Associations of Angiopoietin 2 and Vascular Endothelial Growth Factor-A Concentrations with Clinical End Points

Abstract

Background: Angiopoietin 2 regulates endothelial function partially mediated by vascular endothelial growth factor (VEGF-A) and may play a role in diabetic kidney disease. We assessed the association of angiopoietin 2 and VEGF-A with cardiorenal outcomes and investigated the effect of canagliflozin on angiopoietin 2 and VEGF-A concentrations. Methods: 2565 study participants with diabetic kidney disease and available plasma samples treated with canagliflozin or placebo in the Canagliflozin and Kidney Events in Diabetes with Established Nephropathy Clinical Evaluation trial were included. Angiopoietin 2 and VEGF-A concentrations were measured at baseline, year 1, and year 3. The primary composite endpoint of the trial was a composite of end-stage kidney failure, doubling of the serum creatinine level, and kidney or cardiovascular death. Results: Patients with the highest baseline quartile of angiopoietin 2 but not VEGF-A concentration had the highest risk clinical profile. Treatment with canagliflozin significantly lowered concentrations of angiopoietin 2 (adjusted geometric mean ratio: 0.94; 95lcl confidence interval [CI], 0.92, 0.95, p<0.001), but not VEGF-A. In multivariable-adjusted modeling, each 50% increment in log baseline angiopoietin-2 concentrations was associated with a higher risk of primary composite outcome (hazard ratio:1.27, 95% confidence interval: 1.13-1.43). Angiopoietin 2 change at year 1 compared to baseline explained 10% of the effect of canagliflozin on the primary composite outcome. VEGF-A concentrations were not associated with outcomes, alone or in combination with angiopoietin 2. Conclusions: Higher Angiopoietin 2 levels were associated with cardiorenal risk among individuals with diabetic kidney disease independent of VEGF-A. Canagliflozin lowered angiopoietin 2 concentrations.