Acute kidney injury (AKI) can be a complication seen in patients with type 2 diabetes mellitus (T2DM) who are on glucose-lowering agents. Diabetic kidney disease is a major cause of chronic kidney disease, and the presence of diabetes is an independent risk factor for both AKI and poor clinical outcomes.
Sodium glucose co-transporter-2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new classes of glucose-lowering agents for treating T2DM. However, little is known about the comparative effects of these three glucose-lowering agents on AKI.
Network meta-analysis is a method that enables comparison of these three glucose-lowering agents in the same analysis. Thus, we applied a network meta-analysis to analyze data from 20 event-driven cardiovascular or kidney outcome randomized clinical trials. Of the 20 trials analyzed, 18 included patients with T2DM only, and two trials included patients with or without T2DM. Of the 18 trials, which included a total of 156,690 patients with T2DM receiving these glucose-lowering agents, 2051 AKI events occurred. Interestingly, patients taking SGLT2 inhibitors had a lower risk of AKI than those taking placebo by 24%, whereas both DPP-4 inhibitors and GLP-1RAs had no effect on risk of AKI.
Moreover, SGLT2 inhibitors were significantly associated with a lower risk of AKI than DPP-4 inhibitors (odds ratio [OR] = 0.68) and GLP-1RAs (OR = 0.79). Among the three glucose-lowering agents, SGLT2 inhibitors were the lowest risk for AKI. When we analyzed 20 trials involving patients with or without T2DM, the results remained similar. Therefore, these data suggest that SGLT2 inhibitors may protect against AKI. However, several limitations should be considered, including the various definitions of AKI used in the different trials and AKI not being reported as the primary outcome in the included trials.
As SGLT2 inhibitors cause an acute drop in glomerular filtration rate, our finding of a protective effect for these agents is perhaps surprising and raises questions about the mechanism of AKI. The multifactorial nature of AKI means there are likely multiple mechanisms that lead to the protection against AKI seen with SGLT2 inhibitors. It is possible that the acute reduction in glomerular filtration rate seen with SGLT2 inhibitors appears to confer protection against AKI, potentially through reducing kidney oxygen demands further.
The results of this study suggest that SGLT2 inhibitors not only clearly prevent progressive loss of kidney function and kidney failure but also specifically reduce the risk of AKI.
For details on the study, check out our findings in the January 2021 issue of CJASN (1).
Zhao M, et al. Network meta-analysis of novel glucose-lowering drugs on risk of acute kidney injury. Clin J Am Soc Nephrol 2021; 16:70–78. doi: https://doi.org/10.2215/CJN.11220720