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 (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 (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.
Highlights
Sodium glucose co-transporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic medication for type 2 diabetes.[1,2] At the time of writing, four SGLT2i have been approved for use in clinical practice in the United Kingdom: dapagliflozin (2012), canagliflozin (2013), empagliflozin (2014), and ertugliflozin (2019), respectively.In comparison to other antidiabetic medication,[3] the pharmacological action of SGLT2i works independently of insulin.4–6 SGLT2i competitively bind to SGLT2, are predominantly found in the kidneys, and are responsible for 90% of glucose reabsorption in the body, leading to the inhibition of this transporter
An organ classification that resulted in a statistically significant difference between SGLT2i was suspected infection/infestation adverse drug reactions (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 and in all reported classes of ADRs identified including infections, amputations, and diabetic ketoacidosis (DKA)
SGLT2i have both cardioprotective and nephroprotective features.[7,8,10]. This has been supported by the following EMPA- REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), DAPA-HF (Dapaglifozin and Prevention of Adverse Outcomes in Heart Failure), and CANVAS trials.5,6,11–15 Collectively, the results of the landmark trials demonstrated that SGLT2i correspond to a reduction in all cardiovascular mortality risks, reduced heart failure-associated hospitalization, and decline in chronic kidney disease (CKD) progression in diabetic patients.[16]
Summary
Sodium glucose co-transporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic medication for type 2 diabetes.[1,2] At the time of writing, four SGLT2i have been approved for use in clinical practice in the United Kingdom (approval date in parentheses): dapagliflozin (2012), canagliflozin (2013), empagliflozin (2014), and ertugliflozin (2019), respectively.In comparison to other antidiabetic medication,[3] the pharmacological action of SGLT2i works independently of insulin.4–6 SGLT2i competitively bind to SGLT2, are predominantly found in the kidneys, and are responsible for 90% of glucose reabsorption in the body, leading to the inhibition of this transporter. Diabetes is associated with both macrovascular and microvascular complications, an example being diabetic nephropathy which is caused by damage to blood vessels due to high blood glucose Another indirect action of SGLT2 inhibition is natriuresis; this further reduces blood pressure and slows down the progression of chronic kidney disease (CKD).[6] SGLT2i have both cardioprotective and nephroprotective features.[7,8,10] This has been supported by the following EMPA- REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), DAPA-HF (Dapaglifozin and Prevention of Adverse Outcomes in Heart Failure), and CANVAS (the CANagliflozin cardioVascular Assessment Study) trials.5,6,11–15 Collectively, the results of the landmark trials demonstrated that SGLT2i correspond to a reduction in all cardiovascular mortality risks, reduced heart failure-associated hospitalization, and decline in CKD progression in diabetic patients.[16] These properties were identified to be shared across the SGLT2i class and highlight the potential use in other co-morbidities including non-diabetic CKD.[17]
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