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Kidney Week

Abstract: TH-OR56

Insulin Resistance, Kidney Outcomes, and Effects of the Endothelin Receptor Antagonist Atrasentan in Patients with Type 2 Diabetes and CKD

Session Information

Category: Diabetic Kidney Disease

  • 702 Diabetic Kidney Disease: Clinical

Authors

  • Smeijer, Johannes David, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Kohan, Donald E., University of Utah Health, Salt Lake City, Utah, United States
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Herlev, Capital Region, Denmark
  • Correa-Rotter, Ricardo, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Ciudad de México, Mexico
  • Liew, Adrian, Mount Elizabeth Hospital, Singapore, Singapore, Singapore
  • Tang, Sydney C.W., The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • de Zeeuw, Dick, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Gansevoort, Ron T., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Heerspink, Hiddo Jan L., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
Background

Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes mellitus (T2DM) and associated with chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with T2DM and CKD.

Methods

We used data from the RADAR and SONAR trials that recruited participants with T2DM and CKD [eGFR 25–75 mL/min/1.73 m2, urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model.

Results

In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p=0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks’ treatment in the RADAR trial (N=123), atrasentan reduced HOMA-IR compared to placebo [0.75 mg/d 19.1% (95%CI -17.4, 44.3) and 1.25 mg/d 26.7% (95%CI -6.4, 49.5)]. In the SONAR trial (N=1914), long-term treatment with atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9).

Conclusion

More severe IR is associated with increased risk of cardio-renal and mortality outcomes. The endothelin receptor antagonist atrasentan reduced IR, which may translate into clinical kidney benefits.

Atrasentan reduces insulin resistance. Panel A: Change from baseline in HOMA-IR in the RADAR trial. Panel B: Geometric mean HOMA-IR values per study visit in the SONAR trial.