Accounting for non-adherence: A re-analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial.

BACKGROUND/AIMS: The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial randomized patients with diabetes to liraglutide or placebo. The per-protocol analysis conditioned on post-baseline adherence and therefore lacked a well-defined estimand. This study sought to evaluate a subset of Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results to estimate the effect of sustained liraglutide exposure corresponding to a well-defined per-protocol analysis. METHOD: We used the roadmap of targeting learning to define the estimand for the sustained treatment analysis and estimated it with longitudinal targeted minimum loss-based estimation, accounting for protocol deviations and censoring using post-baseline confounders. The results were compared to the intention-to-treat analysis. We report 3.5-year risks of the primary composite outcome (myocardial infarction, stroke, or cardiovascular mortality) and secondary outcomes (each of the primary outcome's components, revascularization, unstable angina pectoris, heart failure, and all-cause mortality). RESULTS: The intention-to-treat analysis estimated 3.5-year risks for the primary composite outcome of 11.8% (95% confidence interval: 10.8 to 12.8) in the liraglutide arm and 13.3% (95% confidence interval: 12.3 to 14.3) in the placebo arm, with a risk difference of 1.5% (95% confidence interval: 0.1 to 2.9). Accounting for post-baseline confounders, the sustained treatment analysis estimated 3.5-year risks of 11.4% (95% confidence interval: 10.4 to 12.5) for sustained exposure to liraglutide versus 12.6% (95% confidence interval: 11.5 to 13.7) for sustained exposure to placebo, yielding a risk difference of 1.1% (95% confidence interval: -0.4 to 2.6). Sustained exposure to liraglutide showed no statistically significant difference compared with sustained exposure to placebo for any secondary outcomes at 3.5 years. CONCLUSION: We used contemporary methods for causal inference to define and estimate the sustained treatment effects of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results study by accounting for both baseline and time-varying confounders. The results were consistent with the findings of the original Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial.