New sub-analyses further support consistency of Farxiga’s cardiorenal and mortality benefits

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 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. 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), the onset of end-stage kidney disease (ESKD), and death from a kidney or CV cause were 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).

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. Specifically, the effect of dapagliflozin versus placebo on time to the 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 analyzed including diuretics, calcium channels, and beta-blockers.

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 randomized 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). The new data also showed that an acute decline in eGFR associated with the 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 reflects favorable hemodynamic 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 the magnitude of decline.

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. 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. 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.

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 prioritizing earlier screening and diagnosis, we can help patients receive treatment as early as possible, maximizing the opportunity to slow disease progression and improve outcomes.”

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