Menne J, Dumann E, Haller H, et al. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. PLoS Med. 2019 Dec 9;16(12):e1002983. doi: 10.1371/journal.pmed.1002983. eCollection 2019 Dec. (Systematic review)

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.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 7 / 7
General Internal Medicine-Primary Care(US) 7 / 7
Internal Medicine 7 / 7
Endocrine 7 / 7
Nephrology 6 / 7
Comments from MORE raters

Endocrine rater

Data on SGLT2 effectiveness are well-known; data on renal outcomes less commonly appreciated.

Family Medicine (FM)/General Practice (GP) rater

We could not detect an increased risk of acute kidney injury in patients taking SGLT2is. Patients taking SGLT2is had lower odds of suffering an acute kidney injury than those who did not, despite the fact that these drugs increase fluid loss by the body. Our findings indicate that fear of causing acute kidney injury should not stop practitioners prescribing SGLT2is. However, our analysis had some drawbacks, such as inconsistent definitions being used in some of the studies and different patient characteristics in the included studies.

General Internal Medicine-Primary Care(US) rater

Accordingly, heterogeneity in the definition and treatment was common. What about the infection rate? We need prospective studies to provide clear evidence.

Internal Medicine rater

The results are astonishing and the study question is unorthodox.

Nephrology rater

This meta-analysis examined the effects of SGLT2 inhibitors on the risk of acute kidney injury (AKI) in people with type 2 diabetes. SGLT2 inhibitors may provide protection from AKI in individuals with type 2 diabetes; however, prospective studies evaluating this concept are needed. Because of the more prominent decrease in eGFR in patients with moderate CKD, cautious use of SGLT2-i in patients with reduced eGFR is advised and this population should be included in future trials

Nephrology rater

These results are very similar to another SR on the topic (https://pubmed.ncbi.nlm.nih.gov/31495651-sglt2-inhibitors-for-the-prevention-of-kidney-failure-in-patients-with-type-2-diabetes-a-systematic-review-and-meta-analysis/) which only included large RCTs. Same pooled HR (0.75) since those 4 large RCTs contribute >50% patient numbers to the 112 RCTs in this, with actually similar N of AKI events (since the larger RCTs are also longer to capture more events). The additional useful information in this SR is that they also looked at the so-called RWE, observational data, which also mercifully report a result in the similar direction (though even larger magnitude, likely residual confounding or selection bias). This is noteworthy since people are still unaware of these. SGLT2i are added to sick day medication lists often and the risk of euglycemic AKI remains, but risk of AKI is indeed lower. This needs to be more widely known and appreciated.
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