While inflammation is recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), with high-sensitivity C-reactive protein (hs-CRP) serving as a prognostic indicator, the degree to which elevated hs-CRP combined with different atherogenic lipid measures increases long-term ASCVD risk remains unclear in primary prevention cohorts of Mediterranean origin, who exhibit a comparatively favorable inflammatory profile due to lifestyle and dietary habits. Thus, this study aimed to examine the association between combined hs-CRP and various atherogenic lipid measures and long-term 3-point MACE risk in apparently healthy adults from the general population.

A cohort of 3,042 ASCVD-free adults residing in greater Athens, Greece, was recruited in 2002. A 20-year follow-up was conducted in 2022, comprising n = 2,169 participants, of which n = 1,988 had complete data for cardiovascular disease incidence. Participants were grouped based on discordance between biomarkers, defined by established guideline-recommended thresholds.

Hs-CRP was an independent predictor of incident 3-point MACE after adjusting for low-density lipoprotein cholesterol (LDL-C) or nonhigh-density lipoprotein cholesterol (non-HDL-C), but not apolipoprotein B (apoB) or lipoprotein(a) (Lp(a)). High levels of apoB (≥100 mg/dL) were associated with an increased 3-point MACE risk regardless of hs-CRP levels. However, elevated LDL-C (≥100 mg/dL) and non-HDL-C (≥131 mg/dL) showed significant associations only in the presence of hs-CRP ≥ 2 mg/L.

Hs-CRP provides independent, incremental predictive value, even beyond advanced lipid metrics, and is a potent residual risk factor in contexts traditionally considered low-risk.