Specific Increase in Small Dense Low-Density Lipoprotein- Cholesterol Levels beyond Triglycerides in Patients with Diabetes: Implications for Cardiovascular Risk of MAFLD

Aims: Small dense (sd) low-density lipoprotein (LDL)-cholesterol (C) is the most powerful predictor of cardiovascular (CV) disease among lipid biomarkers and is generated by hypertriglyceridemia and insulin resistance. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed liver disease with a high CV risk. We investigated the specific association of sdLDL-C with MAFLD beyond triglycerides (TG) and obesity. Methods: Participants were 839 non-alcoholic drinkers with type 2 diabetes enrolled in a regional diabetes cohort. Fatty liver (FL) and visceral fat area (VFA) was detected by computed tomography scan. sdLDL-C and LDL-TG were measured by our established homogeneous assay. TG rich lipoprotein (TRL) was calculated by subtracting LDL-C plus HDL-C from total-C. Grade of sdLDL-C (<_ 24, 25-34, 35-44, and >_ 45 mg/dL) was classified according to the Hisayama study. Results: Compared to non-FL counterparts, FL subjects were younger, predominantly male and smokers; and had higher body mass index (BMI), VFA, hemoglobin A1c, C-peptide, TG, and sdLDL-C, while had similar levels of LDL-C, LDL-TG, and TRL-C. Multivariate logistic analysis revealed that sdLDL-C was the most powerful lipid parameter for identifying FL, independent of TG, HDL-C, BMI, and VFA. The independent association between TG and FL was lost when sdLDL-C was added to the analysis. These results remained the same when lipid-lowering drug users were excluded. After adjustment for confounders, the odds ratio for FL was 2.4-2.7 at sdLDL >_ 35 mg/dL based on sdLDL <_ 24 mg/dL. Conclusions: sdLDL-C levels are specifically elevated in patients with diabetes and MAFLD, independent of TG and VFA, suggesting liver-centered metabolic abnormalities.