SGLT2i reduces albuminuria in CKD patients with and without T2DM
Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial
Introduction and methods
Aim of the study
Early lowering of albuminuria is associated with a reduced risk of kidney failure . Therefore, albuminuria can be used as a surrogate for kidney failure. The DAPA-CKD trial showed that dapagliflozin reduced the rate of progressive chronic kidney disease, CV death or HF hospitalization, and all-cause mortality investigated in chronic kidney disease (CKD) patients with and without T2DM . In this prespecified analysis of the DAPA-CKD trial, the effects of dapagliflozin on albuminuria were investigated in patients with and without T2DM. Furthermore, the association between early changes in albuminuria and long-term changes in kidney function was assessed.
The DAPA-CKD trial was a double-blind, randomized, placebo-controlled trial of 4304 patients with CKD, defined as an eGFR of 25-75 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g. Patients with and without T2DM were included and all patients were on stable ACEi or ARB treatment. They were randomized (1:1) to dapagliflozin or matched placebo. Median on-treatment follow-up was 2.3 years (IQR 1.8-2.6) and the trial was stopped because the primary endpoint was met.
The prespecified outcome was the mean change in log-transformed UACR from baseline to the end of the study. Furthermore, progression in UACR stage was defined as the initial development of nephrotic range albuminuria (UACR ≥3000 mg/g) and regression in UACR stage as the initial transition from macroalbuminuria (UACR ≥300 mg/g) to microalbuminuria or normoalbuminuria (UACR <300 mg/g).
- The geometric mean percentage change in UACR with dapagliflozin compared to placebo was -26.5% (95%CI:-22.1 to -30.9%, P<0.0001) at week 2. During follow-up, this was -29.3% (95%CI:-33.1 to -25.2%, P<0.0001).
- Treatment with dapagliflozin resulted in a geometric mean percentage change of -35.1% (95%CI:-39.4 to -30.6%, P<0.0001) in patients with type 2 diabetes and -14.8% (95%CI:-22.9 to -5.9%, P=0.0016) in patients without T2DM at follow-up (Pinteraction<0.0001).
- Effects of dapagliflozin compared with placebo on UACR were larger in patients with diabetic nephropathy compared with other causes of CKD.
- The effect of dapagliflozin on UACR was more pronounced in patients with poorer glycemic control.
- Effects of dapagliflozin on UACR were consistent across the spectrum of baseline UACR and eGFR.
- Treatment with dapagliflozin increased the likelihood of regression in UACR stage (HR 1.81, 95%CI:1.60-2.05), in patients with T2DM (HR 2.06, 95%CI:1.78-2.39) and patients without T2DM (HR 1.33, 95%CI:1.0-1.66) with a more pronounced effect in patients with T2DM (Pinteraction=0.0011).
- Treatment with dapagliflozin reduced the likelihood of progression in UACR stage (HR 0.41, 95%CI:0.32-0.52) with no difference between patients with T2DM and without T2DM.
- Large acute declines in eGFR 2 weeks after randomization were associated with a larger reduction in UACR at day 14 (β=0.25, P<0.0001)
- Larger reductions in UACR at week 2 were associated with less steep declines in eGFR over time (β=3.06, P=0.0056).
In this analysis of DAPA-CKD, it was shown that dapagliflozin reduced albuminuria in patients with CKD with and without T2DM, with a larger effect in patients with T2DM. Moreover, dapagliflozin increased the likelihood of regression to normoalbuminuria or microalbuminuria and reduced the likelihood of progression to macroalbuminuria. And early reduction in albuminuria was associated with attenuated long-term eGFR decline. These results together with the evidence on clinical outcomes suggest that the protective effects of dapagliflozin in patients with CKD are partially mediated through pathways unrelated to reduction in albuminuria.
The authors write: ‘These findings highlight the importance of monitoring albuminuria after initiation of dapagliflozin as a prognostic marker of sustained kidney health and to guide patient management’