Association between METS-IR and incident stroke in a nationwide prospective cohort of non-diabetic Chinese adults

BACKGROUND: The metabolic score for insulin resistance (METS-IR) is a novel indicator based on routine clinical parameters and has been validated as a reliable surrogate marker for insulin resistance. However, evidence regarding the association between METS-IR and stroke events remains limited, particularly among non-diabetic adults. Therefore, this study aimed to evaluate the association between METS-IR and the risk of incident stroke in a nationally representative prospective cohort of Chinese adults without diabetes. METHODS: A total of 8,316 nondiabetic participants aged ≥ 45 years were included from the China Health and Retirement Longitudinal Study (CHARLS) spanning 2011–2020. METS-IR was calculated via a validated formula incorporating fasting glucose, triglycerides, HDL-C, and BMI. The incidence of stroke was determined based on self-reported physician diagnoses. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Generalized additive models (GAM) was used to assess nonlinear associations, whereas mediation analysis was used to examine the indirect effect of mean arterial pressure (MAP). RESULTS: In this prospective cohort of 8,316 nondiabetic adults, elevated METS-IR was dose-dependently associated with incident stroke (adjusted HR = 1.63, 95% CI: 1.28–2.06 for Q4 vs. Q1; p-trend < 0.0001). A nonlinear threshold effect was identified at METS-IR 40.95: below this inflection point, each unit increment corresponded to a 4% increased stroke risk (HR = 1.04, 95% CI: 1.03–1.06), whereas no association was observed above it. Mediation analysis suggested that MAP partially mediated the association, accounting for 13.92% of the total effect. In the fully adjusted model, a longitudinal assessment of cumulative exposure (n = 5,693) using Cox proportional hazards models revealed a graded increase in risk, with Q4 exhibiting a 57% greater hazard ratio (HR = 1.57, 95% CI: 1.18–2.09, P = 0.0020). CONCLUSIONS: Among middle-aged and older Chinese adults without diabetes, higher METS-IR was associated with an elevated risk of stroke, characterized by a nonlinear dose–response relationship. Mean arterial pressure may partially explain this association.