Associations of lipoprotein subclasses with risk of all‐cause and cardiovascular disease mortality in individuals with type 2 diabetes: A prospective cohort study

Abstract Aim Although lipoproteins are well‐established risk factors for cardiovascular disease (CVD) mortality, conventional measurements failed to identify lipoprotein particle sizes. This study aimed to investigate associations of lipoprotein subclasses categorized by particle sizes with risk of all‐cause and CVD mortality in individuals with type 2 diabetes. Methods This study included 6575 individuals with type 2 diabetes from the UK Biobank. Concentrations of very low‐, low‐, intermediate‐ and high‐density lipoprotein [very‐low‐density lipoprotein (VLDL), low‐density lipoprotein (LDL), intermediate‐density lipoprotein and high‐density lipoprotein (HDL)] particles in 14 subclasses and lipid constituents within each subclass were measured by quantitative nuclear magnetic resonance. Multivariable‐adjusted Cox proportional‐hazard regression models were used to estimate the hazard ratio (HR) for per standard deviation increment of log‐transformed lipoprotein subclasses with risk of mortality. All p ‐values were adjusted by the false discovery rate method. Results During a median follow‐up of 11.4 years, 943 deaths were documented, including 310 CVD deaths. Small HDL particles were inversely associated with CVD mortality, with HR (95% CI) of 0.78 (0.69, 0.87), whereas very large and large HDL particles were positively associated with CVD mortality with HR (95% CI) of 1.28 (1.12, 1.45) and 1.19 (1.05, 1.35), respectively. A similar pattern was observed for all‐cause mortality [small HDL particle (HR, 95% CI): 0.79, 0.74‐0.85; large HDL particle: 1.15, 1.07‐1.24; very large HDL particle: 1.26, 1.17‐1.36]. For VLDL and LDL, very small VLDL particle was positively, while medium LDL particle was inversely associated with all‐cause mortality, but not associated with CVD mortality. The pattern of association with all‐cause and CVD mortality for cholesterol and triglyceride within lipoprotein particles was similar to those for lipoprotein particles themselves. Conclusions The associations between lipoprotein particles, particularly HDL particles, with all‐cause and CVD mortality among patients with type 2 diabetes were significantly varied by particle sizes, highlighting the importance of particle size as a lipoprotein metric in mortality risk discrimination.