Polypharmacology of clinical sodium glucose co-transport protein 2 inhibitors and relationship to suspected adverse drug reactions

Karan Matharu, Kiran Chana, Charles Ferro, Alan M Jones

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Sodium glucose co-transporter 2 inhibitors (SGLT2i) are a promising second-line treatment strategy for type 2 diabetes mellitus (T2DM) with a developing landscape of both beneficial cardio- and nephroprotective properties and emerging adverse drug reactions (ADRs) including diabetic ketoacidosis (DKA), genetic mycotic infections, and amputations among others. A national register study (MHRA Yellow Card, UK) was used to quantify the SGLT2i's suspected ADRs relative to their Rx rate (OpenPrescribing, UK). The polypharmacology profiles of SGLT2i were data-mined (ChEMBL) for the first time. The ADR reports (n = 3629) and prescribing numbers (Rx n = 5,813,325) for each SGLT2i in the United Kingdom (from launch date to the beginning December 2019) were determined. Empagliflozin possesses the most selective SGLT2/SGLT1 inhibition profile at ~2500-fold, ~10-fold more selective than cangliflozin (~260-fold). Canagliflozin was found to also inhibit CYP at clinically achievable concentrations. We find that for overall ADR rates, empagliflozin versus dapagliflozin and empagliflozin versus canagliflozin are statistically significant (χ2, p < .05), while dapagliflozin versus canagliflozin is not. In terms of overall ADRs, there is a greater relative rate for canagliflozin > dapagliflozin > empagliflozin. For fatalities, there is a greater relative rate for dapagliflozin > canagliflozin > empagliflozin. An organ classification that resulted in a statistically significant difference between SGLT2i was suspected infection/infestation ADRs between empagliflozin and dapagliflozin. Our findings at this stage of SGLT2i usage in the United Kingdom suggest that empagliflozin, the most selective SGLT2i, had the lowest suspected ADR incident rate (relative to prescribing) and in all reported classes of ADRs identified including infections, amputations, and DKA.
Original languageEnglish
Article numbere00867
Number of pages11
JournalPharmacology Research and Perspectives
Issue number5
Early online date29 Sept 2021
Publication statusPublished - Oct 2021

Bibliographical note

Funding Information:
The study was not supported with any funding. The authors thank the ChEMBL, Yellow Card, and OpenPrescribing databases for open-source data.

Publisher Copyright:
© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.


  • SGLT2
  • adverse drug reactions
  • polypharmacology

ASJC Scopus subject areas

  • Neurology
  • Pharmacology, Toxicology and Pharmaceutics(all)


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