Comparative risk assessment of cardiovascular and kidney outcomes in patients with type 2 diabetes using cystatin C and creatinine in DECLARE-TIMI 58

Background The relationship between cystatin C and cardiovascular and kidney outcomes is not well explored in individuals with type 2 diabetes (T2D) and normal or mild kidney dysfunction. Methods This nested prospective biomarker study included patients enrolled in DECLARE-TIMI 58. Participants were categorized into quartiles of CysC/creatinine and eGFR CysC /eGFR Cr and classified according to Kidney Disease Improving Global Outcomes (KDIGO) risk categories. Hazard ratios were estimated for a composite of cardiovascular death and hospitalization for heart failure (CVD/HHF), major adverse cardiovascular events (MACE), and a kidney-specific composite outcome (persistent ≥40% decrease in eGFR, end-stage renal disease, or renal death). Results Among 1899 placebo-treated patients, higher baseline CysC was associated with higher risk for CVD/HHF, MACE, and the kidney-specific composite outcome. A gradient of risk across quartiles was observed for CVD/HHF [Q4 v Q1 1.33 (0.98–1.80), p-trend = 0.016; MACE [Q4 1.34 (1.06–1.69), p-trend = 0.013]; and kidney-specific composite outcome [Q4 1.95 (0.95–3.99), p-trend = 0.036]. When compared with creatinine, CysC showed more pronounced and statistically significant risk gradients (CVD/HHF: KDIGO-CysC p-trend < 0.001 vs. p-trend Cr 0.34; MACE: CysC p-trend < 0.001vs. Cr p-trend 0.52). No heterogeneity was observed in the effect of dapagliflozin across CysC concentrations (p-interactions >0.05). Conclusion In patients with T2D and predominantly preserved Cr-based eGFR, CysC was associated with increased cardiovascular and kidney risk. Although discrimination assessed by c-statistic was similar for CysC and Cr, risk gradients seen with CysC became attenuated and no longer statistically significant when using Cr-based analogs. The effect of dapagliflozin was consistent irrespective of baseline CysC. Trial registration ClinicalTrials.gov Identifier: NCT01730534