Baseline, Early Changes, and Residual Albuminuria: Post-hoc Analysis of a Clinical Trial of Dapagliflozin in Chronic Kidney Disease

Background: Albuminuria is a strong indicator of kidney and cardiovascular risk in patients with chronic kidney disease (CKD). We assessed risk associations between albuminuria at baseline and four months after randomization in a placebo-controlled trial of dapagliflozin and kidney endpoints in patients with CKD and albuminuria, with and without type 2 diabetes. Methods: In this post-hoc analysis of the DAPA-CKD trial, 4304 adult patients with CKD were randomized to dapagliflozin 10mg or placebo as adjunct to maximally tolerated renin-angiotensin-system (RAAS) inhibitors. The primary endpoint was a composite of sustained ≥50% decline in estimated glomerular filtration rate, kidney failure, or death from kidney or cardiovascular cause. The kidney composite endpoint was similar but excluded cardiovascular death. We assessed associations among baseline albuminuria, early change in albuminuria, (baseline to Month 4), and residual albuminuria (Month 4) with the primary composite and kidney composite endpoints using Cox proportional hazards regression analyses. Results: Compared to placebo, dapagliflozin reduced urinary albumin-to-creatinine ratio (UACR; baseline to Month 4) by 36% (95% CI: 30.2%, 42.5%) and 21% (95% CI: 12, 30%) in participants with and without type 2 diabetes, respectively (p-interaction: 0.02). A reduction in UACR from baseline to Month 4 was associated with a lower risk for the primary and kidney composite endpoints with a similar risk gradient for participants with and without type 2 diabetes (p-interaction: 0.10 and 0.19, respectively). Residual albuminuria was associated with a similar risk for the primary and kidney composite endpoints in each treatment arm (p-interaction: 0.19 and 0.18, respectively). Conclusions: Dapagliflozin reduced albuminuria, and the magnitude of albuminuria reduction showed similar proportional reductions in risks for the primary and kidney composite endpoints in participants with and without type 2 diabetes. Patients with residual albuminuria at Month 4 – whether randomized to dapagliflozin or placebo – experienced relatively high rates of CKD progression kidney endpoints, suggesting that therapies added to RAAS inhibitors and dapagliflozin may be required to sustain kidney and cardiovascular health. Clinical trial registry name and registration number: A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD), NCT03036150.