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DAPA-CKD Phase III trial sub-analyses showed that kidney and cardiovascular outcomes were consistent regardless of geographic region or use of background cardiovascular therapies
Three new sub-analyses from the DAPA-CKD Phase III trial of AstraZeneca’s Farxiga (dapagliflozin), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, further support the consistency of dapagliflozin's cardiorenal and mortality benefits in treating patients with chronic kidney disease (CKD), with and without type-2 diabetes (T2D). Additionally, a real-world evidence (RWE) study, REVEAL-CKD, showed the significantly low Stage 3 CKD diagnosis rates globally. These data were presented at the American Society of Nephrology (ASN) Kidney Week 2021.
Data from a regional analysis of kidney, cardiovascular (CV) and mortality outcomes in the DAPA-CKD trial showed that the beneficial effects of dapagliflozin in patients with CKD were similar across pre-specified geographic regions, including North America, Latin America, Europe and Asia.1 The relative risk reduction of the primary composite endpoint of sustained ≥50% decline in estimated glomerular filtration rate (eGFR, a key measure of kidney function), onset of end-stage kidney disease (ESKD) and death from a kidney or CV cause was consistent across the four regions ranging from 30-49% (absolute risk reductions 3.3-8.0% for dapagliflozin compared to placebo). There was no significant heterogeneity between regions (p=0.77).1
Another sub-analysis from the trial evaluated whether baseline CV medications modified the effect of dapagliflozin in patients with CKD. Data showed that the benefits of dapagliflozin on kidney, CV endpoints and mortality in patients with CKD were evident among patients treated and not treated with a variety of CV medications.2 Specifically, the effect of dapagliflozin versus placebo on time to first event of the primary composite outcome (≥50% decline in eGFR, progression to end-stage kidney disease or death from kidney or CV causes) was similar in patients with baseline use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (based on a hazard ratio [HR] of 0.61, 95% confidence interval [CI] 0.51-0.74) versus non-use (HR 0.54, 95% CI 0.20-1.46; p for interaction=0.69). Consistency of effect was also demonstrated across other CV medications analysed including diuretics, calcium channel and beta-blockers 2
A pre-specified analysis from the DAPA-CKD trial showed that dapagliflozin significantly slowed yearly eGFR decline in patients living with CKD over a median duration of 2.3 years, as measured by eGFR slope in patients randomised to dapagliflozin versus placebo (-2.88 mL/min/1.73m2 per year (eGFR slope, mean [standard error]=0.11) for dapagliflozin and -3.83 mL/min/1.73m2 per year (standard error=0.12) for placebo).3 The new data also showed that an acute decline in eGFR associated with initiation of treatment was more common in patients treated with dapagliflozin. This acute change in eGFR is believed to be associated with the mode of action of dapagliflozin and reflect favourable haemodynamic changes in the glomerulus. Importantly, the acute decline upon initiation of treatment was not associated with an increased risk of serious adverse events, discontinuation due to AEs, kidney-related events or volume depletion events, regardless of magnitude of decline.4
The co-chair of the trial and its Executive Committee Prof. Hiddo L. Heerspink, University Medical Center Groningen, The Netherlands, said: “These sub-analyses from the DAPA-CKD Phase III trial add to the growing body of evidence on the efficacy and safety of dapagliflozin for the treatment of chronic kidney disease. Dapagliflozin is an important treatment option that has the potential to transform the current standard of care by slowing disease progression. This makes earlier diagnosis a critical component in improving patient outcomes.”
New data from the REVEAL-CKD RWE study showed that only 4.5% of patients at Stage 3 of CKD in France and 7.9% in Japan, were diagnosed.5 REVEAL-CKD is a multinational, observational study. The goal of the study is to provide the most robust assessment to date of the prevalence and predictors of undiagnosed Stage 3 CKD. REVEAL-CKD will evaluate 11 countries (US, France, Japan, China, Germany, Italy, Spain, Canada, Australia, the UK and Brazil), collecting data on an estimated one million patients.5 Results are extracted from country-specific databases, including reimbursement claims and electronic health records. The study began in December 2020 and is anticipated for completion in December 2021.6
Joris Silon, Senior Vice President, CVRM, BioPharmaceuticals Business Unit, AstraZeneca, said: “These data underscore our commitment to developing new treatments and to raising awareness of the importance of earlier diagnosis of chronic kidney disease. By prioritising earlier screening and diagnosis, we can help patients receive treatment as early as possible, maximising the opportunity to slow disease progression and improve outcomes.”
CKD is a serious, progressive condition defined by decreased kidney function (shown by reduced eGFR or markers of kidney damage, or both, for at least three months).7 The most common causes of CKD are diabetes, hypertension and glomerulonephritis.8 CKD is associated with significant patient morbidity and an increased risk of CV events, such as heart failure (HF) and premature death.9 In its most severe form, known as ESKD, kidney damage and deterioration of kidney function have progressed to the point where dialysis or kidney transplantation are required.10 The majority of patients with CKD will die from CV causes before reaching ESKD.11
DAPA-CKD was an international, multi-centre, randomised, double-blinded Phase III trial in 4,304 patients designed to evaluate the efficacy of Farxiga 10mg, compared with placebo, in patients with CKD Stage 2-4 and elevated urinary albumin excretion, with and without T2D. Farxiga was given once daily in addition to standard of care (SoC). The primary composite endpoint was worsening of renal function or risk of death (defined as a composite of an eGFR decline ≥50%, onset of ESKD or death from CV or renal cause). The secondary endpoints were the time to first occurrence of the renal composite (sustained ≥50% eGFR decline, ESKD or renal death), the composite of CV death or hospitalisation for HF (hHF), and death from any cause. The trial was conducted in 21 countries.12 Detailed results from the trial were published in The New England Journal of Medicine.12
Farxiga (dapagliflozin) is a first-in-class, oral, once-daily SGLT2 inhibitor. Research has shown Farxiga’s efficacy in preventing and delaying cardiorenal disease, while also protecting the organs – important findings given the underlying links between the heart, kidneys and pancreas.12-14 Damage to one of these organs can cause the other organs to fail, contributing to leading causes of death worldwide, including T2D, HF and CKD.15-17
Farxiga is approved as an adjunct to diet and exercise to improve glycaemic control in adults with T2D and in T2D to reduce the risk of hHF or CV death when added to SoC based on the findings of the DECLARE-TIMI 58 Phase III CV outcomes trial.13 Farxiga is also approved for the treatment of HF with reduced ejection fraction and the treatment of CKD based on the findings of the DAPA-HF and DAPA-CKD Phase III trials.12,14,18
DapaCare is a robust programme of clinical trials to evaluate the potential CV, renal and organ protection benefits of Farxiga. It includes more than 35 completed and ongoing Phase IIb/III trials in more than 35,000 patients, as well as more than 2.5 million patient-years’ experience. Farxiga is currently being tested in the DELIVER Phase III trial to evaluate its efficacy in the treatment of patients with HF with preserved ejection fraction with or without T2D and in the DAPA-MI Phase III trial - a first of its kind, indication-seeking registry-based randomised controlled trial in patients without T2D following an acute myocardial infarction or heart attack.
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s main disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.
1. Correa-Rotter R, et al. DAPA-CKD: A regional analysis of kidney and cardiovascular outcomes. Presented at: American Society of Nephrology (ASN) Kidney Week 2021, 4 Nov – 7 Nov 2021.
2. Correa-Rotter R, et al. Effects of dapagliflozin in patients with chronic kidney disease, with and without diabetes, by use and non-use of cardiovascular medications: DAPA-CKD Trial Presented at: American Society of Nephrology (ASN) Kidney Week 2021, 4 Nov – 7 Nov 2021.
3. Heerspink HJL, et al. The effect of dapagliflozin on rate of kidney function decline in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD trial. Presented at: American Society of Nephrology (ASN) Kidney Week 2021, 4 Nov – 7 Nov 2021.
4. Heerspink HJL, et al. Correlates and consequences of an acute decline in estimated glomerular filtration rate in response to the SGLT2 inhibitor dapagliflozin. Presented at: American Society of Nephrology (ASN) Kidney Week 2021, 4 Nov – 7 Nov 2021.
5. Virgitti JB, et al. REVEAL-CKD: Prevalence of Undiagnosed Early Chronic Kidney Disease in France and Japan. Presented at: American Society of Nephrology (ASN) Kidney Week 2021, 4 Nov – 7 Nov 2021.
6. Clinicaltrials.gov [Internet]. REVEAL-CKD: Prevalence and Consequences of Undiagnosed Chronic Kidney Disease (REVEAL-CKD); 2021 [cited 2021 Oct 14]. Available from: https://clinicaltrials.gov/ct2/show/NCT04847531
7. Bikbov B, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709-733.
8. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) [Internet]. Causes of Chronic Kidney Disease; 2016 [cited 2021 Oct 14]. Available from: https://www.niddk.nih.gov/health-information/kidney-disease/chronic-kidney-disease-ckd/causes.
9. Centers for Disease Control and Prevention (CDC) [Internet]. Chronic Kidney Disease: Common - Serious - Costly; 2019 [cited 2021 Oct 14]. Available from: https://www.cdc.gov/kidneydisease/prevention-risk/CKD-common-serious-costly.html.
10. Centers for Disease Control and Prevention (CDC) [Internet]. Chronic kidney disease in the United States; 2021 [cited 2021 Oct 14]. Available from: https://www.cdc.gov/kidneydisease/pdf/Chronic-Kidney-Disease-in-the-US-2021-h.pdf.
11. Briasoulis A, et al. Chronic kidney disease as a coronary artery disease risk equivalent. Curr Cardiol Rep. 2013;15(3):340.
12. Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446.
13. Wiviott SD, et al. for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type-2 diabetes [article and supplementary appendix]. N Engl J Med. 2019;380:347-357.
14. McMurray J, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995-2008.
15. Mayo Clinic [Internet]. Heart failure, 2020; [cited 2021 Oct 14]. Available from: https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142.
16. Centers for Disease Control and Prevention (CDC) [Internet]. A snapshot: Diabetes in the United States, 2020; [cited 2021 Oct 14]. Available from: https://www.cdc.gov/diabetes/library/socialmedia/infographics/diabetes.html.
17. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Internet]. Heart disease & kidney disease, 2016; [cited 2021 Oct 14]. Available from: https://www.niddk.nih.gov/health-information/kidney-disease/heart-disease.
18. FARXIGA (dapagliflozin) US Prescribing Information [Last update: Apr 2021]. Available from: https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/0be9cb1b-3b33-41c7-bfc2-04c9f718e442/0be9cb1b-3b33-41c7-bfc2-04c9f718e442_viewable_rendition__v.pdf
Veeva ID: Z4-38631
Date of Preparation: October 2021