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Analysis of time-dependent alterations of parameters related to erythrocytes after ipragliflozin initiation

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Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors often increase the hematocrit. It remains unclear whether this increase would be observed in all patients administered SGLT2 inhibitors, however. We therefore used the data from the previous study and investigated time-dependent alterations of various outcomes related to erythrocytes, erythropoiesis, and clinical outcome in type 2 diabetes subjects (n = 89) treated with ipragliflozin for 16 weeks. Among a total of 89 participants, 71 subjects (80.0% of total participants) showed the elevation of the hematocrit and 18 subjects (20.0% of total participants) did not at 16 weeks. Although the hematocrit levels at baseline were significantly lower in hematocrit-elevated group than non-elevated group, they reached the same levels 4 weeks after the onset of treatment. Binomial logistic regression analysis demonstrated that a lower baseline hematocrit level was related to the elevation of hematocrit at 16 weeks. Optimal cutoff hematocrit levels at baseline to predict hematocrit elevation were 46.9% (male) and 41.7% (female) in ROC analysis. Random intercept model analysis revealed the serum erythropoietin level increased in both hematocrit-elevated and non-elevated groups, whereas only the former group showed an increase in the percentage of reticulocytes during the first 4 weeks. These results suggest that the ipragliflozin-induced increase in hematocrit which is affected by the baseline hematocrit level is attributable to the responsiveness to, but not to the production of, erythropoietin. Collectively, Ht elevation observed in administration of SGLT2 inhibitors can result from erythropoietin-induced erythropoiesis, which is determined by the pre-treatment Ht level.

Trial registration: This trial has been registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR no. 000015478).

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Acknowledgements

We thank all the patients, SOAR-KOBE study investigators, and staff at participating sites for their contributions to this study. We also thank Prof. Takashi Omori for the helpful suggestion in statistics. The company was not involved in study design, patient selection, data collection/analysis, interpretation of results, or preparation of the manuscript.

Funding

This investigator-initiated trial was funded by Astellas Pharma Inc. (Tokyo, Japan).

Author information

Authors and Affiliations

  1. Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Tomoko Yamada, Kazuhiko Sakaguchi, Yuko Okada, Hiroshi Miura, Natsu Otowa-Suematsu, Anna So, Hisako Komada, Yushi Hirota, Yoshikazu Tamori & Wataru Ogawa

  2. Division of General Internal Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

    Kazuhiko Sakaguchi

  3. Department of Diabetes and Endocrinology, Hyogo Brain and Heart Center, Himeji, Japan

    Takeshi Ohara

  4. Department of Internal Medicine, Kobe Century Memorial Hospital, Kobe, Japan

    Yasuo Kuroki

  5. Department of Diabetes and Endocrine Disease, Kita-Harima Medical Center, Ono, Japan

    Kenta Hara

  6. Department of Internal Medicine, Kaisei Hospital, Kobe, Japan

    Tomokazu Matsuda

  7. Department of Internal Medicine, Nishiwaki Municipal Hospital, Nishiwaki, Japan

    Minoru Kishi

  8. Department of Diabetic and Metabolic Medicine, Shinko Hospital, Kobe, Japan

    Akihiko Takeda

  9. Department of Internal Medicine, Yokota Medical Clinic, Akashi, Japan

    Kazuki Yokota

  10. Division of Creative Health Promotion, Department of Social/Community Medicine and Health Science, Kobe University Graduate School of Medicine, Kobe, Japan

    Yoshikazu Tamori

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  1. Tomoko Yamada
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  2. Kazuhiko Sakaguchi
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  3. Yuko Okada
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  7. Hisako Komada
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  8. Yushi Hirota
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  9. Takeshi Ohara
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  10. Yasuo Kuroki
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  13. Minoru Kishi
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  14. Akihiko Takeda
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  15. Kazuki Yokota
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  16. Yoshikazu Tamori
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  17. Wataru Ogawa
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Corresponding author

Correspondence to Kazuhiko Sakaguchi.

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Conflict of interest

KS, YO, YH, YT, and WO have received unlimited grant support as well as lecture fees from MSD and Astellas Pharma Inc. TO, KH, MK, TM, and AT have received lecture fees from MSD and Astellas Pharma Inc. YK has received lecture fees from MSD. The remaining authors (TY, HM, NO-S, AS, HK, and KY) have nothing to disclose.

Human rights statement

The study was conducted in accordance with the Declaration of Helsinki and its amendments, and it was approved by the institutional review boards of the participating facilities. Written informed consent was obtained from all participants. Date of approval: Apr 13, 2015. Approval number: 1713.

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Appendix

Appendix

Principal investigators at the participating centers are as follows: Kazuhiko Sakaguchi (Kobe University Hospital, Obara Hospital), Takeshi Ohara (Hyogo Brain and Heart Center), Yasuo Kuroki (Kobe Century Memorial Hospital), Kenta Hara (Kita-harima Medical Center), Tomokazu Matsuda (Kaisei Hospital), Minoru Kishi (Nishiwaki Municipal Hospital), Akihiko Takeda (Shinko Hospital), and Kazuki Yokota (Yokota Medical Clinic).

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Yamada, T., Sakaguchi, K., Okada, Y. et al. Analysis of time-dependent alterations of parameters related to erythrocytes after ipragliflozin initiation. Diabetol Int 12, 197–206 (2021). https://doi.org/10.1007/s13340-020-00474-2

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  • DOI: https://doi.org/10.1007/s13340-020-00474-2

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