In the present manuscript the Authors present an umpteenth sub-analysis of the combined inTandem trials, trying to compare efficacy and safety of sota according to BMI (lower or higher than 27 kg/m2).

As this is the cut-off point EMA chose to approve sota, these data appear of interest.

Authors, however, report a substantial similarity in results obtained in the two different BMI classes. A significant difference was found only in placebo corrected HbA1c reduction and in body weight. There were no apparent differences in adverse events.

As a clinician, I do not understand the reason for limiting SGLT inhibitors only to T1D patients with BMI > 27. I could not find any specific result reported in this manuscript in the references (from EMA).

Nor did I find anything in the manuscript on DEPICT in BMI > 27 just published in DOM.

My comments:
1. I suggest caution in the interpretation of DKA episodes. The authors write “In the present analysis, the placebo-adjusted DKA incidence tended to be lower in the BMI ≥27 kg/m2 subgroup relative to those with BMI <27 kg/m2.” If I understand correctly, they were just numerically less. If this is the case, the main interpretation should be “no difference”. This is particularly important in the abstract, where efficacy (different) and DKA (not different) are reported similarly.

1. Some kind of interpretation of their results should be included. All SGLT inhibitors have the same efficacy in type 2 diabetes, whatever the BMI; why should they be different here? My interpretation is that it is just serendipity or, at least, differences in the 2 placebo groups (-0.04 in BMI > 27, -0.06 in BMI < 27).

2. Were there differences in DKA episodes in patients with or without CSII? This is extremely important.

3. Summing DKA and severe hypoglycemia, there were 44 events in BMI < 27 and 44 events in BMI > 27. I don’t see any difference here. If in patients with BMI < 27 there were more DKA events, there were less severe hypos. Why should DKA be more important than severe hypo? DKA can usually be avoided with appropriate education.

4. Regions where the two studies were conducted are different, with different use of CSII. Did these differences influence DKA events and overall results?

5. Time in range was not different. As Authors are well aware, in T1DM TIR improvements are considered as important as HbA1c, especially in the low HbA1c range obtained in these trials.

Minor
7. Insulin doses should be expressed as daily U/kg.

Thanks for your answers.

I still have some points:

In the abstract, the sentence “Consistent with published results for the entire population, fewer severe hypoglycaemia and documented hypoglycaemia ≤3.1 mmol/L events and a higher incidence of diabetic ketoacidosis occurred with sotagliflozin versus placebo”

It is not clear whether you are referring to the overall population or just BMI > 27. If it is the overall, I think that these data have been already published. If it is >27, then it becomes useless, as the focus of the manuscript is >27 vs. < 27.

In the abstract, the sentence “Overall, a trend for an improved efficacy and safety profile was found in patients with baseline BMI >27 kg/m2 compared to those with baseline BMI <27 kg/m2” is not correct.

Safety (hypos + DKA) were just the same.

If Authors wish to differentiate, write less DKA but more hypos (>27 vs <27) in the abstract.

Occurrence of DKA was mainly driven by CSII (table 3 of 10.2337/dc20-0924) much more than BMI.

Apparently, Authors cannot perform any further analysis. At least add a sentence specifying this previously published result on CSII.
Please, provide your responses within the resubmitted manuscript