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SGLT-2 inhibitors and euglycemic diabetic ketoacidosis/diabetic ketoacidosis in FAERS: a pharmacovigilance assessment

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Abstract

Aims

To investigate the main feature and the association between euglycemic diabetic ketoacidosis (euDKA) /diabetic ketoacidosis (DKA) and sodium-dependent glucose transporters 2 inhibitors (SGLT-2i) from the FDA adverse event reporting system (FAERS).

Methods

Cases of SGLT-2i-associated with euDKA/DKA were extracted from the FAERS database and compared with the reports for other hypoglycemia agents (ATC10 class). Disproportionality analyses used the reporting odds ratio (ROR) and information components (IC). The lower limit of the IC 95% credibility interval for IC > 0 is considered a reported signal, with at least 3 cases.

Results

A total of 10,195 cases of euDKA (n = 1680) and DKA (n = 8515) associated with SGLT-2i were identified from the FAERS. The SGLT-2i was associated with higher reporting of euDKA and DKA compared to other hypoglycemia agents (ROR = 16.69 [95% CI 14.89–18.70], IC = 3.27 [95% CI 2.91–3.66] for euDKA; ROR = 16.44 [95% CI 15.72–17.20], IC = 3.19 [95% CI 3.05–3.34] for DKA). In available data, the median onset time of euDKA/DKA was 31 days, and canagliflozin had the longest onset time (96.5 days for euDKA and 75 days for DKA) compared with dapagliflozin and empagliflozin (p < 0.05). Male patients predominate in euDKA (51.9%), and female patients predominate in DKA (53.7%). Most patients discontinue the treatment (95.5% for euDKA, 93.9% for DKA), and approximately 49.0% (n = 3658) of patients had symptomatic remission after discontinuation of SGLT-2i, and 2.3% (n = 173) of patients had no remission. About 75.6% (n = 6126) of patients need hospitalization after euDKA/DKA.

Conclusions

Post-marketing data showed that SGLT-2i was significantly associated with higher reporting of euDKA/DKA. Although euDKA/DKA is rare, clinicians should be aware of SGLT-2i-associated euDKA/DKA events.

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Data availability

The data analyzed during the current study are available in the following resource available in the public domain: http://openvigil.pharmacology.uni-kiel.de/openvigilfda.php.

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Acknowledgments

We would like to express our gratitude to professor Xiao Chen for his expert opinions on this subject.

Author information

Author notes

  1. Zhichao He, Kakei Lam, Wenxia Zhao and Shan Yang have contributed equally.

Authors and Affiliations

  1. Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People’s Republic of China

    Zhichao He, Wenxia Zhao, Shan Yang, Siyuan Gao, Dan Liang, Kaifeng Qiu & Junyan Wu

  2. School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 Waihuan East Road, Guangzhou, 511400, People’s Republic of China

    Kakei Lam, Yu Li, Jiayao Mo & Min Huang

  3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People’s Republic of China

    Zhichao He, Wenxia Zhao, Shan Yang, Siyuan Gao, Dan Liang, Kaifeng Qiu & Junyan Wu

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Contributions

All authors contributed to the study conception and design. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. J.W., M.H. and K.Q. were involved in conceptualization; Z.H., W.Z. and K.L. contributed to methodology; Z.H., W.Z., K.L., S.Y., Y.L., J.M., S.G. and D.L. were involved in formal analysis and investigation; S.Y., Y.L., J.M. and K.L. contributed to writing—original draft preparation; Z.H., W.Z., S.Y. and K.L were involved in writing—review and editing.

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Correspondence to Kaifeng Qiu, Min Huang or Junyan Wu.

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He, Z., Lam, K., Zhao, W. et al. SGLT-2 inhibitors and euglycemic diabetic ketoacidosis/diabetic ketoacidosis in FAERS: a pharmacovigilance assessment. Acta Diabetol 60, 401–411 (2023). https://doi.org/10.1007/s00592-022-02015-6

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