Atrasentan Reduces Albuminuria, Triglycerides in Patients With Type 2 Diabetes and CKD

Atrasentan results in meaningful reductions in a number of cardiovascular data points in patients with type 2 diabetes and chronic kidney disease (CKD).

A team, led by Pragyi Shrestha, Universitair Medisch Centrum Groningen, assessed whether albuminuria and lipids with atrasentan reduction also reduces PCKS9 and/or syndecan-1 shedding.

Reducing Albuminuria

The endothelin receptor antagonist atrasentan is known to reduce albuminuria and coincide with reductions in LDLc and triglycerides.

Previous research shows albuminuria can increase proprotein convertase subtilisin kexin type 9 (PCSK9), syndecan-1 shedding, and/or PCSK9-syndecan-1 interaction. This leads to the impairment of hepatic lipoprotein clearance.

The Phase 2 Study

In the phase 2 study, the investigators examined patients with type 2 diabetes and chronic kidney disease. Each participant was randomized to receive either atrasentam 0.75 mg daily or 1.25 mg daily (n = 94) or placebo (n = 26) for 12 weeks. Each patient was stabilized to a maximum labeled dose of RAAS inhibitor.

The data was presented during the 2022 American Society of Nephrology (ASN) Annual Meeting in Orlando.

The investigators measured urine albumin creatinine ratio (UACR), serum lipids. PCSK9, and syndecan-1 at baseline and week 12.

Reductions

The results show treatment reduced UACR by 37.1% (95% CI, 30.1-43.4; P <0.01). Atrasetan also resulted in reductions in 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 to 1.0 (P = 0.061) compared to placebo.

In addition, they did not observe any effects on HDLc and syndecan-1. After conducting a multivariate analysis adjusted for baseline demographics, lipid, and kidney function parameters, the investigators found achieved albuminuria levels during astratean treatment was associated with achieved PCSK9 levels (β 0.00227 per unit increment in PCSK9; P = 0.0094).

“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,” the authors wrote. “Our study might suggest a mechanism by which atrasentan provides cardio-protection in high-risk patients with type 2 diabetes and CKD.”

The study, “Improvement of Albuminuria by the Endothelin Receptor Antagonist Atrasentan Correlates to PCSK9 Reduction in Type 2 Diabetic Nephropathy Patients,” was published online by ASN.