Research in context
Evidence before this study
We searched PubMed for all English-language publications from Jan 1, 2000, to May 28, 2019, using the search terms “SGLT2”, “CKD”, “kidney disease”, “diabetic nephropathy”, and “eGFR”. Previous trials have shown that the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin slowed the progression of nephropathy in patients with type 2 diabetes. However, most of the patients in these trials had established atherosclerotic cardiovascular disease or mild to moderate chronic kidney disease, or both. In the primary report of the DECLARE–TIMI 58 trial, a cardiorenal secondary composite outcome (≥40% decrease in estimated glomerular filtration rate [eGFR] to <60 mL/min per 1·73 m2, new end-stage renal disease, or death from renal or cardiovascular causes) was reduced by 24%, and a renal-specific composite outcome excluding cardiovascular death was reduced by 47%.
Added value of this study
In this renal analysis of the DECLARE–TIMI 58 trial, we identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73m2 (hazard ratio 0·54 [95% CI 0·43–0·67]; p<0·0001). Despite small numbers of events, we also showed a reduction in the combined risk of end-stage renal disease or renal death (0·41 [95% CI 0·20–0·82]; p=0·012). Furthermore, we have shown the consistent beneficial effects of dapagliflozin on composite renal outcomes compared with placebo in predefined subgroups of patients, including those defined by eGFR status and the presence or absence of atherosclerotic cardiovascular disease at baseline. Thereby, our results show the effect of an SGLT2 inhibitor on both early prevention and reduction in progression of chronic kidney disease in patients with type 2 diabetes. DECLARE–TIMI 58 is the first study to show the effects of an SGLT2 inhibitor on clinically important renal outcomes and on changes in eGFR in a large cohort of patients with type 2 diabetes with and without previous atherosclerotic cardiovascular disease, most of whom had normal or only mildly reduced renal function.
Implications of all the available evidence
On the basis of available evidence, SGLT2 inhibitors seem to reduce the risk of both progression and development of nephropathy in patients with type 2 diabetes, irrespective of the presence of atherosclerotic cardiovascular disease or baseline renal function. The effect of SGLT2 inhibitors on nephropathy is being examined in dedicated studies of renal outcomes, both in patients with and without type 2 diabetes. However, these trials focus on populations with nephropathy at baseline, and therefore should be considered as complementary to our findings.