Cardiovascular disease (CVD) remains the leading global cause of mortality, with insulin resistance as a pivotal metabolic risk factor that promotes endothelial dysfunction, inflammation, and atherosclerosis via mechanisms such as impaired nitric oxide signaling and enhanced oxidative stress. The metabolic score for insulin resistance (METS-IR), a non-insulin-based index derived from fasting blood glucose, triglycerides, high-density lipoprotein cholesterol, and body mass index, offers a practical surrogate for assessing insulin sensitivity. However, its association with incident CVD has not been systematically evaluated in a meta-analysis. This meta-analysis aimed to quantify the relationship between baseline METS-IR and the incidence of composite CVD, coronary artery disease (CAD), and stroke in adults without baseline CVD, including categorical, continuous, and dose-response analyses. We searched PubMed, EMBASE, Cochrane Library, and Web of Science up to August 2, 2025, for cohort studies. Hazard ratios (HRs) were pooled using random-effects models to account for heterogeneity for highest versus lowest METS-IR categories and per standard deviation (SD) increment. Nonlinear dose-response relationships were modeled with restricted cubic splines. Heterogeneity, sensitivity, and publication bias were assessed. Eight cohort studies involving 437, 283 participants were included. Highest vs. lowest METS-IR was associated with increased risks (HR 95% CI; I²): composite CVD (1. 65 1. 36-2. 02; 85. 6%), CAD (1. 82 1. 50-2. 20; 59. 7%), stroke (1. 47 1. 19-1. 83; 76. 3%). Per SD increment: composite CVD (1. 16 1. 10-1. 22; 70. 7%), CAD (1. 18 1. 11-1. 25; 52. 4%), stroke (1. 13 1. 06-1. 19; 67. 9%). Dose-response analyses revealed a nonlinear association for CAD (P for nonlinearity: 0. 011), marginal nonlinearity for stroke (P: 0. 072), and suggested nonlinearity for composite CVD (P: 0. 145), with inflection points at METS-IR values of 40. 56 (composite CVD), 38. 24 (CAD), and 48. 88 (stroke), beyond which risks appeared to accelerate. Elevated METS-IR independently predicts higher incidence of composite CVD, CAD, and stroke with nonlinear thresholds for CAD, marginal nonlinear thresholds for stroke, and potential nonlinear thresholds for composite CVD, despite moderate-to-high heterogeneity, supporting its integration into risk stratification and preventive strategies for metabolic health management. Systematic review registration https: //www. crd. york. ac. uk/PROSPERO/displayᵣecord. php? ID=CRD420251104293, identifier CRD420251104293.
He et al. (2025) studied this question.