Phenomapping-Derived Tool to Individualize the Effect of Canagliflozin on Cardiovascular Risk in Type 2 Diabetes

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors have well-documented cardioprotective effects but are underused, partly because of high cost. We aimed to develop a machine learning–based decision support tool to individualize the atherosclerotic cardiovascular disease (ASCVD) benefit of canagliflozin in type 2 diabetes. RESEARCH DESIGN AND METHODS We constructed a topological representation of the Canagliflozin Cardiovascular Assessment Study (CANVAS) using 75 baseline variables collected from 4,327 patients with type 2 diabetes randomly assigned 1:1:1 to one of two canagliflozin doses (n = 2,886) or placebo (n = 1,441). Within each patient’s 5% neighborhood, we calculated age- and sex-adjusted risk estimates for major adverse cardiovascular events (MACEs). An extreme gradient boosting algorithm was trained to predict the personalized ASCVD effect of canagliflozin using features most predictive of topological benefit. For validation, this algorithm was applied to the CANVAS-Renal (CANVAS-R) trial, comprising 5,808 patients with type 2 diabetes randomly assigned 1:1 to canagliflozin or placebo. RESULTS In CANVAS (mean age 60.9 ± 8.1 years; 33.9% women), 1,605 (37.1%) patients had a neighborhood hazard ratio (HR) more protective than the effect estimate of 0.86 reported for MACEs in the original trial. A 15-variable tool, INSIGHT, trained to predict the personalized ASCVD effects of canagliflozin in CANVAS, was tested in CANVAS-R (mean age 62.4 ± 8.4 years; 2,164 [37.3%] women), where it identified patient phenotypes with greater ASCVD canagliflozin effects (adjusted HR 0.60 [95% CI 0.41–0.89] vs. 0.99 [95% CI 0.76–1.29]; P_interaction = 0.04). CONCLUSIONS We present an evidence-based, machine learning–guided algorithm to personalize the prescription of SGLT2 inhibitors for patients with type 2 diabetes for ASCVD effects.