Thank you for asking me to review this article entitled "" Response of 1,5-anhydroglucitol to intensive glucose- and blood-pressure lowering interventions, and its associations with clinical outcomes in the ADVANCE trial

This is a ancillary study to the ADVANCE trial, examined how 1,5-AG may respond to an intensive glucose- lowering intervention. The study examined the associations of baseline 1,5-AG with long-term microvascular and macrovascular outcomes and mortality as well as the response of 1,5-AG to intensive glucose-lowering and blood pressure reduction interventions in the ADVANCE trial. Indeed, 1,5-AG has been linked to complications of diabetes and low 1,5-AG is thought to be a useful biomarker to monitor glycosuric hyperglycemia.

Overall levels of enthusiasm: Satisfactory, because the information added is a useful tool in the recognition and treatment of microvascular and macrovascular risk.

Key aspects and findings: The study clearly shows that individuals who were in the intensive glucose treatment arm and also in the active blood pressure drug treatment arm had a significant increase in 1,5-AG at 1-year. Another interesting finding was the fact that in the intention-to-treat analysis of ~10% subsample of participants a significant increase in mean 1,5-AG in the intensively treated group compared to the standard arm was observed. The clinical utility of targeting or monitoring 1,5-AG in diabetes care is a matter of debate. The response of 1,5-AG may have a significant clinical importance for the success of the glucose lowering intervention in improving microvascular and macrovascular risk. Additionally the observed a effect of a blood pressure lowering intervention on change in 1,5-AG should be further evaluated.

The paper is well written and scientifically accurate. The title and abstract are informative and they give a clear idea of what to expect from the paper. The overall structures of the manuscript truly facilitate the progress of knowledge in the relevant field.

Weaknesses: The measurement of 1,5-AG in10% of subsample participants at baseline and at the 1-year examination is one of the limitations of this study as well as the lack of additional follow-up information on 1,5-AG

I have no other comments