Abstract
The STEP 1 randomized trial evaluated the effect of taking semaglutide versus placebo on body weight over a 68-week duration. As with any study evaluating an intervention delivered over a sustained period, nonadherence was observed. This was addressed in the original trial analysis within the Estimand Framework by viewing nonadherence as an intercurrent event. The primary analysis applied a treatment policy strategy which viewed it as an aspect of the treatment regimen and thus made no adjustment for its presence. A supplementary analysis used a hypothetical strategy, targeting an estimand that would have been realized had all participants adhered, under the assumption that no post-baseline variables confounded adherence and change in body weight. We propose an alternative instrumental variable (IV) method to adjust for nonadherence which does not rely on the same unconfoundedness assumption. Unlike many previous IV approaches, it makes full use of the repeatedly measured outcome data and allows for a time-varying effect of treatment adherence on a participant’s weight. We show that it provides a natural vehicle for defining the treatment effect if all participants would have fully adhered. Finally, within the context of statin-therapy, we show how the same technique can be used to understand the relationship between medication dose and cholesterol control using genetically phenotyped observational cohort study data from the UK Biobank.