Dapagliflozin Safe and Effective in CKD Stages 4 and 5

SAN DIEGO — Dapagliflozin provides significant benefits in the treatment of chronic kidney disease (CKD) even when initiated in patients with the most severe stages of the disease who are typically excluded from clinical trials, new research shows.

In patients with CKD stage 4-5, dapagliflozin plus integrated CKD care improved total eGFR slope composite renal outcomes, composite renal and heart failure outcomes, and renal and cardiovascular outcomes compared with CKD care alone. 

This is “the first SGLT2 inhibitor renal outcome trial to include patients with an estimated glomerular filtration rate (eGFR) less than 20 mL/min/1.73 m²,” said first author Chi-Chih Hung, MD, of Kaohsiung Medical University, Taiwan, who presented the findings here at the American Society of Nephrology (ASN) Kidney Week 2024.

Patients with stage 4 and 5 CKD have a notably high risk of cardiorenal syndrome, with potential complications of acute kidney injury (AKI) and heart failure. They have typically been excluded from most clinical trials, or are included in only very small numbers, Hung explained.

The EMPA-KIDNEY trial, evaluating the effect of empagliflozin on kidney disease progression and cardiovascular death, extended inclusion criteria to those with an eGFR of ≥ 20 to 2 or ≥ 45 to 2 and a urinary albumin-to-creatinine ratio (UACR) of ≥ 200 mg/g, he noted.

In the current trial, Dapagliflozin and Renal Surrogate Outcomes in Advanced Chronic Kidney Disease (DAPA advKD), Hung and colleagues enrolled patients with eGFR levels as low as 10-30 mL/min/1.73 m² and who had a steady eGFR decline of ≥ 2.5 mL/min/1.73 m² per year. 

Patients aged 20 years and older were randomly assigned 2:1 to treatment with dapagliflozin 5 to 10 mg per day (n = 120), in addition to integrated CKD care, or integrated CKD care alone (n = 60).

The patients had a mean age of 67.5 years in the dapagliflozin group, and 71.4 in the integrated care group. About 34.2% and 45% were female in the two groups, respectively; the mean eGFR at baseline was about 19 mL/min/1.73 m². Notably, 56 of the patients had stage 5 CKD.

Patients with lupus nephritis, ANCA-associated vasculitis, urinary tract obstruction, and urosepsis were excluded from the trial.

With a median follow-up of 84 weeks, for the primary outcome, the change from baseline in eGFR slope was -2.37 in the dapagliflozin group and -3.58 in the integrated care group, for an eGFR slope difference of 1.21 (P = .019). 

In the first of 3 secondary renal outcomes, a composite of renal replacement therapy, eGFR 2, renal or cardiovascular death, or a > 50% decline in eGFR, the dapagliflozin group had lower rates of events, with 24 of 120 (20%) compared with 21 of 60 (35%) in the integrated care group at 96 weeks (hazard ratio [HR] 0.423; P = .005).

For the second renal outcome, a composite including the components of the first renal outcome as well as AKI and heart failure, the outcome events occurred in 26 of 120 (21.7%) patients treated with dapagliflozin and 21 of 60 (35%) participants in the integrated care group at 96 weeks (HR, 0.456; P = .008). 

And for the third secondary outcome, a renal and cardiovascular composite including the renal and heart failure composites plus major adverse cardiac events, including myocardial infarction, stroke, hospitalization for unstable angina or coronary/peripheral artery revascularization, there were 29 events among the 120 (24.2%) treated with dapagliflozin and 21 of 60 (35%) patients with integrated care (HR, 0.531; P = .030).

A subgroup analysis of the renal composite outcome favored the use of dapagliflozin plus integrated care regardless of CDK stage, UACR level, or use of RAS inhibitors.

In terms of safety, serious adverse events occurred in 31.2% of patients in the dapagliflozin group vs 40% with integrated care. There was one case in each group of volume depletion, two cases of an acute eGFR dip greater than 30% from baseline in the dapagliflozin group and none with integrated care, and no cases in either group of diabetic ketoacidosis, with none of the measures being statistically significant.

There were no significant differences between the groups in terms of major adverse cardiovascular events or electrolyte imbalances. 

In terms of nonfatal serious adverse events, leading to long-term dialysis, or renal or cardiovascular death, there was 1 (5.9%) case of AKI hospitalization in the dapagliflozin group vs 7 cases in the integrated care group (41.2%; P = .039).

There were no significant differences between the groups in the other nonfatal serious adverse events including heart failure hospitalization, CKD fluid overload hospitalization, and 5-point major adverse cardiovascular events (MACE).

“Dapagliflozin was found to be safe in patients with CKD stages 4-5,” Hung noted.

“Recognizing the Evidence Gap”

Study discussant David C. Wheeler, MD, a professor of kidney medicine at University College London, noted that current KDIGO guidelines on the management of CKD recommend the use of SGLT2 inhibitors for patients with type 2 diabetes and CKD, CKD and albuminuria, and heart failure with CKD, with the key caveat that the recommendations apply to patients with eGFR greater than 20 mL/min/1.73 m².

These recommendations are typically followed in clinical trials, said Wheeler. “The investigators deciding these trials believed that there was a limit below which we could not go and have any chance of fixing the progression of chronic kidney disease because the kidneys were so badly damaged.” 

Recent studies have enrolled small percentages of patients with more advanced stages of CKD. For example, the DAPA CKD study included 14.5% of patients (n = 624) with stage 4 CKD and found no significant differences or increased risk with dapagliflozin among those patients compared with patients with less severe kidney disease. 

By taking the next step and focusing specifically on patients with stage 4 and 5 CKD in their new trial, Hung and colleagues “recognized this evidence gap in which we have limited data in patients with an eGFR less than 30 mL/min/1.73 m², and virtually no data among patients with eGFR of less than 20 mL/min/1.73 m², when it comes to using SGLT 2 inhibitors.”

Their findings underscore that “we can start dapagliflozin in patients with advanced CKD and an eGFR less than 20 mL/min/1.73 m², and in doing so, we may well preserve renal function and delay the point in time that these patients need to start on renal replacement therapy,” Wheeler said.

Hung has received research support from AstraZeneca. Wheeler’s disclosures include honoraria and/or consultancy fees from Amgen, AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Eledon, Merck, Menarini, Mineralys, Pathaly, ProKidney, and Vifor.