Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Kidney Function in Advanced Chronic Kidney Disease

Overview

The goal of this clinical trial is to evaluate whether dapagliflozin can reduce the risk of worsening kidney function or death from cardiovascular or renal causes in adults with advanced chronic kidney disease (CKD), with or without type 2 diabetes. The main questions it aims to answer are: 1. Does dapagliflozin reduce the rate of decline in kidney function or progression to end-stage kidney disease in adults with advanced CKD? 2. Does dapagliflozin reduce the risk of death from cardiovascular or renal causes in patients with advanced CKD? Researchers will compare dapagliflozin to a placebo to see if dapagliflozin improves kidney and cardiovascular outcomes in this high-risk population.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally developed as oral antihyperglycemic agents for managing type 2 diabetes, have quickly gained recognition for their broad therapeutic benefits beyond glycemic control. Since their clinical introduction in 2012, SGLT2 inhibitors have demonstrated significant renoprotective and cardioprotective effects, reshaping treatment approaches in nephrology and cardiology. Although these drugs have shown great promise, major clinical trials have typically excluded patients with advanced chronic kidney disease (CKD) (eGFR \< 20 mL/min/1.73m²), those already on dialysis, and kidney transplant recipients-populations at the highest risk of kidney failure, cardiovascular complications, and mortality. This exclusion has left a critical gap in understanding the full potential of SGLT2 inhibitors in the most vulnerable patients. As such, current KDIGO guidelines have not recommended initiating SGLT2 inhibitors in patients with eGFR \< 20 mL/min/1.73m². CKD is a global health crisis, affecting approximately 10% of adults worldwide, with prevalence rising in Egypt, where 13% of adults are affected, especially in underserved rural areas. By 2040, CKD is projected to become the fifth leading cause of death worldwide. For patients with kidney failure, the primary treatment options are renal replacement therapies like dialysis or transplantation. However, due to the scarcity of donor kidneys and the frequent presence of comorbidities in older populations, transplantation is often unfeasible. Consequently, most end-stage kidney disease (ESKD) patients rely on dialysis, a therapy that significantly lowers quality of life and increases mortality risk. Preserving kidney function is a critical goal in CKD management, which is closely linked to better patient outcome. Incremental dialysis, a strategy aimed at preserving residual kidney function (RKF), shows promise but lacks robust clinical validation. Increasing evidence suggests that SGLT2 inhibitors, even in patients with advanced CKD, may offer significant reno- and cardioprotective benefits, reinforcing the need for further research into their efficacy in this population. For instance, in the DAPA-CKD trial, which included patients with an eGFR as low as 25 mL/min/1.73m², dapagliflozin demonstrated a consistent reduction in cardiovascular and renal outcomes, even in those with severely impaired kidney function. A subgroup analysis of the DAPA-CKD trial comparing 624 patients with an eGFR \<30 mL/min/1.73m2 to the remainder of the trial population with better kidney function, demonstrated that the efficacy of dapagliflozin in reducing cardiovascular and renal outcomes persisted in the population with impaired kidney function. Remarkably, patients who initiated dialysis during the trial continued to receive dapagliflozin or placebo, and those treated with dapagliflozin experienced a 21% reduction in relative risk for mortality. These findings challenge the traditional boundaries of SGLT2 inhibitor use, indicating potential benefits even in populations previously excluded from major trials. Recent findings from the DAPA advKD trial (NCT05196347) further support this potential: in 180 patients with CKD stages 4-5 (eGFR 10-30 mL/min/1.73m²), dapagliflozin significantly slowed eGFR decline (-2.24 vs. -3.67 mL/min/1.73m²/yr in controls, p=0.019) and reduced composite renal outcomes (HR 0.50, p=0.019) over 1.6 years, despite a higher incidence of transient eGFR dips in the treatment group. The 2023 UK Kidney Association Clinical Practice Guideline reinforces this paradigm shift, issuing a Grade 2B recommendation to consider SGLT2 inhibitor initiation in patients with eGFR \<20 mL/min/1.73m² to slow disease progression. This guidance is supported by indirect evidence from trials continuing SGLT2 inhibition until kidney replacement therapy initiation, as well as EMPA-KIDNEY data showing unattenuated renal benefits down to eGFR 15 mL/min/1.73m². Emerging clinical data further supports the efficacy of SGLT2 inhibitors in preserving RKF in patients undergoing dialysis. Recent case series have shown promising results, such as significant improvements in residual kidney urea clearance and reduced proteinuria among patients undergoing incremental hemodialysis while receiving SGLT2 inhibitors. Similarly, in patients on peritoneal dialysis, SGLT2 inhibitors have been effective in preserving RKF. Pharmacokinetic data also suggest that dapagliflozin is well tolerated, minimally dialyzable, and exhibits non-accumulating pharmacokinetic properties in patients on dialysis. Given the substantial benefits of SGLT2 inhibitors in patients with less severe CKD, coupled with preliminary evidence suggesting their potential in advanced CKD and dialysis populations, there is a pressing need to explore their long-term efficacy and safety in these high-risk groups. This research aims to fill that gap, with the potential to redefine CKD management and offer new hope to patients facing the highest risks of poor outcomes.