Content of review 1, reviewed on March 26, 2019

“Response of 1,5-anydroglucitol to intensive glucose- and blood-pressure lowering interventions, and its associations with clinical outcomes in the ADVANCE trial” is a very interesting and well written paper. This study measures 1,5-AG levels at baseline and at 1 year on available samples from the ADVANCE trial and correlates baseline 1,5-AG levels to clinical outcomes and the effects of glucose and blood pressure lowering therapies on 1,5-AG levels.

With clarification of the below comments, this paper warrants publication. My main concern is the use of “model 2” to analyze the baseline 1,5-AG levels, which does not account for the difference in A1c between groups and confounds the conclusion that 1,5-AG predicts macrovascular events or mortality.

  1. There needs to be a discussion/explanation on which of the 3 models for baseline 1,5-AG levels should be used, and the results and conclusion should reflect this. The results listed in the abstract for microvascular events and mortality are using “model 2”, which does not account for the different in baseline A1c between the groups (8.7% vs 6.8%).

By using model 2 and not adjusting for A1c, this confounds the results and some may conclude that low 1,5-AG is just a marker of high A1c. Model 3 which adjusts for the differences in A1c between groups is the more appropriate method, and with this only microvascular events were significant. I would suggest adding into the discussion why you chose which model to use.

  1. The first sentence of the first introduction paragraph misspells the word 1,5-anhydroglucitol.

  2. In the discussion it is mentioned that the improvement in 1,5-AG seen in the intensive blood pressure arm could have been due to the effects ACE inhibitors on intraglomerular pressure. While this is true, I would clearly state that the improvement could have been due to improved blood pressure, the ACE inhibitor renal effects, or the thiazide renal effects and that this study is unable to discern this

Source

    © 2019 the Reviewer.

Content of review 2, reviewed on April 22, 2019

Overall good work with the revisions, I have no further comments

Source

    © 2019 the Reviewer.

References

    Elizabeth, S., Dan, W., William, M. J., P., J. S., Mariana, L., Pavel, H., E., C. M., Michel, M., Bryan, W., Stephen, H., John, C., Mark, W. 2019. Response of 1,5-anhydroglucitol level to intensive glucose- and blood-pressure lowering interventions, and its associations with clinical outcomes in the ADVANCE trial. Diabetes, Obesity and Metabolism.