PREreview of SGLT2 transcriptomic expression atlas supports a kidney-centric role for empagliflozin’s benefits in heart failure

We, Aline Wisnivesky and Gabriela Catão Diniz Braga, are PhD students at the Medical School of University of São Paulo, and review emerged as a product of the graduate-level course titled “How to Read and Evaluate Scientific Papers and Preprints”, which was designed to offer students the chance to analyze scientific articles, foster critical and constructive discussions and grasp how the peer review process works.

The pre-print entitled “SGLT2 transcriptomic expression atlas supports a kidney-centric role for empagliflozin’s benefits in heart failure” hypothesizes that inhibitors of SGLT2 (SGLT2i) act directly on the heart, and its aim is to examine the expression of SLC5A2 at the single cell level with a focus on cells in the cardiovascular system. This aim is important due to the known benefits of SGLT2i, as reduction of mortality and hospitalization for heart failure (HF) (1), and because its mechanisms still need to be elucidated. We found this study interesting because of the analysis of the SGLT2 transcriptomicexpression in the kidney and heart, which is similar to our study field. We understood that this study is at its beginning and we went ahead to try to contribute with other perspectives:

Results. Figure 1A- 1F: This result shows if there is SLC5A1 and SLC5A2 transcriptomic expression in the kidney and heart. The figure 1A, C, D and E are in concordance with datas in the literature. However, the lack of SLC5A1 expression in the kidney (Figure 1B) contradicts some studies (2, 3, 4), so we were wondering if it would be interesting to have SLC5A1 expression from other databases to make sure about this result. Figure 1G: The heart-on-a-chip is an incredibly interesting experimental model, which was used to analyze the passive tension after treatment with empagliflozin (EMPA). The result showing that EMPA does not improve the passive tension is relevant, and it could be interesting to include other parameters, commonly used in cardiomyocytes function studies, such as cell hypertrophy, contractility and calcium handling, that could improve your data and may lead to a more solid conclusion. In addition, we think that this graph could be improved by adding the name of the cell used in the control group and adding a fibroblast control group, if possible; and the population number used in each group would be interesting to be shown in the graph.Your data shows that EMPA does not ameliorate diastolic dysfunction, but other studies have proved that it can prevent it (5, 6). Therefore, if it would be in the interest of the authors, we thought about an experiment with diastolic dysfunction, inicial diastolic function and health cells, all treated with EMPA, in order to answer if this drug has any impact on any developmental stage of this condition. Some points of comparison between the benefits found in the Kwong-Man Ng et al’s study (reference #7 in the preprint) can be a bit confusing, once they used a diabetic model of cellular dysfunction, with glucose to induce stress. Because of that, we believe that perhaps looking for other models that are more similar to the result of Figure 1G could make the comparison more easy and accurate.

Conclusion. Some studies indicate that EMPA has pleiotropic effects in heart and kidney (7-14). Given that the authors expressed an opposing view about the direct effects on the heart, it might be worthwhile for them to incorporate additional studies that support this conclusion.

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Thank you for the possibility of reading your pre-print. We hope our comments will be of good use.

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Competing interests

The author declares that they have no competing interests.