Dapagliflozin reduces cardiorenal events in CKD patients with or without T2DM
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, first used as glucose-lowering therapies in type 2 diabetes mellitus (T2DM), have demonstrated improvements in cardiovascular (CV) outcomes in heart failure (HF) patients. In the DAPA-CKD study, reported recently at the European Society of Cardiology Congress 2020 (ESC 2020), the SGLT2 inhibitor dapagliflozin was shown to reduce renal and CV events in patients with chronic kidney disease (CKD) with or without T2DM, highlighting its potential role in CKD treatment.
DAPA-CKD: Dapagliflozin shows cardiorenal benefits in CKD
The DAPA-CKD study evaluated the efficacy of dapagliflozin in reducing renal and CV events in CKD patients with or without T2DM. A total of 4,304 patients (mean age, 62 years) were randomized to receive dapagliflozin 10 mg once daily or placebo, on top of standard therapy including a maximum tolerated dose of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). [Heerspink HL, et al, ESC 2020]
The study’s primary endpoint was a composite of worsening kidney function (defined as sustained ≥50 percent decline in estimated glomerular filtration rate [eGFR]), onset of end-stage kidney disease (ESKD), and death due to renal or CV cause.
At baseline, patients in both treatment groups had a mean eGFR of 43 mL/min/1.73m2. Notably, 35 percent of patients in the dapagliflozin group and 33 percent in the placebo group were Asian. Around two-third of patients in both groups had T2DM, while 97 percent were on an ACEI or ARB.
Study terminated early due to overwhelming efficacy
“The study was terminated prematurely [at 60 percent of planned primary endpoint events] in view of overwhelming efficacy observed with dapagliflozin,” reported investigator Professor Hiddo Heerspink of the University Medical Center Groningen, Groningen, the Netherlands.
After a median follow-up of 2.4 years, a 39 percent relative reduction in risk of the primary outcome was observed with dapagliflozin vs placebo (197 events vs 312 events; hazard ratio [HR], 0.61; 95 percent confidence interval [CI], 0.51 to 0.72; p=0.000000028). (Figure 1)
“Improvements in primary outcome with dapagliflozin were observed across prespecified subgroups, including patients with vs without T2DM, those with baseline urine albumin-to-creatinine ratio [UACR] ≤1,000 mg/g vs >1,000 mg/g, and those with eGFR <45 mL/min/1.73m2 vs ≥45 mL/min/1.73m2,” reported Heerspink. (Figure 2)
A 44 percent relative risk reduction was observed with dapagliflozin vs placebo in the secondary outcome of sustained ≥50 percent decline in eGFR, onset of ESKD and renal death (142 events vs 243 events; HR, 0.56; 95 percent CI, 0.45 to 0.68; p=0.000000018). Meanwhile, the risk of the composite of chronic dialysis, kidney transplantation and renal death was reduced by 34 percent with dapagliflozin vs placebo (71 events vs 103 events; HR, 0.66; 95 percent CI, 0.49 to 0.90; p=0.0072).
CV death or HF hospitalization was reduced by 29 percent with dapagliflozin vs placebo (100 events vs 138 events; HR, 0.71; 95 percent CI, 0.55 to 0.92; p=0.0089), while all-cause mortality was reduced by 31 percent (101 events vs 146 events; HR, 0.69; 95 percent CI, 0.53 to 0.88; p=0.0035).
“Dapagliflozin was well tolerated in DAPA-CKD, in keeping with its established safety profile,” said Heerspink.
What DAPA-CKD adds
SGLT2 inhibitors have demonstrated CV and renal benefits in studies in T2DM patients, such as the DECLARE-TIMI 58 study of dapagliflozin. [N Engl J Med 2019;380:347-357; N Engl J Med 2015;373:2117-2128; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:2295-2306]
“As shown in the DAPA-HF study, benefits of SGLT2 inhibitors extend to nondiabetic patients with HF,” said discussant Professor Diederick Grobbee of the University Medical Center Utrecht, Utrecht, the Netherlands. “Notably, all these trials included a proportion of CKD patients and showed improvements in renal outcomes.” [N Engl J Med 2019;381:1995-2008; Cardiovasc Diabetol 2019;18:99]
“Results of the DAPA-CKD study expand the cardiorenal benefits of dapagliflozin previously demonstrated in DECLARE-TIMI 58 and DAPA-HF to CKD patients with or without T2DM. The benefits were observed on top of standard CKD treatments,” he commented.
Revisiting SGLT2 inhibitors in HF
The efficacy of SGLT2 inhibitors in patients with HF with reduced ejection fraction, with or without T2DM, was evaluated in the DAPA-HF study and the recently published EMPEROR-Reduced study. [N Engl J Med 2019;381:1995-2008; N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
“Taken together, the two trials demonstrated benefits of SGLT2 inhibitors in reducing HF hospitalization, CV death, HF symptoms, and renal function deterioration. Importantly, the benefits were seen on top of conventional therapy, including sacubitril/valsartan,” said Professor John McMurray of the University of Glasgow, Glasgow, UK, in a symposium during ESC 2020. “Reductions in all-cause and CV mortality were statistically significant with dapagliflozin in DAPA-HF, but they were numerical with empagliflozin in EMPEROR-Reduced, and the reason remains to be elucidated.”
DAPA-CKD, the first dedicated renal outcome trial of an SGLT2 inhibitor in CKD patients with or without T2DM, has shown cardiorenal benefits of dapagliflozin on top of standard therapy.
Results of the DAPA-HF and DAPA-CKD studies extend the benefits of dapagliflozin in reducing HF hospitalization and renal disease deterioration shown in the DECLARE-TIMI 58 study in T2DM patients to patients with HF or CKD with or without T2DM.