192Effect of dapagliflozin on cardiovascular outcomes in patients with type 2 diabetes according to baseline renal function and albuminuria status: Insights from DECLARE-TIMI 58

Abstract Background Renal dysfunction including both reduced estimated glomerular filtration rate (eGFR) and the presence of albuminuria have each been shown to predict cardiovascular (CV) outcomes. Sodium glucose co-transporter 2 inhibitors (SGLT2i), which promote glucose excretion in the kidneys, reduce CV events and hospitalizations for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM). Purpose To analyze the CV efficacy of dapagliflozin according to baseline renal function and albuminuria status in DECLARE-TIMI 58. Methods The DECLARE-TIMI 58 trial compared dapagliflozin vs. placebo in 17,160 patients with T2DM and a creatinine clearance >60 ml/min/1.73m2 at enrollment. The dual primary endpoints were CV death/HHF and MACE (MI, stroke, CV death). We categorized patients according baseline eGFR [<60 vs. ≥60 ml/min/1.73m2 according to the CKD-EPI formula] and urinary albumin:creatinine ratio (UACR) [<30 vs. ≥30 mg/g]. Cox regression models with interaction testing were applied. The Gail-Simon test was used to test for interaction of the absolute risk differences. Results In total, 5198 (30.3%) patients had albuminuria (UACR 30–300: n=4029; UACR >300: n=1169) and 1265 (7.4%) had an eGFR <60 ml/min/1.73m2. Accordingly, 10958 (63.9%) patients had no manifestation of CKD, 5367 (31.3%) had either an eGFR <60 ml/min/1.73m2 or albuminuria, and 548 (3.2%) patients had both manifestations. Patients with more abnormal markers had higher event rates for CV death/HHF (KM event rates at 4 years of 3.9%, 8.3%, 17.4%) and MACE (7.5%, 11.7%, and 18.9%) for no, 1, or 2 markers of CKD, respectively. The relative risk reductions for CV death/HHF and MACE were generally consistent across the subgroups (both P-interaction >0.29), though numerically greatest (42%) in patients with reduced eGFR and albuminuria. However, the absolute risk difference increased substantially in patients with greater kidney damage (absolute risk difference of CV death/HHF: −0.5%, −1.0%, and −8.3%, respectively; P-INT for ARD 0.002; Figure). See figure for MACE and component outcomes. Conclusions Patients with baseline renal disease had higher rates of adverse CV outcomes. Dapagliflozin reduced events with generally consistent relative risk, but reduced the absolute risk of CVD/HHF by the greatest amount in patients with kidney disease evidenced by both reduced eGFR and albuminuria. Acknowledgement/Funding AstraZeneca, Deutsche Forschungsgemeinschaft (ZE 1109/1-1)

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