Development and Internal Validation of a Discrete Event Simulation Model of Diabetic Kidney Disease Using CREDENCE Trial Data

Abstract

Introduction: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study showed that compared with placebo, canagliflozin 100 mg significantly reduced the risk of major cardiovascular events and adverse renal outcomes in patients with diabetic kidney disease (DKD). We developed a simulation model that can be used to estimate the long-term health and economic consequences of DKD treatment interventions for patients matching the CREDENCE study population.

Methods: The CREDENCE Economic Model of DKD (CREDEM-DKD) was developed using patient-level data from CREDENCE (which recruited patients with estimated glomerular filtration rate 30 to < 90 mL/min/1.73 m2, urinary albumin to creatinine ratio > 300-5000 mg/g, and taking the maximum tolerated dose of a renin-angiotensin-aldosterone system inhibitor). Risk prediction equations were fit for start of maintenance dialysis, doubling of serum creatinine, hospitalization for heart failure, nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. A micro-simulation model was constructed using these risk equations combined with user-definable kidney transplant event risks. Internal validation was performed by loading the model to replicate the CREDENCE study and comparing predictions with trial Kaplan-Meier estimate curves. External validation was performed by loading the model to replicate a subgroup of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program with patient characteristics that would have qualified for inclusion in CREDENCE.

Results: Risk prediction equations generally fit well and exhibited good concordance, especially for the placebo arm. In the canagliflozin arm, modest underprediction was observed for myocardial infarction, along with overprediction of dialysis, doubling of serum creatinine, and all-cause mortality. Discrimination was strong (0.85) for the renal outcomes, but weaker for the macrovascular outcomes and all-cause mortality (0.60-0.68). The model performed well in internal and external validation exercises.

Conclusion: CREDEM-DKD is an important new tool in the evaluation of treatment interventions in the DKD population.

Trial registration: ClinicalTrials.gov identifier, NCT02065791.

Keywords: Canagliflozin; Diabetic kidney disease; Economic simulation model; Renal; Risk prediction; Type 2 diabetes mellitus.

Figures

Fig. 1

CREDEM-DKD model structure. AE adverse event, CV cardiovascular, CVD cardiovascular disease, CREDEM-DKD CREDENCE Economic Model of DKD, CREDENCE Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation, DoSCr doubling of serum creatinine, eGFR estimated glomerular filtration rate, HF heart failure, HHF hospitalization for heart failure, Hx history, ICER incremental cost-effectiveness ratio, MI myocardial infarction, LY life-year, RRT renal replacement therapy, UACR urine albumin to creatinine ratio

Fig. 2

Kaplan–Meier cumulative incidence curves for risk equation predictions and observed CREDENCE values, by outcome. CREDENCE Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation, HHF hospitalization for heart failure, HR hazard ratio, MI, myocardial infarction

Fig. 3

Kaplan–Meier cumulative incidence curves for predicted and observed CREDENCE trial values, by outcome. CREDENCE Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation, HHF hospitalization for heart failure, HR hazard ratio, MI myocardial infarction

Fig. 4

Kaplan–Meier cumulative incidence curves for predicted and observed CANVAS Program subgroup values, by outcome. CANVAS CANagliflozin cardioVascular Assessment Study, HHF hospitalization for heart failure, HR hazard ratio, MI, myocardial infarction