Early insulin resistance in low-risk subjects with normal glycemia is associated with subclinical atherosclerosis

Background Higher glycated hemoglobin (HbA1c) levels are directly associated with subclinical atherosclerosis burden. However, the association between earlier insulin resistance markers and the development of subclinical atherosclerosis is poorly understood. Purpose To assess the association between the Homeostatic Model Assessment of Insulin Resistance Index (HOMA-IR) and subclinical atherosclerosis, on top of cardiovascular risk factors in individuals with normal HbA1c. Methods A cohort of 3,741 middle-aged individuals from the PESA study, with basal HbA1c <6.0% and without known CV disease, underwent extensive imaging (multi-territorial vascular ultrasound and coronary artery calcium score, CACS) to assess for the presence, burden, and extent of subclinical atherosclerosis. Results Individuals with higher HOMA-IR values had a higher prevalence of both traditional and non-traditional CV risk factors. Higher HOMA-IR values showed a positive association with the multi-territorial extent of subclinical atherosclerosis and CACS (p<0.001), Figure 1, and an increased global plaque volume by 3DVUS (p<0.001), Figure 2. The association was observed in both individuals with HbA1c levels below and above the median value of 5.4% (p < 0.001). This trend held for three individual territories (carotid, femoral, and coronary artery). Overall, after adjusting for key CV risk factors and HbA1c levels, HOMA-IR values ≥3 were associated with both the multi-territorial extent of subclinical atherosclerosis and CACS>0: odds ratio of 1.41 (95CI: 1.01 to 1.95, p=0.041), and 1.74 (95CI: 1.20 to 2.54, p=0.004) respectively, as compared to HOMA-IR <2 (reference). In a stratified analysis, this association remained significant in low-to-moderate SCORE2 risk individuals (75.6% of the cohort) but not in high-risk adults. Conclusions The use of HOMA-IR identified low-risk individuals with a higher burden of subclinical atherosclerosis on top of traditional CV risk factors and HbA1c. HOMA-IR is a simple measure in clinical practice that could facilitate earlier implementation of CV primary prevention strategies. HOMA-IR and subclinical atherosclerosis. HOMA-IR and 3D vascular ultrasound.