Association of small, dense LDL-cholesterol concentration and lipoprotein particle characteristics with coronary heart disease: A systematic review and meta-analysis

Objectives The aim of this study was to systematically collate and appraise the available evidence regarding the associations between small, dense low-density lipoprotein (sdLDL) and incident coronary heart disease (CHD), focusing on cholesterol concentration (sdLDL-C) and sdLDL particle characteristics (presence, density, and size). Background Coronary heart disease (CHD) is the leading cause of death worldwide. Small, dense low-density lipoprotein (sdLDL) has been hypothesized to induce atherosclerosis and subsequent coronary heart disease (CHD). However, the etiological relevance of lipoprotein particle size (sdLDL) versus cholesterol content (sdLDL-C) remains unclear. Methods PubMed, MEDLINE, Web of Science, and EMBASE were systematically searched for studies published before February 2020. CHD associations were based on quartile comparisons in eight studies of sdLDL-C and were based on binary categorization in fourteen studies of sdLDL particle size. Reported hazards ratios (HR) and odds ratios (OR) with 95% confidence interval (CI) were standardized and pooled using a random-effects meta-analysis model. Results Data were collated from 21 studies with a total of 30,628 subjects and 5,693 incident CHD events. The average age was 67 years, and 53% were men. Higher sdLDL and sdLDL-C levels were both significantly associated with higher risk of CHD. The pooled estimate for the high vs. low categorization of sdLDL was 1.36 (95% CI: 1.21, 1.52) and 1.07 (95% CI: 1.01, 1.12) for comparing the top quartiles versus the bottom of sdLDL-C. Several studies suggested a dose response relationship. Conclusions The findings show a positive association between sdLDL or sdLDL-C levels and CHD, which is supported by an increasing body of genetic evidence in favor of its causality as an etiological risk factor. Thus, the results support sdLDL and sdLDL-C as a risk marker, but further research is required to establish sdLDL or sdLDL-C as a potential therapeutic marker for incident CHD risk reduction.