Apolipoprotein b discordance at very low low-density lipoprotein cholesterol thresholds: a patient-level analysis
J Bernhard, F Wollmann, P Haider, L Galli, C Hengstenberg, W S Speidl, K A KrychtiukAbstract
Introduction
Low-density lipoprotein cholesterol (LDL-C) target attainment can mask residual atherogenic particle burden when Apolipoprotein B (ApoB) remains elevated, particularly at very low LDL-C levels where cholesterol-depleted, ApoB-rich particles (remnant/VLDL-related) may predominate. The prevalence of LDL-C-ApoB discordance at contemporary very high and extreme-risk LDL-C thresholds (<55 and <40 mg/dL) and its association with PCSK9 inhibitor–based intensification in routine care is not well defined. We therefore aimed to quantify LDL-C-ApoB discordance across lipid-lowering therapy intensities at these LDL-C thresholds and assessed associations with PCSK9i-based intensification.
Methods
We analyzed a prospective tertiary lipid-clinic registry using a cross-sectional patient-level approach. Triglycerides, ApoB, non–HDL-C, and Lp(a) were measured on fasting blood samples, and LDL-C was calculated using the Friedewald equation. Discordance was defined as LDL-C <40 mg/dL with ApoB ≥65 mg/dL or LDL-C <55 mg/dL with ApoB ≥80 mg/dL. Lipid-lowering therapy was categorized as statin monotherapy, statin plus ezetimibe, or statin plus ezetimibe plus a PCSK9 inhibitor; non-PCSK9i therapy (statin ± ezetimibe) was pooled and compared with triple therapy including PCSK9i. Group differences in discordance prevalence were assessed, and standardized mean differences (pooled SD) for ApoB, triglycerides, non–HDL-C, and Lp(a) were calculated within each LDL-C target stratum (<40 and <55 mg/dL).
Results
At LDL-C <40 mg/dL, LDL-C-ApoB discordance was common with non-PCSK9i therapy (statin ± ezetimibe: 17.6%, 13/74) but was rare with triple therapy including PCSK9i (1.7%, 2/119; Δ −15.9%; p<0.001). At LDL-C <55 mg/dL, discordance occurred in 6.9% (14/204) under statin ± ezetimibe and in 0.0% (0/141) under triple therapy (Δ −6.9%; p<0.001). Discordant patients showed a consistent atherogenic phenotype with higher triglycerides and non–HDL-C across both LDL-C thresholds, whereas Lp(a) was only modestly higher.
Conclusion
In a real-world tertiary lipid clinic cohort, achieving LDL-C <55 and <40 mg/dL did not reliably indicate ApoB control under statin ± ezetimibe, with clinically relevant discordance persisting in a meaningful proportion of patients. Intensification with PCSK9i-based triple therapy was associated with near-elimination of discordance and a lower residual atherogenic signature. Phenotype profiling further indicated that discordance at target LDL-C predominantly clustered with higher triglycerides and non-HDL-C. These findings support incorporating ApoB assessment, particularly when triglycerides or non-HDL-C remain elevated and suggest that PCSK9i-based intensification can effectively resolve LDL-C-ApoB discordance among LDL-C target achievers.Fig. 1:Prevalence of DiscordanceFig. 2:Discordance Phenotype