Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers

Abstract

Background: Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers 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 kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function.

Methods: The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes.

Results: A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively.

Conclusions: The PRE score predicted clinically meaningful reductions in kidney and HF events 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.

Keywords: clinical trial; dapagliflozin; diabetic kidney disease; heart failure; risk markers.

FIGURE 1

Mean changes in risk markers from baseline to Month 6 in the included population of the dapagliflozin Phase 3 programme with UACR >200 mg/g. Changes are presented as mean (±95% CI) and are given for placebo, dapagliflozin 5 mg and dapagliflozin 10 mg.

FIGURE 2

Predicted risk change for (A) kidney and (B) HF outcomes for patients with UACR >200 mg/g, based on changes in single risk markers and the integrated effects of all risk markers. Circles indicate the point estimates of the percentage mean change in relative risk induced by dapagliflozin compared with placebo and is given with its 95% CI.

FIGURE 3

Simulated UACR changes and the effect on kidney outcomes.