Remnant lipoprotein cholesterol and cardiovascular and cerebrovascular events in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by an atherogenic dyslipidaemia and an increased cardiovascular risk. Remnant lipoprotein cholesterol (RLP-C) is emerging as a novel cardiovascular risk factor, but its predictive value in patients with NAFLD is unknown. We investigated factors affecting RLP-C levels, and the association with major adverse cardiovascular and cerebrovascular events (MACCE) in NAFLD. A prospective observational cohort study was carried out including 798 unselected patients with cardio-metabolic diseases screened by ultrasound for the presence of NAFLD. Fasting RLP-C (mg/dL) was calculated as total cholesterol-(HDL (high-density lipoprotein) + LDL (low-density-lipoprotein)). Primary endpoint of the follow-up study was a combined endpoint of MACCE. Patients with NAFLD (79.2%) had higher median fasting RLP-C in comparison to those without (27.0 vs. 20.0 mg/dL, respectively p < 0.001). Metabolic syndrome, NAFLD, age above median, and female sex were independently associated to fasting RLP-C above the median. In patients with NAFLD, values of RLP-C were associated with liver disease severity, as shown by the increasing value of RLP-C across tertiles of aspartate aminotransferase (AST) (p = 0.002) and gamma-glutamyl transpeptidase (GGT) (p < 0.001). Furthermore, levels of RLP-C and Hamaguchi score, were significantly correlated (r = 0.193, p < 0.001). During a median follow-up of 32 months (interquartile range: 14.2-51.7, 1700 person-years), 41 MACCE (2.41%/year) were registered in 596 NAFLD patients. The rate of events was higher in NAFLD patients with RLP-C above the median compared to those below (log-rank test p = 0.040). Age (hazard ratio (HR) 1.039, 95% confidence interval (CI), 1.005-1.074, p = 0.024), previous cardiovascular events (HR 2.210, 95% CI, 1.052-4.643, p = 0.036), female sex (HR 0.454, 95% CI, 0.208-0.989, p = 0.047) and RLP-C above the median (HR 2.202, 95% CI, 1.132-4.285, p = 0.020) were associated with MACCE. In conclusion, we found that NAFLD was independently associated with higher circulating RLP-C, and that high RLP-C levels were predictive of MACCE in patients with NAFLD.