Low high-density lipoprotein cholesterol, but not high low-density lipoprotein cholesterol, associates with systemic metabolic alterations

Abstract

Aim: Dyslipidemia encompasses various forms of lipid abnormalities and represents a central component of metabolic syndrome. The relationship between dyslipidemia subtypes and broader metabolic profiles is poorly characterized in modern populations. This study provides a comprehensive metabolic characterization of patients presenting with distinct dyslipidemic patterns – low high-density lipoprotein cholesterol (HDL-c) and elevated low-density lipoprotein cholesterol (LDL-c) – at a dedicated tertiary-center outpatient clinic.
Methods: Patients evaluated at the Metabolic Health Clinic of San Raffaele Hospital, Milan, between January 2023 and October 2024, were included. Medical history, anthropometrics (i.e. body mass index, BMI, and waist circumference), serum lipids and liver enzymes were recorded. Patients with low HDL-c or high LDL-c, as defined according to current guidelines, were compared to patients with normal values. Network analysis identified patient distinct metabolic clusters.
Results: A total of 496 individuals were included. Patients with low HDL-c levels (n=193, 38.9%) exhibited higher BMI (28.6 vs 25.6 kg/m², p<0.001), waist circumference (100.0 vs 94.0 cm, p<0.001), ALT levels (28.0 vs. 23.0 U/L, p<0.001), and triglycerides (146.0 vs. 99.0 mg/dL, p<0.001), and a greater prevalence of fatty liver disease (33% vs. 21%, p 0.006) and arterial hypertension (51% vs. 39%, p 0.012) than those with normal HDL-c levels. HDL-c showed significant inverse correlations with both BMI (R coefficient -0.272, p<0.0001) and waist circumference (R coefficient -0.325, p<0.0001). Network analysis highlighted strong associations among HDL-c, triglycerides, ALT levels, BMI, and waist circumference. Conversely, high LDL-c levels, found in 382 (77%) patients, showed no association with metabolic parameters.
Conclusions: Low HDL-c was associated with obesity, central adiposity, hypertriglyceridemia, and fatty liver disease. In striking contrast, LDL-c appears to be independent of these metabolic alterations. These findings underscore the interconnectedness of HDL-c with the metabolic landscape, while emphasizing the importance of assessing LDL-c levels regardless of patient anthropometrics and metabolic phenotype.