Donna Shu-Han Lin1, Jen-Kuang Lee1,2,3,4,5, Wen-Jone Chen1,4,6. 1. Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 2. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. 3. Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. 4. Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan. 5. Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan. 6. Department of Emergency, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract
OBJECTIVES: This meta-analysis aimed to investigate the occurrence of various adverse events (AEs) associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and to examine the level of risk of AEs in patients with different underlying diseases. BACKGROUND: SGLT2i are first-line antidiabetic agents with demonstrated cardiovascular benefits. Prior meta-analyses have examined AEs associated with these drugs in general, but such knowledge needs to be updated with the results of more recent trials. In addition, the occurrence of various AEs with different underlying diseases is unknown. METHODS: We conducted a quantitative meta-analysis of randomized controlled trials (RCTs) retrieved from the MEDLINE and EMBASE databases and the Cochrane library were searched on January 31 th, 2021. Outcomes of interest included 4 overall safety outcomes (AEs) and 12 specified safety outcomes. Further analyses were performed on various subgroups, which were defined based on the status of diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and congestive heart failure, and by the dosage of SGLT2i (high dose versus low dose). RESULTS: Our analysis included 10 eligible studies with a total of 71,553 participants. The meta-analysis showed that SGLT2i led to increased risks of genital infection (risk ratio [RR] 3.56, 95% confidence interval [CI] 2.84-4.46), urinary tract infection (RR 1.06, 95% CI 1.00-1.12), diabetic ketoacidosis (RR 2.23, 95% CI 1.36-3.63), and volume depletion (RR 1.14, 95% CI 1.06-1.23). However, the use of SGLT2i was associated with reduced risks of any serious AE (RR 0.92, 95% CI 0.90-0.94), acute kidney injury (AKI) (RR 0.84, 95% CI 0.77-0.91), and hyperkalemia (RR 0.84, 95% CI 0.72-0.99). Within the different subgroups, the risk of amputation was higher in patients with ASCVD than in those without (RR 1.44 vs. 0.96, P = 0.066). CONCLUSIONS: The use of SGLT2i is generally safe. SGLT2i may be associated with increased risks of genital infection but is protective against AKI. Of note, the risk of amputation was higher in patients with ASCVD. The key to the safe use of SGLT2i lies in the identification of high-risk populations and close surveillance of patients after treatment.
OBJECTIVES: This meta-analysis aimed to investigate the occurrence of various adverse events (AEs) associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and to examine the level of risk of AEs in patients with different underlying diseases. BACKGROUND: SGLT2i are first-line antidiabetic agents with demonstrated cardiovascular benefits. Prior meta-analyses have examined AEs associated with these drugs in general, but such knowledge needs to be updated with the results of more recent trials. In addition, the occurrence of various AEs with different underlying diseases is unknown. METHODS: We conducted a quantitative meta-analysis of randomized controlled trials (RCTs) retrieved from the MEDLINE and EMBASE databases and the Cochrane library were searched on January 31 th, 2021. Outcomes of interest included 4 overall safety outcomes (AEs) and 12 specified safety outcomes. Further analyses were performed on various subgroups, which were defined based on the status of diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and congestive heart failure, and by the dosage of SGLT2i (high dose versus low dose). RESULTS: Our analysis included 10 eligible studies with a total of 71,553 participants. The meta-analysis showed that SGLT2i led to increased risks of genital infection (risk ratio [RR] 3.56, 95% confidence interval [CI] 2.84-4.46), urinary tract infection (RR 1.06, 95% CI 1.00-1.12), diabetic ketoacidosis (RR 2.23, 95% CI 1.36-3.63), and volume depletion (RR 1.14, 95% CI 1.06-1.23). However, the use of SGLT2i was associated with reduced risks of any serious AE (RR 0.92, 95% CI 0.90-0.94), acute kidney injury (AKI) (RR 0.84, 95% CI 0.77-0.91), and hyperkalemia (RR 0.84, 95% CI 0.72-0.99). Within the different subgroups, the risk of amputation was higher in patients with ASCVD than in those without (RR 1.44 vs. 0.96, P = 0.066). CONCLUSIONS: The use of SGLT2i is generally safe. SGLT2i may be associated with increased risks of genital infection but is protective against AKI. Of note, the risk of amputation was higher in patients with ASCVD. The key to the safe use of SGLT2i lies in the identification of high-risk populations and close surveillance of patients after treatment.