Sodium/glucose cotransporter 2 inhibitors (SGLT2i / gliflozins) are a novel class of medications which act by inhibiting the SGLT2 transporter located in the S1 segment of the proximal convoluted tubule. This transporter is responsible for 90% of the filtered glucose reabsorption. SGLT2 inhibition increases urinary glucose excretion thereby reducing plasma glucose levels. Though the use of SGLT2 inhibitors was primarily intended for lowering glucose, they also cause modest diuresis and weight loss and lower blood pressure and uric acid in patients with type 2 diabetes mellitus (T2DM), thus extending benefits beyond glycemic control.

Three landmark trials, EMPA-REG OUTCOME, CANVAS, and CREDENCE, have shown significant reductions in cardiovascular mortality and slowing of chronic kidney disease (CKD) progression in patients with T2DM. More recently, the DAPA-CKD study with dapagliflozin was stopped early after investigators reported “overwhelming benefit” for reducing risk of kidney disease progression and death compared to placebo in patients without T2DM.

During safety profile analysis, the FDA Adverse Events Reporting System (FAERS) reported cases of acute kidney injury (AKI) associated with canagliflozin and dapagliflozin use. The FDA label on gliflozins warns about potential AKI and recommends cautious prescription of these drugs based on post-marketing reports.

SGLT2 inhibitors induce a mild acute decline in eGFR by 5 mL/min/1.73 m², attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback through increased macula densa sodium delivery leading to afferent arteriole vasoconstriction and reduced intraglomerular pressure and a decline in eGFR. This functional effect with a subsequent  rise in creatinine fulfills the creatinine-based criteria for AKI defined in clinical practice and trial settings which has the potential to muddy the water.

Other potential mechanisms have been proposed as to how SGLT2 inhibitors lead to AKI. High urinary glucose loss causes osmotic diuresis leading to volume depletion. Increased urinary uric acid level can also cause AKI through crystal-dependent or independent mechanisms. Uptake of glucose in the proximal S3 segment by SGLT1 might lead to activation of aldose reductase, leading to fructose generation. Subsequent metabolism of fructose by fructokinase can lead to intratubular oxidative stress, which can stimulate chemokines, local inflammation, and tubular injury.

In this context, a pre-CREDENCE retrospective cohort study by Rampersad et al recently published in AJKD compared 1:1 matched sets of 4,778 patients with a new prescription for an SGLT2 inhibitor with patients given a new prescription for other glucose lowering drugs (oGLD) in the preceding one-year. Data were acquired from 6 population-wide, administrative health databases in the province of Manitoba, Canada. Patients were followed from June 2014 until March 2017.

Table 3 from Rampersad et al, AJKD, Crown Copyright © 2020

The primary outcome studied was incidence of AKI, identified as a composite of documented AKI diagnostic codes and laboratory data. Serum creatinine value but not urine output was used to identify and stage AKI as defined by KDIGO criteria, while taking glucose-lowering drugs across matched groups. Only the first AKI event while on treatment with gliflozins was included in the analysis. Consistent with previous evidence, AKI risk was lower in SGLT2 inhibitor users (HR, 0.64; 95% CI, 0.40–1.03; P = 0.06). A total of 117 AKI events occurred in total, 47 in the SGLT2 inhibitor group vs 70 in the control group (oGLD). Sensitivity analyses to account for multiple scenarios were all consistent with the primary analysis and did not show higher AKI risk with SGLT2 inhibitors.

In this study by Rampersad et al, it is important to note that >80% of patients did not have laboratory data in the immediate post-prescription phase of SGLT2 inhibitors or oGLDs. It is possible that during this phase, asymptomatic, milder AKI may have been undetected. The authors also mentioned the possibility of some ascertainment bias due to incomplete coverage by provincial database or under-reporting of AKI using appropriate ICD codes. Differences between the association of individual SGLT2is with AKI were not determined in this study.

Table 4 from Rampersad et al, AJKD, Crown Copyright © 2020

Several other studies explored the real world risk of AKI with SGLT2 inhibitors. A propensity-matched analysis of data of >3,000 patients from two large health systems comparing SGLT2 inhibitor users and non-users did not show increased risk of AKI with SGLT2i use. A large clinical study from Israel compared eGFR among users of SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP-4i) which showed that risk of AKI is lower in patients using SGLT2 inhibitors compared to DPP-4i (OR, 0.47; 95% CI, 0.27-0.80). Subsequent meta-analyses of large randomized control trials by Neuen et al and Menne et al, and a population-based cohort study by Iskander et al revealed SGLT2 inhibitor use actually reduced the risk of AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more adverse events related to hypovolemia were reported.

The mechanisms reducing incidence of AKI with SGLT2 inhibitor use in type 2 diabetes are unclear. Potential factors contributing to renoprotection with SGLT2i include:

1. Increased nitric oxide-dependent vasodilatation reduces ischemia-reperfusion injury and AKI.
2. Decreased peritubular hemorrhage and renal fibrosis.
3. Increased vascular endothelial growth factor A expression in response to ischemia/reperfusion injury.

In conclusion, robust evidence from clinical studies, propensity-matched analyses, and meta-analyses demonstrate that SGLT2 inhibitor use does not predispose to clinically significant AKI which needs treatment but actually appear to provide protection against AKI. All of this is also in the context of the undeniable benefits of long-term SGLT2 inhibitor use to reduce the risk of dialysis, transplant, or death due to kidney disease in patients with T2DM.

– Post prepared by Krishna Penmatsa, AJKDBlog Guest Contributor. Follow him @krishnadoctor1.

To view Rampersad et al (FREE until Feb 1, 2021), please visit AJKD.org. 

Title: Acute Kidney Injury Events in Patients With Type 2 Diabetes Using SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs: A Retrospective Cohort Study
Authors: C. Rampersad, E. Kraut, R.H. Whitlock, P.Komenda, V. Woo, C. Rigatto, and N. Tangri
DOI: 10.1053/j.ajkd.2020.03.019