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Abstract: SA-PO270

Improvement of Albuminuria by the Endothelin Receptor Antagonist Atrasentan Correlates to PCSK9 Reduction in Type 2 Diabetic Nephropathy Patients

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Shrestha, Pragyi, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Zijp, Tanja R., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Pena, Michelle, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Dullaart, Robin P., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • L Heerspink, Hiddo Jan, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • van den Born, Jacob, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
Background

The endothelin receptor antagonist atrasentan reduces albuminuria. This effect coincides with striking reductions in LDLc and triglycerides. Albuminuria has been shown to increase proprotein convertase subtilisin kexin type 9 (PCSK9), syndecan-1 shedding, and/or PCSK9-syndecan-1 interaction, leading to impaired hepatic lipoprotein clearance. Here, we investigated whether reduction of albuminuria and lipids with atrasentan, reduces PCSK9 and/or syndecan-1 shedding.

Methods

Patients with type 2 diabetes and chronic kidney disease (CKD) participating in a phase II clinical trial (RADAR; NCT01356849) were randomized to placebo (N=26) or atrasentan (0.75mg/d or 1.25mg/d) (N=94) treatment for 12 weeks. Patients were stabilized to a maximum labeled dose of RAAS inhibitor. Urine albumin creatinine ratio (UACR), serum lipids, PCSK9 and syndecan-1 were measured at baseline and week 12.

Results

Atrasentan treatment reduced UACR by 37.1% (95% CI30.1, 43.4; p<0.01), LDLc by 17.12 mg/dL (95%CI 8.8, 25.4; p<0.01), triglycerides by 47.4 mg/dL (95% CI 40.4, 90.5; p<0.01) and PCSK9 by -25.9 ng/mL (95% CI -52.7, 1.0; p=0.061) compared to placebo. No effects were observed on HDLc and syndecan-1. Multivariate analysis, adjusted for baseline demographics, lipid and kidney function parameters revealed that achieved albuminuria levels during atrasentan treatment correlated with achieved PCSK9 levels (β 0.00227 per unit increment in PCSK9; P=0.0094).

Conclusion

In patients with type 2 diabetes and CKD, atrasentan reduces albuminuria, LDLc and triglycerides. At 12 weeks of atrasentan treatment, achieved albuminuria correlated with achieved PCSK9. Our study might suggest a mechanism by which atrasentan provides cardio-protection in high-risk patients with type 2 diabetes and CKD.

Funding

  • Government Support – Non-U.S.