Abstract: SA-PO270
Improvement of Albuminuria by the Endothelin Receptor Antagonist Atrasentan Correlates to PCSK9 Reduction in Type 2 Diabetic Nephropathy Patients
Session Information
- Diabetic Kidney Disease: Clinical - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
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.