Research in context
Evidence before this study
We searched PubMed between Jan 1, 2000, and April 2, 2021, for trials published in English, using the search terms “SGLT2”, “SGLT2 inhibitor”, “chronic kidney disease”, “albuminuria”, “UACR”, and “randomised controlled clinical trial’. Albuminuria is an established risk marker for progression of chronic kidney disease. Previous clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce albuminuria in patients with type 2 diabetes and chronic kidney disease. For example, in the DELIGHT study, the SGLT2 inhibitor dapagliflozin reduced the urinary albumin-to-creatinine ratio (UACR) by 28% at 4 weeks compared with placebo in patients with chronic kidney disease and type 2 diabetes. Two small clinical studies in patients with chronic kidney disease without diabetes reported that the albuminuria-lowering effect of dapagliflozin was diminished compared with patients with diabetes. Because these studies were relatively small and of short duration, no definitive conclusions could be drawn over whether the different effects of dapagliflozin on albuminuria between patients with and without diabetes were an actual or chance finding.The DAPA-CKD trial was a large international clinical trial to assess the effects of dapagliflozin on clinical outcomes in patients with chronic kidney disease with and without type 2 diabetes. The results of the trial showed that dapagliflozin compared with placebo significantly decreased the relative risks of kidney failure, cardiovascular death or heart failure hospitalisation, and all-cause mortality. In this prespecified analyses of the DAPA-CKD trial, we assessed the effect of dapagliflozin on albuminuria, investigated the consistency of these effects in patients with and without type 2 diabetes, and explored the association between early changes in albuminuria and subsequent longer-term changes in kidney function.
Added value of this study
The acute decline in estimated glomerular filtration rate (eGFR) after 2 weeks treatment with dapagliflozin correlated with the reduction in UACR at week 2. This association was present in patients with and without type 2 diabetes. The reduction in UACR after 2 weeks was associated with a lower rate of decline in eGFR during the trial both in patients with and without type 2 diabetes.
Implications of all the available evidence
In this prespecified analysis of the DAPA-CKD trial, we showed that dapagliflozin reduced albuminuria in patients with chronic kidney disease with and without type 2 diabetes, with a larger reduction in patients with type 2 diabetes. These data, in combination with the available evidence that dapagliflozin consistently reduces the risk of clinical outcomes in patients with and without type 2 diabetes, suggest that the protective effects of dapagliflozin in patients with chronic kidney disease are likely to be mediated in part through pathways related, and in part through pathways unrelated, to reduction in albuminuria. The association between an early reduction in albuminuria with attenuated longer-term eGFR decline highlights the importance of monitoring albuminuria as a marker to guide patient management.