Dapagliflozin in Patients with Chronic Kidney Disease

Abstract

BACKGROUNDPatients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known. METHODSWe randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m 2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. RESULTSThe independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed. CONCLUSIONSAmong patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by Astra-Zeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.

Empagliflozin Inhibits Basal and IL-1β-Mediated MCP-1/CCL2 and Endothelin-1 Expression in Human Proximal Tubular Cells

“…We present novel evidence for the interference of Empa with tubular inflammatory response mechanisms under normoglycemic conditions. In light of the results of the DAPA-CKD trial demonstrating SGLT2i-mediated nephroprotection in CKD patients regardless of the presence or absence of diabetes [20], our results provide evidence for one potential mechanism underlying SGLT2i-mediated renoprotection in normoglycemic CKD patients. However, further studies are necessary to elucidate the downstream molecular mechanisms of Empa-mediated effects on the tubular inflammatory response as well as to assess the potential beneficial effects of SGLT2i-mediated tubular MCP-1/CCL2 and/or ET-1 suppression in animal models and humans.…”

“…Interestingly, SGLT2i reduce the risk of worsening heart failure or CV death independently of diabetes status [19]. Even more intriguingly, the DAPA-CKD trial recently demonstrated that dapagliflozin reduces the risk of eGFR decline, end-stage renal disease, or death from renal or CV causes in CKD patients regardless of the presence or absence of diabetes [20]. The renal benefit of SGLT2i is not associated with their HbA1c-lowering capacity but rather attributable to multiple effects that have been extensively investigated and reviewed before [12,21]: SGLT2i reduce glomerular hyperfiltration via restoring the tubuloglomerular feedback mechanism; lower body weight, plasma volume and systemic blood pressure; and reduce renal hypoxia via decreasing tubular oxygen demand.…”

The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

“…inhibitors show a strong benefit in slowing the progression of diabetic kidney disease, with the greatest absolute benefits in those with higher albuminuria, and evidence for SGLT2 inhibitors in non-diabetic CKD is emerging. 18,19,66,67 Another class of glucose lowering agents, glucagon-like peptide-1 (GLP-1) receptor agonists, significantly reduce cardiovascular outcomes among persons with CKD, 68 and may slow diabetic kidney disease progression. 69,70 Treatment of metabolic acidosis in CKD G3 with fruits and vegetables or oral bicarbonate may preserve GFR and additional studies are ongoing.…”

Emerging Modes of Treatment of IgA Nephropathy

“…IgAN made up a significant proportion of the non-diabetic subgroup and the HR was an impressive 0.79 for IgAN. Unlike corticosteroid, the side effect profile is likely more favourable [40].…”