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Large cardiovascular outcome trials have demonstrated the beneficial effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes at high risk of cardiovascular events.1-3 Preservation of renal function was reported in these trials; however, the proportion of participants with chronic kidney disease (CKD) was low.
As Professor Hiddo J.L. Heerspink (University Medical Centre Groningen, the Netherlands) described in a Hot Line at ESC Congress 2020 today, the Dapagliflozin And Prevention of Adverse outcomes in CKD (DAPA-CKD) trial aimed to test the hypothesis that dapagliflozin could reduce the risk of renal and cardiovascular events in patients with CKD (with or without type 2 diabetes).
This international trial enrolled 4,304 adult patients with estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio 200–5,000 mg/g who were already receiving a stable dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Patients were randomised to dapagliflozin 10 mg or placebo once daily on top of background therapy.
The primary endpoint was worsening kidney function (defined as ≥50% sustained decline in eGFR or onset of end-stage kidney disease) or death due to kidney disease or cardiovascular disease. During a median follow-up of 2.4 years, treatment with dapagliflozin significantly reduced the primary endpoint compared with placebo (197 vs. 312 events; hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.51–0.72; p=0.000000028). Two-thirds of the patients (67.5%) had type 2 diabetes and the benefit of dapagliflozin on the primary endpoint was consistent in patients with and without type 2 diabetes.
Furthermore, dapagliflozin vs. placebo significantly reduced the secondary endpoints of worsening renal function or death from kidney failure (HR 0.56; 95% CI 0.45–0.68; p<0.0001) and hospitalisation for heart failure or cardiovascular death (HR 0.71; 95% CI 0.55–0.92; p=0.0089). A significant reduction in all-cause mortality was also observed with dapagliflozin vs. placebo (HR 0.69; 95% CI 0.53–0.88; p=0.0035).
In the dapagliflozin and placebo groups, a similar proportion of patients discontinued the study due to an adverse event (5.5% and 5.7%, respectively) or experienced a serious adverse event (29.5% and 33.9%, respectively). Diabetic ketoacidosis was not reported in any patient randomised to dapagliflozin and occurred in two patients in the placebo group. Neither diabetic ketoacidosis nor severe hypoglycaemia were observed in patients without type 2 diabetes.
To conclude, dapagliflozin met all primary and secondary endpoints in DAPA-CKD – a trial that provides important insights into the benefits of SGLT2 inhibitors in patients across multiple CKD stages both with and without diabetes.
Watch the presentation
1. Zinman B, et al. N Engl J Med 2015;373:2117–2128.
2. Neal B, et al. N Engl J Med 2017;377:644–657.
3. Wiviott SD, et al. N Engl J Med 2019;380:347–357.
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