N-of-1 analysis of circadian data reveals potential for precision chrono-medicine approach of concomitant exercise and metformin recommendations.

The integration of chrono-medicine into disease management has potential for cost-effective improvements, particularly in type 2 diabetes care. While both exercise and metformin are effective in lowering glycaemia, their combined effect is non-additive. Individual circadian rhythms suggest that personalised timing of interventions may optimise outcomes. This study aims to investigate the heterogeneity in response to the timing of exercise and metformin intake using an n-of-1 approach within a randomised crossover trial, thereby exploring the potential for individualised chrono-medicine strategies. A previously published 16-week randomised crossover study was conducted to explore the potential therapeutic effects of prescribed moderate exercise timings in participants undergoing metformin monotherapy. Physical activity, heart rate, sleep, and glucose levels were tracked using wearable technology and continuous glucose monitors. Data were collected during baseline, and throughout the intervention periods. Analysis focused on individual responses to the timing of exercise and metformin intake. Morning exercise significantly lowered 24-hour post-exercise blood glucose levels compare to evening exercise. Both exercise timings reduced mean blood glucose levels, but morning exercise had a greater effect (mean difference: -0.63 mmol/L, p<0.001) than evening exercise (mean difference: -0.34 mmol/L, p=0.016). Individual responses varied, with some participants displaying a substantial reduction in glucose levels in response to morning or evening exercise, while others did not benefit from either exercise intervention. Pre-breakfast metformin intake significantly lowered area under the curve (AUC) glucose values in response to morning exercise compared to post-breakfast, an effect not observed with evening exercise. Morning exercise combined with pre-breakfast metformin intake is the most effective strategy for lowering blood glucose levels in the greatest number of participants with type 2 diabetes. However, individual response heterogeneity suggests that chrono-medicine approaches must be personalised. Further research is needed to understand the underlying mechanisms of individual variability in response to exercise and medication timing. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIExercise prescription and metformin treatment are both effective in lowering glycaemia but their combined effect is non-additive. C_LIO_LIIt is unknown how individual circadian rhythmicity interacts with these diabetes treatment strategies. C_LI What is the key question?O_LIIs there potential for personalisation of a chrono-medicine approach to diabetes management? C_LI What are the new findings?O_LIMorning exercise combined with pre-breakfast metformin intake is the most effective strategy for lowering blood glucose levels in the greatest number of participants with type 2 diabetes. C_LIO_LIFurther research is needed to understand the underlying mechanisms of individual variability in response to exercise and medication timing. C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur study shows that integrating chrono-medicine into disease management has potential for cost-effective improvements, particularly in type 2 diabetes care. C_LI