Cardiometabolic risk phenogroups from a data-driven classification with expanded risk factors

Abstracts Background and Aims Current diagnostic criteria for metabolic syndrome (MetS) may inadequately capture underlying metabolic heterogeneity and associated cardiovascular risks. We aimed to use expanded cardiometabolic variables to identify new cardiometabolic phenogroups with relevance to prognosis and risk stratification. Methods Latent class analysis (LCA) was applied to a discovery cohort (RESET; n=1,034), using the six conventional MetS measures and eight additional variables. A decision tree model was constructed using the most important variables to enable practical phenogroup classification and facilitate external validation. External validation was conducted in three independent cohorts, PICMAN (n = 120), UK Biobank (n = 344,817), and CHARLS (n = 12,145), analysing for proteomic signatures and cardiovascular outcomes. Results Five latent phenogroups were identified in the discovery cohort: Metabolically Preserved with and without isolated hypertension (each n=244; 23.6%), Lean-Insulin Resistant (IR) (n=140; 13.5%), Obese-Insulin Sensitive (IS) (n=211; 20.4%), and Obese-IR (n=195; 18.9%). Lean-IR and Obese-IS showed discordant adiposity and insulin/glycemic status, and a low prevalence of MetS (21.4% and 31.3%, respectively), whereas MetS was high (75.9%) only in the Obese-IR group. A decision tree model using four binary indicators (visceral adiposity, IR, elevated SBP, and HbA1c) accurately classified individuals into the five latent phenogroups and was subsequently deployed for external validation. Validation in PICMAN showed significantly higher liver fat (Mean 9.0% [SD 6.3%]) in Lean-IR versus Metabolically Preserved (Mean 2.8% [SD 1.8%], P=0.002). Plasma proteomic analyses further reflected unique metabolic–inflammation signatures across the 5 groups. Validation in the UK Biobank showed significant association between the latent phenogroups with outcomes of myocardial infarction and stroke. Hazard ratios for the composite outcome after adjusting for age and sex were 1.52 (95% CI, 1.43-1.61) for isolated hypertension, 1.86 (1.75-1.98) for Lean-IR, 1.85 (1.75-1.97) for Obese-IS, and 2.75 (2.56-2.95) for Obese-IR, compared with the Metabolically Preserved group. Conclusion Expanded cardiometabolic risk factors reveal metabolic heterogeneity obscured by current MetS criteria. Incorporating visceral adiposity and IR into a novel classification system refines cardiovascular risk stratification for the management of cardiometabolic disease. Key Question : Whether expanded variables beyond current Metabolic syndrome (MetS) criteria offer a data-driven approach to uncover distinct cardiometabolic phenogroups? Key Finding : Five reproducible latent classes were identified representing differential metabolic, proteomic, and cardiovascular risk profiles. Take-home Message : Expanded cardiometabolic risk assessment, in particular by incorporating visceral adiposity and insulin resistance, reveals metabolic heterogeneity obscured by current MetS criteria, and impacts cardiovascular risk stratification. Graphic Abstract BMI, body mass index; WC, Waist circumference; TG, Triglyceride; LDL-C, Low density lipoprotein cholesterol; HDL-C, High density lipoprotein cholesterol; FPG, Fasting plasma glucose; HbA1c, Glycated Hemoglobin A1c; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; SBP, systolic blood pressure; DBP, diastolic blood pressure; MI, myocardial infarction.