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Dapagliflozin reduces cardiorenal events in CKD patients with or without T2DM regardless of CKD aetiology

Prof. Hiddo Heerspink
University Medical Center Groningen
The Netherlands
Prof. David Wheeler
University College London
UK
Prof. Robert Toto
University of Texas South-western Medical Center
Texas, US
17 Nov 2020
DAPA-CKD is the first dedicated renal outcome study of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to demonstrate robust reductions in cardiorenal events in patients with chronic kidney disease (CKD) regardless of type 2 diabetes mellitus (T2DM) status. In a prespecified secondary analysis of the DAPA-CKD trial reported recently at the American Society of Nephrology Kidney Week 2020 (ASN 2020) virtual meeting, the SGLT2 inhibitor dapagliflozin demonstrated consistent efficacy and safety in diabetic and nondiabetic patients with CKD regardless of  aetiology or baseline diuretic and mineralocorticoid receptor antagonist (MRA) use.
 
"SGLT2 inhibitors have been shown to reduce the risk of composite kidney disease endpoints in T2DM patients, such as in the DECLARE-TIMI 58 study of dapagliflozin,”  said DAPA-CKD lead investigator Professor Hiddo Heerspink of the University Medical Center Groningen, Groningen, the Netherlands. [Lancet Diabetes Endocrinol 2019;7:606-617; N Engl J Med 2016;375:323-334; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:2295-2306; Cardiovasc Diabetol 2019, doi: 10.1186/s12933-019-0903-4]
 
“In nondiabetic populations, studies such as the DIAMOND trial of dapagliflozin in CKD patients showed favourable renal effects of SGLT2 inhibitors,” he added. [N Engl J Med 2019;381:1995-2008; Obesity (Silver Spring) 2014;22:1042-1049; Lancet Diabetes Endocrinol 2020;8:582-593] “Subgroup analyses of the DAPA-HF trial similarly found a significantly lower rate of decline of estimated glomerular filtration rate [eGFR] with dapagliflozin vs placebo, irrespective of baseline diabetes. In patients without vs those with diabetes treated with dapagliflozin, the significantly slower eGFR decline during days 14–720 after the acute initial drop demonstrated the beneficial ef-fect of dapagliflozin on long-term preservation of kidney function.”  [Solomon SD, et al, ASN 2019, abstract FR-OR133; N Engl J Med 2019;381:1995-2008]
 
Dapagliflozin benefits CKD patients with or without T2DM

“DAPA-CKD is the first dedicated clinical trial to explore the effect of an SGLT2 inhibitor on kidney outcomes in CKD patients with or without T2DM, across CKD stages, who are already receiving standard-of-care renoprotective therapy,” said Heerspink. [Nephrol Dial Transplant 2020;35:274-282; N Engl J Med 2020;383:1436-1446]
 
The DAPA-CKD study, which was prematurely terminated at 2.4 months in view of the overwhelming efficacy observed with dapagliflozin, included 4,304 patients (mean age, 62 years; about one-third Asians) who were randomized to receive dapagliflozin 10 mg once daily or placebo. At baseline, patients in both groups had a mean eGFR of 43 mL/min/1.73 m2. Around two-thirds of patients in both groups had T2DM, while 97 percent were receiving an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) and 5.3 percent were on an MRA. Diabetic nephropathy was the investigator-reported cause of kidney disease in 86.4 percent of patients with T2DM. [N Engl J Med 2020;383:1436-1446; Nephrol Dial Transplant 2020;35:1700-1711]
 
After a median follow-up of 2.4 years, a 39 percent relative reduction in risk (RRR) of the primary outcome (a composite of worsening kidney function, defined as sustained ≥50 percent decline in eGFR, onset of end-stage kidney disease [ESKD], and death due to renal or cardiovascular [CV] cause) 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). 
 
“Dapagliflozin’s number needed to treat [NNT] of 19 is much lower than what has been seen in ACEI or ARB trials among similar populations of patients,” noted Heerspink. 
 
A 44 percent RRR with early curve separation was observed with dapagliflozin vs placebo in the secondary renal-specific 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, dapagliflozin reduced the risk of the composite of chronic dialysis, kidney transplantation and renal death by 34 percent vs placebo (71 events vs 103 events; HR, 0.66; 95 percent CI, 0.49 to 0.90; p=0.0072). 
 
Dapagliflozin benefit across prespecified subgroups
 
“Improvements in primary and secondary outcomes 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/1.73 m2 vs ≥45 mL/min/1.73 m2,” reported Heerspink. “The benefit of dapagliflozin was consistent and significant across all prespecified subgroups.” (Figure) [Wheeler DC, ASN 2020; N Engl J Med 2020;383:1436-1446]

hk-ast-432_01

Dapagliflozin’s effect on the renal composite outcome was consistent in patients with (HR, 0.61; 95 percent CI, 0.24 to 1.57) or without baseline MRA use (HR, 0.56; 95 percent CI, 0.45 to 0.69).  
 
“Consistent effects of dapagliflozin were also observed in the primary, secondary  renal-specific, CV and all-cause mortality outcomes regardless of CKD aetiology,” noted DAPA-CKD investigator Professor David Wheeler of the University College London, London, UK.
 
“The number of patients with immunoglobulin A [IgA] nephropathy in DAPA-CKD was comparable to other CKD trials such as TESTING and STOP-IgA. In DAPA-CKD, an impressive 71 percent RRR in the primary composite outcome [HR, 0.29; 95 percent CI, 0.12 to 0.73] was observed in these patients treated with dapagliflozin vs placebo – a magnitude not often seen in trials in nephrology or other disciplines,” said Professor Robert Toto of the University of Texas South-western Medical Center, Texas, US. [Nephrol Dial Transplant 2020;35:1700-1711]
 
Safety and clinical perspective
 
“Dapagliflozin was well tolerated in  DAPA-CKD, in keeping with its established safety profile. Occurrence of any serious adverse events was consistent across all prespecified subgroups,” stated Wheeler. “Notably, in patients without diabetes, there was no diabetic ketoacidosis or major hypoglycaemia in both treatment groups, providing reassurance on dapagliflozin’s safety in nondiabetic CKD patients.”
 
“DAPA-CKD demonstrated a positive benefit-risk ratio in patients with eGFR as low as 25 mL/min/1.73 m2, with reduced hospitalization rate for heart failure and all-cause mortality. Most patients continued the study drug when eGFR was well below 25 mL/min/1.73 m2 and discontinued treatment when chronic dialysis was initiated. These results will change practice in CKD care, which has been stagnant for nearly 20 years,” concluded Toto. 
 
The Kidney Disease: Improving Global Outcomes (KDIGO) 2020 Clinical Practice Guideline for Diabetes Management in CKD recommends the use of an SGLT2 inhibitor with documented kidney or CV benefits. Once started, continued use of an SGLT2 inhibitor is reasonable even if eGFR falls below 30 mL/min/1.73 m2 unless not tolerated or renal replacement therapy is initiated. [Kidney Int 2020;98(4S):S1-S115]
 

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