Association of the Atherogenic Index of Plasma and High-Sensitivity C-Reactive Protein with Incident Stroke Among Individuals Without Diabetes: A National Cohort Study

Abstract Background Both the atherogenic index of plasma (AIP), a surrogate marker of insulin resistance, and high-sensitivity C-reactive protein (hsCRP) are predictors of stroke risk and clinical outcomes. However, most existing evidence is derived from studies involving diabetic patients, which may lead to the overestimation of the impact of the AIP and hsCRP on stroke due to the confounding effects of diabetes. This study aimed to assess the combined and interactive effects of the AIP and hsCRP on stroke events in individuals without diabetes. Methods A total of 8,909 participants from the China Health and Retirement Longitudinal Study (CHARLS) 2011 who were free of stroke and diabetes at baseline were included. The AIP was calculated as lg[total cholesterol (mmol/L)/high-density lipoprotein cholesterol (mmol/L)]. A subset of 5,954 participants was studied to investigate the relationship between cumulative AIP (CumAIP) and hsCRP (CumAIP) exposure and stroke incidence.The CumAIP and CumCRP were also calculated using the same algorithm.The primary outcome was physician-diagnosed stroke occurring before 2020. We employed adjusted Cox proportional hazards regression and mediation analysis to investigate the associations between the AIP, hsCRP, and stroke events. Results Over nine years of follow-up, 696 new stroke cases were recorded.Compared with individuals with low AIP (<0.302 [median level]) and hsCRP <1 mg/L, those with elevated levels of both the AIP and hsCRP had the highest overall risk of stroke (adjusted HR [aHR]: 1.69; 95% CI: 1.36–2.10). In a 5-year subset analysis, 497 participants suffered a stroke. Compared with individuals with low risk (CumAIP<1.29 [median level] and CumhsCRP < 4.02 mg/L [median level]), those with high risk had the highest overall risk of stroke (adjusted HR [aHR]: 1.41; 95% CI: 1.10-1.82). Moreover, hsCRP significantly mediated 5.61% of the association between the AIP and stroke, whereas the AIP mediated 1.86% of the association between hsCRP and stroke. Conclusions The AIP and hsCRP exhibit coexposure effects and mutual mediation in with regard to the risk of stroke. The combined assessment of the AIP and hsCRP should be promoted for residual risk stratification and primary prevention of stroke in individuals without diabetes, particularly among middle-aged populations.