Applying a hypothetical strategy to the intercurrent event of non-adherence with the parametric g-formula: a post hoc secondary analysis of the MET-PREVENT randomised controlled trial

Journal article

Background: We conducted a post hoc secondary analysis of the MET-PREVENT randomised placebo-controlled trial to target an estimand that uses a hypothetical strategy on the intercurrent event of non-adherence. Methods: We viewed the targeting of this estimand that uses a hypothetical strategy to handle the intercurrent event of non-adherence as a type of causal mediation problem, where randomised treatment is a binary exposure, adherence is a binary mediator, there is an exposure-mediator interaction, and mediator-outcome confounders that are caused by the exposure (e.g. gastrointestinal symptoms) are present. We used the parametric g-formula to estimate the average controlled direct effect (CDE) of metformin (versus placebo) on 4-m walk speed, which is interpreted as the average treatment effect under the hypothetical scenario that all trial participants adhered to assigned treatment. Variables identified as confounders were informed by a literature review and discussions with an expert; assumptions about the causal structure were represented in a directed acyclic graph. We applied a probabilistic bias analysis (PBA) to understand the potential for bias assuming adherence had been misclassified; observed adherence based on returned tablet count may be an inaccurate version of “true adherence” based on actual consumption. Results: Our sample size was 70 trial participants (34 metformin, 36 placebo). Our estimate of the CDE was 0.072 m/s (percentile-based bootstrap 95% CI − 0.292, 0.445). Results from PBA indicated that the greater the extent of misclassification, the more the CDE may be estimated with bias and over-optimistic precision. Conclusions: Our study provided supporting information on metformin’s potential role as a repurposed medication to improve physical performance in nondiabetic older adult patients with physical prefrailty/frailty and probable sarcopenia. Unlike the main trial results, our results do not rule out the possibility of either a meaningful benefit or meaningful harm of metformin, provided that full adherence can be assured. We highlighted the parametric g-formula as a useful method in trials to target estimands with a hypothetical strategy to handle treatment non-adherence. Trial registration: ISRCTN ISRCTN29932357.

Authors: Hiu, S; Wilson, N; Wilson, K; Lin, N; Witham, MD

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Trials
• Volume: 27
• Issue: 1
• Article number: 369
• Publication date: 2026-04-10
• Acceptance date: 2026-04-02
• DOI: 10.1186/s13063-026-09708-1
• EISSN: 1745-6215
• ISSN: 1745-6215
• Language: English
• Keywords: Mediation; Quantitative bias analysis; G-formula; Secondary analysis; Estimands; Causal inference