg lower with liraglutide vs placebo
    • HR 3 bpm higher with liraglutide vs placebo

 

Generalizability

  • This trial represents a population of patients with long-standing diabetes (~13 years) with suboptimal glycemic control (baseline A1c 8.7%) at very high CV risk (primary outcome rate ~4%/year with placebo)
    • The relative risk reduction for the primary outcome components are likely generalizable to a lower-risk population, though this will ultimately lead to a lower absolute benefit (larger NNT) & perhaps no/minimal reduction in death
  • This trial did not evaluate a "more vs less intensive" glycemic control; it randomized patients with diabetes to liraglutide, which lowers glucose, among many other things, or placebo
    • The liraglutide had better glycemic control than placebo by ~1% at 3 months, but the trial's glycemic control protocol later resulted in much smaller differences in A1c between group
    • The benefit of liraglutide in this setting may be related to improved glycemic control, weight loss, other improvements in metabolic parameters, or to a yet-undefined mechanism
  • Heart failure
    • Only 14% of patients enrolled in this trial had HF, which was not limited to patients with reduced ejection fraction/LV dysfunction. Two small trials raise concerns about the use of liraglutide in individuals with HF:
      • FIGHT: This double-blind RCT of 300 patients evaluated the effect of liraglutide vs placebo in patients with HFrEF (HF with LVEF 40% or lower) hospitalized for HF in the previous 2 weeks on clinical outcomes & LVEF, with or without T2DM. After 6 months, liraglutide did not improve the primary outcome, LVEF, distance on a 6-minute walk test, quality of life, or NT-proBNP. There was, however, a concerning increase in the secondary outcome of death, re-hospitalization/ED visit for CV reasons (liraglutide 63%, placebo 55%, HR 1.34 [1.00-1.80])
      • LIVE: Similarly, this double-blind RCT of 241 patients evaluated the effect of liraglutide vs placebo in patients with stable HFrEF (<45%) NYHA class 1-3 on LVEF. Liraglutide did not significantly improve LVEF or any other echocardiographic measurement vs placebo, but it did increase the risk of cardiac serious adverse events (10% vs 3%, p<0.05). Notably, this was a heterogeneous collection of outcomes that included VT death, VT, AF requiring DC cardioversion, ACS, worsening HF.

Internal validity

  • Risk of bias
    • Low risk of allocation & detection bias
      • Allocation concealment maintained by computerized central allocation
      • Blinding with matching placebo
      • All macrovascular & microvascular outcomes adjudicated by company blind to assigned study intervention
    • Low risk of performance bias
      • Blinding with matching placebo
      • Standardized protocols to control CV risk factors
      • More patients in the placebo group received intensification of medications to reduce CV risk factors (likely because liraglutide produced mild improvements in metabolic parameters), particularly antihyperglycemic agents such as insulin, though this should produce a "conservative bias" towards the null in favor of the placebo group
    • Low risk of attrition bias
      • Analyzed by intention-to-treat
      • Low loss-to-follow-up (3.2% did not complete trial follow-up; 0.3% for mortality)
  • Use of composite primary outcome was completely appropriate
    • All components important (even silent MI is prognostically important)
    • Biologically rational to combine these macrovascular outcomes with overlap in pathophysiology
    • Similar contribution from each component of the composite outcome; MI and stroke both had estimates of effect nearly identical to that of the composite (HR ~0.86), making it appropriate to conclude that liraglutide reduced the risk of the composite, as well as each of the individual components
  • 2-week placebo run-in period to exclude early non-adherence to subcutaneous injections
    • Not a source of bias, but does exclude those individuals least likely to be adherent long-term
  • Per FDA guidance, designed to first prove non-inferiority trial of liraglutide vs placebo (to ensure CV safety to avoid issues as seen with other diabetes drugs rosiglitazone), then - if safe - to show superiority 
    • Not a source of bias; pre-defined & appropriate