Is There a Role for SGLT2 Inhibitors in Patients with End-Stage Kidney Disease?

Abstract

Purpose of review: Chronic kidney disease and end-stage kidney disease (ESKD) are well-established risk factors for cardiovascular disease (CVD), the leading cause of mortality in the dialysis population. Conventional therapies, such as statins, blood pressure control, and renin-angiotensin-aldosterone system blockade, have inadequately addressed this cardiovascular risk, highlighting the unmet need for effective treatment strategies. Sodium-glucose transporter 2 (SGLT2) inhibitors have demonstrated significant renal and cardiovascular benefits among patients with type 2 diabetes, heart failure, or CKD at risk of progression. Unfortunately, efficacy data in dialysis patients is lacking as ESKD was an exclusion criterion for all major clinical trials of SGLT2 inhibitors. This review explores the potential of SGLT2 inhibitors in improving cardiovascular outcomes among patients with ESKD, focusing on their direct cardiac effects.

Recent findings: Recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population. SGLT2 inhibitors may provide cardiovascular benefits to dialysis patients, not only indirectly by preserving the remaining kidney function and improving anemia but also directly by lowering intracellular sodium and calcium levels, reducing inflammation, regulating autophagy, and alleviating oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells. This review examines the current clinical evidence and experimental data supporting the use of SGLT2 inhibitors, discusses its potential safety concerns, and outlines ongoing clinical trials in the dialysis population. Further research is needed to evaluate the safety and effectiveness of SGLT2 inhibitor use among patients with ESKD.

Keywords: Autophagy; Chronic kidney disease; Dialysis; End-stage kidney disease; Heart failure; Inflammation; Mortality; Oxydative stress; Residual kidney function; Sodium-glucose cotransporter-2 inhibitors.

Fig. 1

Potential direct and indirect cardiovascular benefit of SGLT2 inhibitors in the dialysis population. Potential indirect benefits include preservation of kidney function, which can lead to multiple benefits from various aspects including uremic toxin levels, volume and blood pressure (BP) control, and nutrition. SGLT2 inhibitors also improve anemia and iron utilization, leading to less requirement of erythropoietin stimulating agents (ESAs), which is known to increase the risk of cardiovascular events. SGLT2 inhibitors also directly act on cardiomyocytes and endothelial cells and lower intracellular sodium and calcium level, reduce inflammation, mitigate oxidative stress and endoplasmic reticulum (ER) stress, and regulate autophagy. Created using BioRender.com

Fig. 2

Potential pathways of direct cardiovascular benefits via SGLT2 inhibitor use. SGLT2 inhibitors can prevent or improve cardiac dysfunction and remodeling by lowering intracellular sodium and calcium levels, reducing oxidative and endoplasmic reticulum (ER) stress, suppressing the inflammatory process, and regulating autophagy. These mechanisms are interrelated. Created using BioRender.com