Netherlands: Study on Atrasentan in High-Risk Patients with T2D and CKD

In high-risk patients with type 2 diabetes (T2D) and CKD (chronic kidney disease), atrasentan provides cardioprotection, is the conclusion drawn from a recent study.

The study findings presented at the 2022 Annual Meeting of the ASN (American Society of Nephrology) held in Orlando showed that atrasentan reduces triglycerides, LDL-C, and albuminuria. At 12 weeks of treatment with atrasentan, achieved albuminuria corresponded to achieved PCSK9.

Albuminuria has been demonstrated to increase proprotein convertase subtilisin kexin type 9 (PCSK9), syndecan-1 shedding, and PCSK9-syndecan-1 interaction, resulting in impaired clearance of hepatic lipoprotein. Atrasentan, the endothelin receptor antagonist, reduces albuminuria. This effect coincides with distinct reductions in triglycerides and LDL-C.

Against the above background, Pragyi Shrestha, Universitair Medisch Centrum Groningen, and colleagues aimed to determine whether a reduction of albuminuria and lipids with atrasentan lowers PCSK9 and syndecan-1 shedding.

For this purpose, the researchers included patients with type 2 diabetes and CKD who participated in RADAR, a phase II clinical trial. Ninety-four patients were randomized to atrasentan (0.75mg/d or 1.25mg/d) treatment and 26 to placebo for 12 weeks. Patients were stabilized to a maximum labelled dose of RAAS inhibitor. Measuring serum lipids, urine albumin creatinine ratio (UACR), syndecan-1, and PCSK9 were done at baseline and 12 weeks.

Study Findings

• Atrasentan treatment reduced UACR by 37.1%, LDL-C by 17.12 mg/dL, triglycerides by 47.4 mg/dL and PCSK9 by -25.9 ng/mL compared to placebo.
• No effects were observed on HDL-C and syndecan-1.
• Multivariate analysis after adjusting for lipid and kidney function parameters and baseline demographics showed that achieved albuminuria levels during atrasentan treatment correlated with achieved levels of PCSK9 (β 0.00227 per unit increment in PCSK9).

"Atrasentan reduces LDL-C, albuminuria, and triglycerides in patients with T2D and CKD. At 12 weeks of treatment with atrasentan, achieved albuminuria correlated with achieved PCSK9," the researchers wrote. "Our findings might suggest a pathway by which atrasentan provides cardio-protection in high-risk patients with T2D and chronic kidney disease."

Reference

SA-PO270 Poster Saturday Diabetic Kidney Disease: Clinical - II Improvement of Albuminuria by the Endothelin Receptor Antagonist Atrasentan Correlates to PCSK9 Reduction in Type 2 Diabetic Nephropathy Patients was presented at the ASN Kidney Week 2022.