Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.
Sara Freeman/MDedge News
Dr. Chantal Mathieu
DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m2 and albuminuria with/without type 2 diabetes.
The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.
“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m2 [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.
Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.
The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.
Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.
Dr. Glenn M. Chertow
“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!
“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.
“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”
“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
Dapagliflozin risks and benefits in advanced CKD
Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.
However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.
The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m2 and albuminuria at baseline.
Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.
A total of 293 patients received dapagliflozin and 331 patients received placebo.
During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).
In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:
- A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
- A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
- All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).
The eGFR slope declined by 2.15 mL/min per 1.73 m2 per year and by 3.38 mL/min per 1.73 m2 per year in the dapagliflozin and placebo groups, respectively (P = .005).
“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.
The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.
There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.
The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.
The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.