Abstract
The current cholesterol guidelines recommend maintaining low levels of low-density lipoprotein cholesterol (LDL-C) in patients with coronary artery disease (CAD). However, recent studies have suggested that both very low and very high LDL-C levels may be associated with increased mortality in the general population. We utilized data from TriNetX, a global health research network, to investigate the association between LDL-C levels and all-cause mortality in patients with CAD. CAD patients were identified using the International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code and stratified into six LDL-C categories: <50 mg/dL (cohort 1), 50-69.9 mg/dL (cohort 2), 70-99.9 mg/dL (cohort 3), 100-129.9 mg/dL (cohort 4), 130-159.9 mg/dL (cohort 5), and ≥ 160 mg/dL (cohort 6). Mortality data were obtained by linking patient records to death registries spanning the 15 years prior to the analysis. Weighted Cox proportional hazards regression models were employed to estimate hazard ratios (HRs) for mortality outcomes along with their 95% confidence intervals (CIs). A total of 2,145,732 individuals with CAD (mean age 72 years, SD 13; mean LDL-C 87.7 mg/dL, SD 37.7) were included in the analysis. Over a 15-year follow-up period, 191,779 deaths (8.9%) were recorded. After propensity score matching, patients with LDL-C < 50 mg/dL (37.05% vs. 33.11%, HR 1.144, 95% CI 1.125-1.164, p < 0.0001), LDL-C 130-159.9 mg/dL (26.47% vs. 25.71%, HR 1.032, 95% CI 1.007-1.059, p = 0.0136), and LDL-C ≥ 160 mg/dL (26.29% vs. 24.38%, HR 1.121, 95% CI 1.082-1.163, p < 0.0001) demonstrated a higher risk of all-cause mortality compared to those with LDL-C 100-129.9 mg/dL. Conversely, patients with LDL-C 50-69.9 mg/dL (27.88% vs. 29.68%, HR 0.898, 95% CI 0.883-0.913, p = 0.0002) and LDL-C 70-99.9 mg/dL (26.21% vs. 27.84%, HR 0.908, 95% CI 0.893-0.923, p = 0.0057) exhibited a lower risk of all-cause mortality compared to the reference group (LDL-C 100-129.9 mg/dL). In conclusion, our findings suggest a U-shaped relationship between LDL-C levels and all-cause mortality in patients with CAD, where both very low (< 50 mg/dL) and high (≥ 130 mg/dL) LDL-C levels are associated with increased mortality risk. These results highlight the need for individualized LDL-C targets in managing patients with CAD.