Prediction of the Effects of Empagliflozin on Cardiovascular and Kidney Outcomes Based on Short-Term Changes in Multiple Risk Markers

Abstract

Aims: The EMPA-REG OUTCOME trial demonstrated that the sodium-glucose cotransporter-2 inhibitor (SGLT2) empagliflozin reduces the risk of cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. We previously developed the parameter response efficacy (PRE) score, which translates drug effects on multiple short-term risk markers into a predicted long-term treatment effect on clinical outcomes. The main objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of empagliflozin in reducing the risk of CV and kidney outcomes. Methods: Short-term (baseline to 6-months) changes in glycated hemoglobin (HbA1c), systolic blood pressure (SBP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, uric acid, and potassium were determined among 7020 patients with type 2 diabetes and established CV disease in the EMPA-REG OUTCOME trial. The beta-coefficients, derived from a Cox proportional hazards model in a pooled database consisting of 6355 patients with type 2 diabetes, were applied to the short-term risk markers in the EMPA-REG OUTCOME trial to predict the empagliflozin-induced impact on CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, or CV death) and kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) outcomes. Results: Empagliflozin compared to placebo reduced HbA1c (0.6%), SBP (4.2 mmHg), UACR (13.0%), body weight (2.1 kg), uric acid (20.4 μmol/L), and increased hemoglobin (6.6 g/L), LDL-cholesterol (0.1 mmol/L) and HDL-cholesterol (0.04 mmol/L) (all p<0.01). Integrating these effects in the PRE score resulted in a predicted relative risk reduction (RRR) for the CV outcome of 6.4% (95% CI 1.4-11.7), which was less than the observed 14.7% (95% CI 1.3-26.4%) RRR. For the kidney outcome, the PRE score predicted a RRR of 33.4% (95% CI 26.2-39.8); the observed RRR was 46.9% (95% CI 26.8-61.5). In a subgroup of 2,811 patients with UACR ≥30 mg/g at baseline, the PRE score predicted RRR was 40.8% (95% CI 31.2-49.1) vs. the observed RRR of 40.8% (95% CI 12.4-60.0) for the kidney outcome. Conclusions: Integrating multiple short-term risk marker changes in the PRE score underestimated the effect of empagliflozin on CV and kidney outcomes, suggesting that the currently used risk markers do not fully capture the effect of empagliflozin. In patients with increased albuminuria, the PRE score adequately predicted the effect of empagliflozin on kidney outcomes.

Keywords: cardiovascular outcomes; diabetes; empagliflozin; kidney outcomes; risk markers.

FIGURE 1

Mean changes in risk markers from baseline to 6-months in the total population of the EMPA-REG OUTCOME trial (N = 7020). Changes are presented as mean with 95% confidence interval, for the placebo and empagliflozin group. HbA1c, glycated hemoglobin; BP, blood pressure; UACR, urinary-albumin-creatinine-ratio; HDL, high-density-lipoprotein; LDL, low-density-lipoprotein.

FIGURE 2

Mean changes in risk markers from baseline to 6-months in the population with UACR ≥30 mg/g of the EMPA-REG OUTCOME trial (N = 2811). Changes are presented as mean with 95% confidence intervals, for the placebo and empagliflozin group. HbA1c, glycated hemoglobin; BP, blood pressure; UACR, urinary-albumin-creatinine-ratio; HDL, high-density-lipoprotein; LDL, low-density-lipoprotein.

FIGURE 3

Predicted risk change for (A) the composite cardiovascular (CV) outcome consisting of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death in the total population; (B) the composite CV outcome in patients with UACR ≥30 mg/g; (C) the composite kidney outcome (doubling of serum creatinine or end-stage kidney disease) in the total population; and (D) the composite kidney outcome in patients with UACR ≥30 mg/g, (E) the composite CV outcome in patients with UACR <30 mg/g; (F) the composite kidney outcome in patients with UACR <30 mg/g based upon single and the multiple risk marker changes using the PRE score. Bars indicate the mean percentage reduction in the relative risk with 95% confidence intervals, following empagliflozin treatment. HbA1c, glycated hemoglobin; BP, blood pressure; UACR, urinary-albumin-creatinine-ratio; HDL, high-density-lipoprotein; LDL, low-density-lipoprotein; PRE score, Parameter Response Efficacy score.

FIGURE 4

Mean changes in risk markers from baseline to 6-months in the subset of the EMPA-REG OUTCOME trial according to the EMPA-KIDNEY trial inclusion criteria (N = 1222). Changes are presented as mean with 95% confidence intervals, for the placebo and empagliflozin group. HbA1c, glycated hemoglobin; UACR, urinary-albumin-creatinine-ratio; BP, blood pressure; HDL, high-density-lipoprotein; LDL, low-density-lipoprotein.

FIGURE 5

Predicted risk change for the composite kidney or cardiovascular death outcomes in the ongoing EMPA-KIDNEY trial based on single risk marker changes as well as the PRE score. The estimation of risk change was performed in a subset of the EMPA-REG OUTCOME trial population fulfilling the EMPA-KIDNEY trial inclusion criteria (N = 1222). HbA1c, glycated hemoglobin; BP, blood pressure; UACR, urinary-albumin-creatinine-ratio; HDL, high-density-lipoprotein; LDL, low-density-lipoprotein; PRE score, Parameter Response Efficacy score.

FIGURE 6

Simulated risk marker changes and the effect on the composite kidney and cardiovascular death outcomes for the prospective EMPA-KIDNEY trial based on the selected EMPA-REG OUTCOME trial population. The shaded area indicates the 95% confidence intervals for the simulated risk marker changes. Risk prediction was estimated from short-term risk marker changes in the EMPA-KIDNEY population (N = 1222) chosen from the EMPA-REG OUTCOME trial, and simulated values for UACR, systolic blood pressure, HbA1c, and body weight. The red dot indicates the PRE score predicted risk change in the EMPA-KIDNEY trial without enrichment with responders. The blue dots represent changes observed in the different proportion of responders and non-responders for each risk marker. HbA1c, glycated hemoglobin; UACR, urinary-albumin-to-creatinine ratio.