Abstract: TH-OR037
Prediction of the Effect of Dapagliflozin on Renal and Heart Failure Outcomes Based on Short-Term Changes in Multiple Risk Markers
Session Information
- Diabetic Kidney Disease Trials: Progress Being Made
October 25, 2018 | Location: 5A, San Diego Convention Center
Abstract Time: 05:42 PM - 05:54 PM
Category: Diabetic Kidney Disease
- 602 Diabetic Kidney Disease: Clinical
Authors
- Idzerda, Nienke, University Medical Center Groningen, Groningen, Netherlands
- Sjostrom, David, AstraZeneca LP, Molndal, Sweden
- Stefansson, Bergur V., AstraZeneca, Molndal, Sweden
- Wheeler, David C., University College London, London, lONDON, United Kingdom
- Lambers Heerspink, Hiddo Jan, University Medical Center Groningen, Groningen, Netherlands
Background
Sodium glucose cotransporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). We previously developed an algorithm, the PRE score, to predict how short term effects of a drug on risk factors may translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on renal and heart failure (HF) outcomes in T2DM patients with impaired renal function.
Methods
The relationships between multiple risk markers and long-term outcome were determined by means of a multivariable Cox model in a subgroup of T2DM patients derived from the ALTITUDE trial. These relationships were applied to short-term changes in risk markers observed in a pooled database of seven dapagliflozin clinical trials to predict the expected drug-induced changes to renal and HF outcomes. Patient characteristics within the background population were matched with respect to UACR and eGFR to those from the dapagliflozin trial participants. The renal outcome was defined as a composite of end-stage renal disease (ESRD) and a sustained doubling of serum creatinine. The heart failure outcome was defined as hospitalization due to HF.
Results
A total of 372 and 136 patients had UACR>30 mg/g and UACR>200 mg/g at baseline, respectively. The PRE score predicted a renal risk reduction of 39% (95% CI 17 to 61%) and 43% (95% CI 4 to 83%) with dapagliflozin 10 mg/day for the UACR>30 mg/g and UACR>200 mg/g subgroups. The predicted reduction in HF events was 21% (95% CI 8 to 35%) and 28% (95% CI 7 to 49%), respectively. Dapagliflozin decreased albuminuria by approximately 35% in both UACR subgroups. Simulation analyses showed that even with a smaller albuminuria lowering effect of dapagliflozin (10%), the estimated renal risk reduction was still 26.5% and 26.8% in the two UACR subgroups.
Conclusion
The PRE score predicted clinically meaningful reductions in renal and HF endpoints associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints.
Funding
- Commercial Support –