People with chronic kidney disease (CKD) are at high risk of both cardiovascular (CV) events and further deterioration of renal function, and have decreased quality of life and reduced life expectancy. Until recently, the only demonstrated ways to reduce the rate of renal decline were tight glycaemic control and treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The DAPA-CKD trial was therefore designed to assess whether treatment with dapagliflozin 10 mg, compared with placebo, would alter the risk of renal and CV events in people with CKD already receiving the standard of care, whether or not they had type 2 diabetes.
A total of 4304 people with CKD and an estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2, and a urinary albumin:creatinine ratio (UACR) between 22.6 and 565 mg/mmol, who were stable on a maximum tolerated dose of an ACEi or ARB for at least 4 weeks (if not contraindicated) were randomised to receive dapagliflozin 10 mg or placebo. The primary outcome was a renal and CV composite – sustained 50% decline in eGFR (two readings at a 28-day interval), end-stage renal disease (dialysis, transplantation or eGFR <15 mL) or renal or CV death. The independent data monitoring committee recommended the trial be stopped in June 2020 due to evidence of efficacy, at which time the median exposure to dapagliflozin or placebo was 2.4 years. The primary outcome was significantly reduced by 39% in the dapagliflozin-treated group compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.51–0.72), with a number needed to treat of just 19 to prevent one primary outcome event. Subgroup analysis demonstrated similar results in those with and without type 2 diabetes, and in those with eGFR above or below 45 mL/min/1.73 m2.
Secondary endpoints evaluated in the hierarchical testing were all significantly reduced in the dapagliflozin group compared with those receiving placebo:
- Renal composite – sustained ≥50% decline in eGFR, end-stage renal disease or renal death: 44% reduction.
- CV composite – CV death or hospitalisation for heart failure: 29% reduction.
- All-cause death occurred in 101 people (4.7%) in the dapagliflozin group and 146 (6.8%) in the control group: a significant 31% reduction.
Adverse and serious adverse event rates were similar between the treatment and placebo groups, and there were no unanticipated adverse events. There were no cases of diabetic ketoacidosis (DKA) in those treated with dapagliflozin and there was no DKA or hypoglycaemia in those without type 2 diabetes.
These benefits are clinically significant and of importance to people with CKD, and occurred irrespective of type 2 diabetes status. The DAPA-CKD study extends the range of people with CKD demonstrated to benefit from treatment with a sodium–glucose cotransporter 2 (SGLT2) inhibitor to those with and without type 2 diabetes, and to a lower eGFR (down to 25 mL/min/1.73 m2) compared with the previously published CREDENCE trial of canagliflozin or any of the CV outcome trials of SGLT2 inhibitors.
Based on the renal benefits observed in the CREDENCE trial, in which people with type 2 diabetes and an eGFR as low as 30 mL/min/1.73 m2 were enrolled, there has been a recent licence change to canagliflozin. It is likely that the DAPA-CKD study will result in a licence change for dapagliflozin in the future, while results from the EMPA-KIDNEY study of empagliflozin are expected in 2021. The licence change allows canagliflozin 100 mg to be initiated in those with a sustained eGFR between 45 and 60 mL/min/1.73 m2, and initiation down to an eGFR of 30 mL/min/1.73 m2 in those with significant albuminuria (>300 mg/g [>33.9 mg/mmol]). Once on therapy, it can be continued until end-stage renal disease. Due to the mode of action of SGLT2 inhibitors, the glucose-lowering effects will probably be reduced in those with eGFR <60 mL/min/1.73 m2, and therefore the need for additional glucose-lowering medication should be considered.
The renal benefits of SGLT2 inhibitors appear to be independent of their glucose-lowering effects and are postulated to relate to a variety of mechanisms, including glucose-induced osmotic diuresis and a reduction in intraglomerular pressure.
Results of DAPA-CKD were presented at the European Association for the Study of Diabetes Annual Meeting and simultaneously published in the New England Journal of Medicine. Click here to access the full report.
