Markers of Kidney Injury, Inflammation, and Fibrosis Associated With Ertugliflozin in Patients With CKD and Diabetes

Abstract

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that are incompletely understood. In this exploratory post-hoc analysis of the VERTIS RENAL trial, we report the association between the SGLT2 inhibitor, ertugliflozin, and markers of kidney injury, inflammation, and fibrosis in participants with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD).

Methods: Participants were randomized to ertugliflozin (5 or 15 mg/d) or placebo, and plasma samples for biomarker analysis were collected at baseline, 26 weeks, and 52 weeks.

Results: Ertugliflozin-treated participants had lower plasma levels of kidney injury molecule-1 (KIM-1) at 26 weeks (P = 0.044) and 52 weeks (P = 0.007) and higher eotaxin-1 at 52 weeks (P = 0.007) postrandomization compared with placebo. The change in KIM-1 was not associated with the baseline urine albumin to creatinine ratio (UACR) or the estimated glomerular filtration rate (eGFR, P interaction > 0.05). Additionally, the change in KIM-1 was positively correlated with the change in UACR in participants treated with ertugliflozin (P = 0.0071). No other significant associations between ertugliflozin and changes in the markers of tubular injury, inflammation, fibrosis, oxidative stress, and endothelial dysfunction were observed.

Conclusion: In conclusion, in participants with T2D and stage 3 CKD, ertugliflozin was associated with a sustained lowering of the tubular injury marker KIM-1 regardless of baseline kidney function.

Keywords: biomarkers; chronic kidney disease; ertugliflozin; kidney injury molecule-1; sodium-glucose cotransporter-2 inhibition; type 2 diabetes.

Graphical abstract

Figure 1

A flow diagram of the study participants.

Figure 2

The change in kidney injury molecule-1 (KIM1) after ertugliflozin treatment and placebo. Black lines/circles, placebo; red lines/circles, ertugliflozin (pooled 5 and 15 mg/d). Data are presented as median % change ± interquartile range for presentation purposes. Data were analyzed using the mixed-effect regression model and post-hoc least squares mean results for individual time points, ∗P ≤ 0.05.

Figure 3

The change in eotaxin-1 after ertugliflozin treatment and placebo. Black lines/circles, placebo; red lines/circles, ertugliflozin (pooled 5 and 15 mg/d). Data are presented as median % change ± interquartile range for presentation purposes. Data were analyzed using the mixed-effect regression model and post-hoc least squares means results for individual time points, ∗P ≤ 0.05.

Figure 4

The change in kidney injury molecule-1 (KIM1) after ertugliflozin treatment stratified by urine albumin to creatine ratio (UACR) (≥30 mg/g, n = 112 or <30 mg/g, n = 111; P interaction = 0.089) and estimated glomerular filtration rate (eGFR) (≥45 ml/min per 1.73 m², n = 158 or <45 ml/min per 1.73 m², n = 68; P interaction = 0.973) at 26 and 52 weeks. Data are presented as least square mean (LSM) change ± 95% confidence interval. Data were analyzed using the mixed-effect regression model and post-hoc least squares means results for individual time points.

Figure 5

The correlation of the change in kidney injury molecule-1 (KIM1) and the change in urine albumin to creatinine ratio (UACR) from baseline to 26 weeks (blue lines/dots, Pearson’s r = 0.1716, P = 0.0442) and baseline to 52 weeks (red lines/dots, Pearson’s r = 0.2334, P = 0.0071) in the ertugliflozin group.

Figure 6

The correlation of the baseline kidney injury molecule-1 (KIM1) with the change in estimated glomerular filtration rate (eGFR) from baseline to 52 weeks in placebo- and ertugliflozin-treated participants (Pearson’s r = −0.21508, P = 0.0031).