Clinical Significance of Small Dense Low-density Lipoprotein Cholesterol Measurement in Type 2 Diabetes

Overview

Journal J Diabetes Investig

Date 2025 Jan 8

PMID 39778086

Authors

Tsutomu Hirano

Affiliations

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Abstract

Low-density lipoprotein cholesterol (LDL-C) is known to be a causal substance of atherosclerosis, but its usefulness as a predictive biomarker for atherosclerotic cardiovascular disease (ASCVD) is limited. In patients with type 2 diabetes (T2D), LDL-C concentrations do not markedly increase, while triglycerides (TG) concentrations are usually elevated. Although TG is associated with ASCVD risk, they do not play a direct role in the formation of atheromatous plaques. TG changes the risk of ASCVD in a way that is dependent on LDL-C, and TG is the primary factor in reducing LDL particle size. Small dense (sd)LDL, a potent atherogenic LDL subfraction, best explains the "Atherogenic Duo" of TG and LDL-C. Although hypertriglyceridemia is associated with small-sized LDL, patients with severe hypertriglyceridemia and low LDL-C rarely develop ASCVD. This suggests that quantifying sdLDL is more clinically relevant than measuring LDL size. We developed a full-automated direct sdLDL-C assay, and it was proven that sdLDL-C is a better predictor of ASCVD than LDL-C. The sdLDL-C level is specifically elevated in patients with metabolic syndrome and T2D who have insulin resistance. Due to its clear link to metabolic dysfunction, sdLDL-C could be named "metabolic LDL-C." Insulin resistance/hyperinsulinemia promotes TG production in the liver, causing steatosis and overproduction of VLDL1, a precursor of sdLDL. sdLDL-C is closely associated with steatotic liver disease and chronic kidney disease, which are common complications in T2D. This review focuses on T2D and discusses the clinical significance of sdLDL-C including its composition, pathophysiology, measurements, association with ASCVD, and treatments.

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