The Phase III DAPA-CKD study will be terminated earlier than planned due to proven efficacy in patients with chronic renal failure. Dapagliflozin is the first SGLT2 inhibitor to show meaningful benefit in chronic renal failure in a study of patients both with and without type 2 diabetes.
It is another milestone in the field of nephroprotection. Prof. Thomas Fehr, MD, Chief of Medicine and Head of the Department of Internal Medicine at the Cantonal Hospital Graubünden, commented on the positive outcome as follows: “SGLT-2 inhibitors have brought significant progress in nephroprotection for patients with diabetic nephropathy in recent years. With the early termination of the DAPA-CKD trial due to positive data, it is becoming apparent that the same finding could apply to patients with non-diabetic chronic renal failure of other causes (except ADPKD). This could open up a new therapeutic option for nephrologists for these patients more than 20 years after the introduction of RAS blockade.”
DAPA-CKD is part of a large study program
The once-daily oral SGLT2 (sodium-glucose co-transporter-2) inhibitor dapagliflozin (Forxiga®) is being studied in an extensive clinical trial program with over 35 completed and ongoing phase IIb/III studies in over 35,000 patients [1]. After studies in diabetic patients showed additional cardiovascular and nephroprotective benefits of SGLT2 inhibitors, studies in other patient populations were launched. It was found that patients without diabetes can also benefit from cardiac and renal benefits [1,2]. The phase III DAPA-CKD (“Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease”) study is an international, multicenter, randomized, double-blind study in 4245 patients to assess the efficacy of dapagliflozin 10 mg versus placebo in patients in CKD stages 2-4 with increased albumin excretion and with or without T2D. Dapagliflozin is administered once daily as an add-on to the standard of care. The primary composite endpoint is worsening renal function (decrease in eGFR ≥50%, onset of TNI, and CV death or renal death) in CKD patients regardless of the presence of type 2 diabetes (T2D) [3]. The decision to terminate the study early followed a routine assessment of efficacy and safety by an independent data monitoring committee, in which the benefits of dapagliflozin became apparent earlier than initially expected. The full results will be submitted for presentation at an upcoming medical congress, and pharmaceutical company AstraZeneca will now begin discussions with global health authorities regarding early approval.
Benefit for patients with chronic kidney disease
Chronic renal failure (CKD) is a severe, progressive decreased renal function diagnosed by measurements of eGFR and/or markers of renal damage over a three-month period [4]. The most common causes of CKD are diabetes, hypertension, and glomerulonephritis [5]. CKD is associated with significant morbidity and increased risk of CV events such as heart failure (HF) and premature death [6,7]. In its most severe form, end-stage renal disease, renal damage and deterioration have progressed to a stage where dialysis or kidney transplantation is required [8]. Most CKD patients die due to cardiovascular causes before reaching the stage of TNI [9]. “Treatment options are limited for patients with chronic renal failure, particularly those without type 2 diabetes. We are very pleased that the Data Monitoring Committee has certified a benefit for patients,” said Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D.
Source: Astra Zeneca
Literature:
- Swissmedic: Specialist information Forxiga®, www.swissmedicinfo.ch
- Wiviott SD, et al: Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380(4): 347-357.
- Heerspink HJL, et al: Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrology Dialysis Transplantation 2020; 35 (2): 274-282.
- Mallappallil M, et al. Chronic kidney disease in the elderly: evaluation and manage-ment. Clinical Practice (London) 2014; 11(5): 525-535.
- National Kidney Foundation. Kidney Disease: Causes, 2017; www.kidney.org
- Bikbov B, et al: Global, regional, and national burdens of chronic kidney disease, 1990-2017: a Systematic Analysis for the Global Burden of Disease Study 2017. Lancet 2020; 395(10225): 709-733.
- Segall L, et al: Heart failure in patients with chronic kidney disease: A systematic-integrative review. Biomed Res Int 2014; 2014: 937398. doi: 10.1155/2014/937398.
- Centers for Disease Control and Prevention (CDC): Chronic Kidney Disease in the United States, 2019; www.cdc.gov
- Thompson S, et al: Cause of Death in Patients with Reduced Kidney Function. Journal of the American Society of Nephrology 2015; 26 (10): 2504-2511.
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