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

Abstract

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. 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). 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. 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.