Risks of amputation and fracture due to sodium glucose co-transporter 2 inhibitors: a study based on the related data in the US Food and Drug Administration Adverse Event Reporting System

Objective To evaluate the risk of acute kidney injury (AKI) induced by sodium glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin). Methods Reports of AKI events induced by SGLT2 inhibitors and non-SGLT2 inhibitors received from January 1, 2013 to September 30, 2018 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database were collected. The relationship between the drugs mentioned above and the AKI events in all patients and especially in patients with diabetes mellitus, respectively, were analyzed by the method of reporting odds ratio (ROR). Results A total of 2 949 reports of SGLT2 inhibitors-induced AKI (2.50% of 117 843 AKI event reports in the database during the study period), and 114 894 reports of non-SGLT2 inhibitors-induced AKI were retrieved from the database. The ROR values of AKI events induced by overall SGLT2 inhibitors, canagliflozin, dapagliflozin, and empagliflozin in all patients were 4.14 (95%CI: 3.98-4.30), 5.58 (95%CI: 5.35-5.83), 2.62 (95%CI: 2.35-2.92), and 1.96 (95%CI: 1.76-2.19), respectively, and in patients with diabetes mellitus were 2.84 (95%CI: 2.71-2.98), 3.90 (95%CI: 3.69-4.12), 1.70 (95%CI: 1.48-1.94), and 1.30 (95%CI: 1.15-1.48), respectively. Due to the short time to market, less than 3 reports of AKI events induced by ertugliflozin were reported, thus ROR analysis was not conducted for ertugliflozin. The analyses of combined medication showed that in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 8.05 (95%CI: 7.10-9.13) when SGLT2 inhibitors were combined with diuretics, which increased by 80.90% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 6.07 (95%CI: 5.27-7.00), which increased by 92.09%; in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 5.87 (95%CI: 4.89-7.04) when SGLT2 inhibitors were combined with non-steroidal anti-inflammatory drugs (NSAID), which increased by 39.43% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 4.66 (95%CI: 3.79-5.74), which increased by 61.25%; in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 5.60 (95%CI: 5.12-6.14) when SGLT2 inhibitors were combined with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which increased by 25.56% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 4.05 (95%CI: 3.66-4.48), which increased by 27.36%. Conclusions SGLT2 inhibitors might increase the risk of AKI and this risk was mainly from canagliflozin, suggesting that dapagliflozin and empagliflozin were relatively safe to patients. The risk of AKI might increase when SGLT2 inhibitors were combined with diuretics or NSAID. Key words: Sodium-glucose transporter 2 inhibitors; Diabetes mellitus; Acute kidney injury; Odds ratio; Drug interaction; Adverse drug reaction reporting systems