SGLT2i reduces clinical outcomes in CKD patients with and without T2DM
Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial
Introduction and methods
SGLT2 inhibitors slow down the rate of decline of eGFR and albuminuria in patients with type 2 diabetes  and in patients with chronic kidney disease and type 2 diabetes . Clinical studies and experimental data on use of SGLT2 inhibitors support a beneficial hemodynamic effect in the kidneys. This suggests that use of SGLT2 inhibitors results in beneficial kidney outcomes independent of effects on glucose and therefore in patients with CKD with etiologies other than T2DM [3,4].
In the DAPA-CKD trial, dapagliflozin reduced risk of kidney failure, death from CV causes or hospital admission for heart failure and death from any cause in a broad group of individuals with CKD .
In this prespecified analysis of DAPA-CKD, it was investigated whether the presence or absence of type 2 diabetes at baseline and the underlying etiology of kidney disease modified the effects of dapagliflozin on clinical outcomes.
Patients in the DAPA-CKD trial were randomized to dapagliflozin once daily or matching placebo in a 1:1 ratio, in addition to standard care. At screening visit diagnosis of kidney disease was recorded with the following categories: diabetic nephropathy, chronic glomerulonephritides (a subgroup of IgA nephropathy was analyzed separately), ischemic or hypertensive CKD, other or unknown causes of CKD. Primary outcome was a composite of sustained decline of 50% or more in eGFR, onset of end-stage kidney disease, or death from kidney or CV causes. In the main trial, 4303 patients were enrolled with a mean eGFR of 43 ml/min/1.73m2, a median UACR of 949 mg/g, who were followed for a median of 2.4 years (IQR 2.0-2.7). 32% Of patients did not have T2DM and 396 participants with T2DM had CKD due to other causes than diabetic nephropathy.
- In patients with T2DM, dapagliflozin reduced the primary composite outcome compared to placebo (HR 0.64, 95%CI: 0.52-0.79). Also in patients without T2DM, dapagliflozin reduced the primary outcome when compared to placebo (HR 0.50, 95%CI: 0.35-0.72). There was no interaction by diabetes status (Pinteraction=0.24). NNT was 19 for both groups.
- No differences in the effects of dapagliflozin vs. placebo on the components of the primary outcome or the prespecified composite outcome of chronic dialysis, kidney transplantation and kidney-related death by diabetes status were observed.
- A consistent effect of dapagliflozin on the secondary kidney-specific composite outcome (sustained eGFR decline ≥50%, end-stage kidney disease or kidney-related death) was seen in patients with and without T2DM. Also, for the composite outcome of CV death or hospital admission for heart failure; or the outcome of all-cause mortality no effect medication by diabetes status was observed.
- Effect of dapagliflozin on the primary composite outcome was consistent in patients with diabetic nephropathy (n=2510, HR 0.63, 95%CI: 0.51-0.78), glomerulonephritides (n=695, HR 0.43, 95%CI:0.26-0.71), ischemic or hypertensive CKD (n=687, HR 0.75, 95%CI: 0.44-1.26) and CKD of other or unknown cause (n=412, 95%CI: 0.59, 95%CI: 0.29-1.19). Similar findings were seen for secondary outcomes.
- Dapagliflozin reduced the risk of the primary outcome compared with placebo in 270 patients with IgA nephropathy (HR 0.29, 95%CI: 0.12-0.73).
- Proportions of patients in the dapagliflozin and placebo groups with serious adverse events or that discontinued study drug due to adverse events did not differ by diabetes status (but numerically more events in T2DM patients, and more with dapagliflozin than with placebo). Proportions that discontinued due to adverse events appeared to vary by etiological subgroup.
This prespecified analysis of the DAPA-CKD trial demonstrated that the reduction of major adverse kidney and CV outcomes by dapagliflozin when compared to placebo in patients with CKD was irrespective of diabetes status and the underlying cause of CKD.