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

KEY POINTS: Dapagliflozin reduced albuminuria in participants with CKD, with reductions being proportional to reductions in the risk of disease progression. Residual albuminuria (at month 4) was linked to higher risks of primary and kidney end points, with no heterogeneity by diabetes status or allocated treatment. Participants with residual albuminuria at month 4 had high rates of kidney end points, implying the need for added therapy for long-term kidney and cardiovascular benefits.

BACKGROUND: Albuminuria is a strong indicator of kidney and cardiovascular risk in patients with CKD. We assessed risk associations between albuminuria at baseline and 4 months after randomization in a placebo-controlled trial of dapagliflozin and kidney end points in patients with CKD and albuminuria, with and without type 2 diabetes.

METHODS: In this post hoc analysis of the dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD) trial, 4304 adult patients with CKD were randomized to dapagliflozin 10 mg or placebo as an adjunct to maximally tolerated renin-angiotensin system inhibitors. The primary end point was a composite of sustained ≥50% decline in eGFR, kidney failure, or death from kidney or cardiovascular cause. The kidney composite end point 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 end points using Cox proportional hazards regression analyses.

RESULTS: Compared with placebo, dapagliflozin reduced urinary albumin–creatinine ratio (baseline to month 4) by 36.4% (95% confidence interval, 30.2% to 42.5%) and 20.5% (95% confidence interval, 11.6% to 29.5%) in participants with and without type 2 diabetes, respectively (P-interaction: 0.02). A reduction in urinary albumin–creatinine ratio from baseline to month 4 was associated with a lower risk of the primary and kidney composite end points 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 of the primary and kidney composite end points 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 of the primary and kidney composite end points in participants with and without type 2 diabetes. Participants with residual albuminuria at month 4—whether randomized to dapagliflozin or placebo—experienced relatively high rates of CKD progression kidney end points, suggesting that therapies added to renin-angiotensin system 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 CKD (DAPA-CKD), NCT03036150.