Efficacy and Safety of Dapagliflozin in Patients with Chronic Kidney Disease Stage 4-5 Under Integrated CKD Care Program: an Investigator-led, Randomized, Open-label, Blinded-endpoint, Multicenter Study

eGFR 30 mL/min/1.73m2 is a clinical cut point, below which advanced chronic kidney disease (CKD) (stage 4 and 5) is associated with a significantly increased risk of mortality and a 50-fold increased requirement of renal replacement therapy (RRT). Physicians are suggested to refer patients to nephrologists when eGFR <30 mL/min/1.73m2 for multidisciplinary care. The pre-ESRD care program of CKD stage 3b-5 patients in Taiwan for modifiable risk factors of CKD progression and for preparation of renal replacement therapy (RRT) has shown to improve clinical outcomes.

"Advanced" CKD was usually viewed as "predialysis" CKD and sometimes used interchangeably, probably because of limited time of treatment and limited medications in advanced CKD. The time of treatment in CKD stage 4 in our cohort (median survival of RRT or mortality) was still up to 4.7 (IQR 2.1-8.7) years under the practice of late dialysis initiation (median eGFR 5 mL/min/1.73m2). However, renin-angiotensin system blockade was the only effective medication in patients with advanced CKD, implied by albuminuria reduction and proved for reduction of renal outcome only in some randomized controlled trials (RCTs). Furthermore, there is no effective medication for patients with normoalbuminuria, tubulointerstitial nephropathy, hyperkalemia or blood pressure <130/80 mmHg. Thus, the unmet need in advanced CKD patients is the lack of effective medication.

Recently, two large renal outcome RCTs of sodium-glucose co-transporter 2 inhibitors (SGLT2is), which has been developed as an oral anti-hyperglycemic agent for type 2 diabetes mellitus (T2DM), show a reduction of renal composite outcome and probably of mortality in CKD stage 2 and 3 (CREDENCE and DAPA-CKD trials). Subgroup analyses show similar reduction of renal composite outcome in patients with or without diabetes, albuminuria, or high blood pressure. Consistent with previous large cardiovascular (CV) outcome trials, patients with eGFR 25-30 mL/min/1.73m2 also suggest promising benefits.

Beside, in view of the high atherosclerotic CV risk in advanced CKD, SGLT2is show a reduction of major adverse cardiovascular event in large CV outcome RCTs in T2DM, especially in patients with high CV risk. Also considering the high incidence of cardiorenal syndrome and fluid overload in advanced CKD, SGLT2is show a reduction of congestive heart failure (CHF) event in large CHF RCTs, regardless of T2DM and regardless of preserved or reduced ejection fraction. Analysis in patients with eGFR <30 mL/min/1.73m2 suggest similar protection for atherosclerotic and CHF events.

Diuresis is an important mechanism of the benefit of SGLT2i as observed in the above renal and CV RCTs. Our previous studies demonstrated that overhydration measured by bioimpedance is associated with renal function progression and all-cause mortality. SGLT2i improves overhydration in studies. We would further ask whether the cardiorenal effect of SGLT2i is independent of its diuretic effects in advanced CKD patients.