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Abstract: TH-PO922

Prediction and Validation of Exenatide Risk Marker Effects on Progression of Renal Disease: Insights from EXSCEL

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Clegg, Lindsay, AstraZeneca, Gaithersburg, Maryland, United States
  • Idzerda, Nienke, University Medical Center Groningen, Groningen, Netherlands
  • Bakris, George L., The University of Chicago Medicine, Chicago, Illinois, United States
  • Penland, Robert C., Astrazeneca Pharmaceuticals, Watertown, Massachusetts, United States
  • Boulton, David W., AstraZeneca, Gaithersburg, Maryland, United States
  • L Heerspink, Hiddo Jan, University Medical Center Groningen, Groningen, Netherlands
Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) may slow progression of renal disease in patients with type 2 diabetes (T2D). We previously developed the PRE score that translates multiple short-term drug effects into a predicted effect on long-term outcomes. We assessed the short-term effects of the GLP-1 RA exenatide on multiple cardio-renal risk markers, and aimed to determine whether the PRE score could predict the renal effects of exenatide observed in the EXSCEL cardiovascular outcomes trial.

Methods

Changes from baseline to six months in multiple risk markers were evaluated for glycated hemoglobin (HbA1c), systolic blood pressure (SBP), urine albumin:creatinine ratio (UACR), body mass index (BMI), hemoglobin and total cholesterol. The renal outcome was defined as a composite of a sustained 30% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease. The effect of exenatide on the composite of 40% eGFR decline or ESRD was also assessed. Relationships between multiple risk markers and long-term renal outcomes were determined in patients with T2D from the ALTITUDE study using multivariable Cox regression analysis. These relationships were applied to short-term changes in risk markers observed in EXSCEL to predict the likely drug induced impact on renal outcomes.

Results

Compared with placebo, mean HbA1c, BMI, SBP, and total cholesterol were lower at six months with exenatide, as was the incidence of micro- or macroalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline / ESRD endpoint of 11.3% (HR 0.89; 95%CI 0.83 to 0.94), compared with 12.7% (HR 0.87; 95%CI 0.77 to 0.99) observed risk reduction. For the 40% eGFR / ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 95%CI 0.82 to 0.97) and 13.7% (HR 0.86, 95%CI 0.72 to 1.04), respectively.

Conclusion

The PRE score, integrating multiple short-term risk marker changes, predicted the observed renal risk reduction with exenatide treatment as observed in the EXSCEL trial. The results of the present study support further clinical trials to prospectively assess the renal efficacy of exenatide.

Funding

  • Commercial Support