Negative Association of SGLT2 Inhibitors with Epilepsy Risk Compared with DPP-4 Inhibitors in Type 2 Diabetes: A Target Trial Emulation

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In their manuscript Doege et al. investigate the association between SGLT2 inhibitor therapy and incident of epilepsy in patients with type 2-diabetes using a trial emulation approach. The topic is clinically relevant and the manuscript is generally well written. However, I believe that the manuscript would benefit from a more comprehensive discussion of the recently published study, which reported highly similar findings, as well as from a more cautious interpretation of the observed associations and potential residual confounding factors.

Point 1. It may be worthwhile to discuss and cite the recently published study by Zhao et al. Diabetes Care 2025, as the overall observations of the present study appears highly consistent with their findings, including a remarkably similar results, e.g. HR 0.71 vs HR 0.72.

Point 2. The title, abstract, and parts of the discussion may overstate the clinical interpretation of the findings. Although the reported association reached statistical significance, the absolute difference between treatment groups was relatively small, 2.05 vs 2.45 cases per 1000 person-years, corresponding to approximately 0.04%. In my opinion, despite the well structure study design and statistical adjustment procedures, residual confounding factors cannot be excluded. Obviously, in the manuscript there is a limited detailed characterization of potential residual differences between treatment groups beyond statistical weighting procedures. Clinically relevant variables such as diabetes duration, renal function, cardiovascular burden, treatment adherence, and socioeconomic or lifestyle-related factors may still have differed between groups and could partially account for the observed association. Therefore, more cautious wording emphasizing association rather than causal interpretation would be appropriate throughout the manuscript, and importantly may also contribute to a more balanced evaluation of the previously reported resutls by Zhao et al., where similar methodological limitations and concenrs may also be applied.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

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Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

All the comments have been addressed. The manuscript was improved enough to be published in Diabetology.