Table 2

Cox modeling for mediation of time to first MACE with liraglutide versus placebo by HbA1c, body weight, UACR, SBP, LDL cholesterol, confirmed hypoglycemic episodes, SU use, and insulin use, assessed using two approaches

AnalysisRisk of MACE with liraglutide vs. placebo, HR (95% CI)Percentage mediation (95% CI)
Total treatment effect (primary LEADER analysis)0.868 (0.778; 0.968)
Treatment effect adjusted for:
 HbA1c
  Change as time-dependent covariate0.880 (0.787; 0.984)9.9 (−11.4; 59.0)
  Updated mean as time-dependent covariate*0.920 (0.820; 1.033)41.1 (8.6; 161.0)
 Body weight
  Change as time-dependent covariate0.860 (0.770; 0.962)−7.4 (−43.9; 13.3)
  Updated mean as time-dependent covariate*0.864 (0.772; 0.968)−3.9 (−47.0; 26.2)
 UACR
  Change as time-dependent covariate0.899 (0.804; 1.004)21.9 (7.5; 106.4)
  Updated mean as time-dependent covariate*0.907 (0.812; 1.013)28.6 (12.3; 132.8)
 Confirmed hypoglycemia
  Change as time-dependent covariate0.868 (0.778; 0.967)−0.3 (−4.5; 2.2)
  Updated mean as time-dependent covariate*0.868 (0.778; 0.968)−0.1
 SBP
  Change as time-dependent covariate0.874 (0.784; 0.975)5.2 (−0.6; 21.2)
  Updated mean as time-dependent covariate*0.877 (0.787; 0.979)7.7 (0.2; 31.7)
 LDL cholesterol
  Change as time-dependent covariate0.869 (0.778; 0.970)0.6 (−4.2; 7.7)
  Updated mean as time-dependent covariate*0.869 (0.778; 0.970)0.7 (−4.2; 8.8)
 Insulin use
  Change as time-dependent covariate0.889 (0.796; 0.993)16.9 (3.1; 85.7)
  Updated mean as time-dependent covariate*0.894 (0.801; 0.998)20.7
 SU use
  Change as time-dependent covariate0.861 (0.772; 0.960)−5.6 (−25.2; −0.3)
  Updated mean as time-dependent covariate*0.865 (0.776; 0.965)−2.3
  • SBP, systolic blood pressure; SU, sulfonylurea.

  • * Calculated as the trapezoidal area under the curve divided by time.

  • CI for the percentage mediation was estimated using a bootstrap resampling procedure.