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

Abstract

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 ( R x 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 ( χ 2 , 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.

Suspected adverse drug reactions of the type 2 antidiabetic drug class dipeptidyl‐peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?

“…Whilst standardization is often ADRs/100000 R x , 19 , 75 the resulting numbers were not suitable for Chi‐squared analysis (which is only valid where numbers are >5). 76 Therefore, standardizing the ADRs per million prescriptions improved the validity; however, it should be noted that any significant difference in the data reported relates to a population‐level risk rather than individual risk.…”

Suspected Adverse Drug Reactions of the Type 2 Antidiabetic Drug Class Dipeptidyl-Peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?

“…S3 shows the tablet strengths available for each DPP4i and therefore if multiple tablets are prescribed to make the BNF indicated dose, ADRs may appear higher than the true value (the exception being linagliptin which has only one formulated strength tablet). Whilst standardisation is often ADRs/100,000 Rx, [19] [75] the resulting numbers were not suitable for Chi squared analysis (which is only valid where numbers are >5). [76] Therefore, standardised the ADRs per million prescriptions improve the validity; however, it should be noted that any significant difference in the data reported relates to a population level risk rather than an individual risk.…”

“…Whilst standardisation is often ADRs/100,000 R x ,[19][75] the resulting numbers were not suitable for Chi squared analysis (which is only valid where numbers are >5). [76] Therefore, standardised the ADRs per million prescriptions improve the validity; however, it should be noted that any significant difference in the data reported relates to a population level risk rather than an individual risk.…”

Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective National Register Study into suspected associated adverse drug reactions

“…21 Understanding the pharmacology of a drug may help predict ADR prevalence as unwanted protein-drug interactions can have unintended consequences in certain patient populations. [22][23][24] Studies have assessed ARB ADRs 2 but the relationship between the pharmacology of ARBs and their respective ADRs has yet to be investigated. Furthermore, recent media attention regarding the detection of potential carcinogens in specific ARB products warranted an application of our technique to understand the potential relationship between ARB ADRs and the presence of a mutagenic contaminant in certain batches.…”

“…Understanding the pharmacology of a drug may help predict ADR prevalence as unwanted protein–drug interactions can have unintended consequences in certain patient populations 22–24 . Studies have assessed ARB ADRs 2 but the relationship between the pharmacology of ARBs and their respective ADRs has yet to be investigated.…”