Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis

Abstract

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI).

Methods and findings: We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53-0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66-0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10-1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33-0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I-III).

Conclusions: SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: JM has received lecture fees from Boehringer Ingelheim and Astra Zeneca. HH has received lecture fees, advisory board Consultant fees, and Research funds from Boehringer Ingelheim and Astra Zeneca.

Figures

Fig 1. PRISMA diagram.

AE, adverse event; AKI, acute kidney injury; NCBI, National Center for Biotechnology Information; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SAE, serious AE.

Fig 2. Effect of SGLT2is on serious AKI AEs in RCTs (Ease 2 and 3 are two separate trials).

AE, adverse event; AKI, acute kidney injury; CI, confidence interval; RCT, randomized controlled trial; SAE, serious AE; SGLT2i, sodium-glucose cotransporter-2 inhibitor.

Fig 3. Effect of SGLT2is on serious and nonserious AKI AEs in RCTs (Ease 2 and 3 are two separate trials).

AE, adverse event; AKI, acute kidney injury; CI, confidence interval; RCT, randomized controlled trial; SAE, serious AE; SGLT2i, sodium-glucose cotransporter-2 inhibitor.

Fig 4. Effect of SGLT2is on AKI in observational cohort studies.

AKI, acute kidney injury; CI, confidence interval; SGLT2i, sodium-glucose cotransporter-2 inhibitor.