Potential future directions for research into hypoglycaemia awareness and mental health: The role of substance use, sedative exposure and sleep

Potential future directions for research into hypoglycaemia awareness and mental health: The role of substance use, sedative exposure and sleepWe thank Ma & Wei for their thoughtful letter regarding our study examining the association between impaired awareness of hypoglycaemia (IAH) and mental health in adults with type 1 diabetes (T1D) and insulin-treated type 2 diabetes (T2D).We agree that alcohol use, sedative exposure, and sleep are biologically plausible factors that may contribute to both IAH and a greater mental health burden, and therefore warrant further investigation.We also support their call for prospective studies specifically designed to evaluate these relationships.Hypo-METRICS was a 10-week multinational prospective observational study designed to explore the clinical, psychological, and health economic impacts of hypoglycaemia in people living with T1D and insulin-treated T2D. 1 Our work exploring associations between IAH and mental health in the Hypo-METRICS population was a planned secondary analysis of the original trial data.As we acknowledge in our paper, the observational design of this study does not allow us to establish causality.2 However, observational analyses can identify clinically important associations.Our study provides evidence that IAH is associated with a greater mental health burden in both T1D and insulin-treated T2D, extending previous observations in T1D 3 to adults with insulin-treated T2D.This finding has important potential implications in the delivery of integrated diabetes care.As Ma & Wei note, simply adding further variables to existing models would not be sufficient to elucidate the potentially complex relationships between substance use, sedative exposure, IAH and mental health.Multivariable analyses require careful consideration of model complexity, collinearity and interpretability, and overadjustment may obscure rather than clarify clinically meaningful associations.Furthermore, alcohol misuse, sedative use, and poor mental health are themselves closely related, 3,4 making disentangling these relationships within an