LDL-C target achievement does not equal risk resolution after ACS: residual atherogenic and inflammatory burden despite maximal oral triple lipid therapy

Background Early aggressive LDL-C lowering after acute coronary syndrome (ACS) is recommended to reduce recurrent events. Upfront triple oral lipid-lowering therapy is increasingly used to rapidly achieve LDL-C <55 mg/dL. Whether achieving an LDL-C target translates into early normalization of biological risk remains uncertain. Purpose To characterize ApoB–corrected LDL discordance and multidomain residual atherogenic and inflammatory risk one month after ACS treated with PCI and universal high-intensity rosuvastatin–ezetimibe–bempedoic acid therapy. Methods In a prospective single-centre cohort of 426 consecutive ACS patients undergoing PCI, all received triple oral lipid-lowering therapy from index hospitalization. At 1 month, corrected LDL-C, ApoB, triglycerides, remnant cholesterol, Lp(a), and hsCRP were assessed. ApoB–LDL discordance was defined using a 2×2 framework (corrected LDL <55 vs ≥55 mg/dL; ApoB ≤65 vs >65 mg/dL). Residual risk domains included LDL non-response, non-HDL-C ≥85 mg/dL, ApoB ≥65 mg/dL, triglycerides ≥150 mg/dL, remnant cholesterol ≥30 mg/dL, Lp(a) >50 mg/dL, and hsCRP ≥2 mg/L. A residual risk burden index was constructed (0, 1, 2, ≥3 domains). Results Corrected LDL-C <55 mg/dL was achieved in 350 patients (82%). However, among LDL achievers, 86 patients (23.8%) demonstrated ApoB >65 mg/dL despite target LDL-C. This discordant group exhibited higher triglycerides (149 vs 121 mg/dL), higher remnant cholesterol (21 vs 16 mg/dL), and a higher median hsCRP (0.72 vs 0.48 mg/L) than concordant-low patients. Strikingly, Lp(a) >50 mg/dL was present in 94.2% of discordant patients versus 50.8% of concordant-low individuals. Across the entire cohort, complete residual risk normalization was uncommon. Only 19% of patients had zero risk domains at 1 month, whereas 52% exhibited ≥2 domains and 33% had ≥3 domains, indicating substantial clustering of atherogenic and inflammatory risk despite maximal oral therapy. Conclusions In 426 ACS patients treated with upfront triple oral lipid therapy, achieving LDL-C targets did not equate to biological risk resolution. Nearly one-quarter of LDL achievers demonstrated ApoB discordance with marked enrichment of elevated Lp(a), remnant lipoproteins, and inflammatory activity. Residual risk was multidimensional and frequently clustered early after ACS. These findings support moving beyond LDL-centric assessment toward particle-based phenotyping and provide a mechanistic rationale for early Lp(a)-targeted and anti-inflammatory therapeutic strategies.Figure 1Figure 2