Risk-Based Stratification Approach for Cardiovascular-Kidney-Metabolic Syndrome Stage 2 Using a Simple Algorithm

Abstract Background Cardiovascular-kidney-metabolic (CKM) syndrome is staged to reflect increasing cardiometabolic risk. Substantial heterogeneity exists within stage 2, which includes individuals with metabolic risk factors or chronic kidney disease (CKD) without established cardiovascular disease and affect nearly half of US adults. This study aimed to develop and validate a sex-specific, clinically pragmatic model to subdivide CKM stage 2 into lower-risk (stage 2a) and higher-risk (stage 2b) subgroups Methods We analyzed participants aged ≥18 years with CKM syndrome stage 2 from the 1999-2018 NHANES cycles linked to the US National Death Index. Participants were assigned to development and validation cohorts comprising five survey cycles each. Predictor variables were selected using modified LASSO-regression and Cox-regression model, with cardiovascular mortality as the primary outcome. Model performance was assessed using time-dependent area under the receiver operating characteristic curve (AUC) and the C-statistics. TriNetX database with patient-level data from medical records was analyzed to provide clinical validation using major adverse cardiovascular events (MACE) as the outcome. Results Stage 2b in women was defined by the presence of at least two of the following: age ≥66 years, CKD, diabetes, or hypertension (AUC 0.79; C-index 0.78). In men stage 2b required at least two of the following: age ≥61 years, CKD, diabetes, or current smoking (AUC 0.73; C-index 0.72). Discrimination was preserved in external validation (women: AUC 0.70, C-index 0.69; men: AUC 0.75, C-index 0.68) with significantly distinct 10-year absolute risk difference of cardiovascular death (women: 4.9% [95% CI 2.2-7.5]; men: 8.5% [95% CI 5.0-12.0]). In TriNetX database, 10-year MACE risk increased from 11.3% to 24.6% in women and from 13.1% to 30.8% in men from stage 2a to stage 2b. Conclusions Subdividing CKM stage 2 into stages 2a and 2b identifies clinically meaningful differences in cardiovascular risk and may support targeted preventive strategies.