Abstract Body (Do not enter title and authors here): Introduction: It remains uncertain whether dietary supplementation of marine n-3 polyunsaturated fatty acids (PUFAs) improves atherosclerosis and lipoprotein subclasses in patients with type 2 diabetes (T2D). In addition, whether the anti-atherosclerotic effect of n-3 PUFA supplementation is modified by genetics remains unclear.
Research Questions: We aim to evaluate the effects of marine n-3 PUFA on atherosclerotic plaque risk in Chinese T2D patients; assess changes in NMR-derived lipoprotein subclasses and their mediating effects and explore potential interactions between marine n-3 PUFA supplementation and genetics.
Methods: In this 14-month double-blind, randomized controlled trial (RCT), 415 patients with T2D were randomly assigned to receive high-dose (3.0g/day) or low-dose (1.5g/day) marine n-3 PUFAs or placebo (refined olive oil). The primary outcome was the prevalence of carotid artery plaques assessed by ultrasound. Secondary outcomes included changes in NMR-derived lipoprotein subclasses and their mediation effects on carotid plaque. Genetic interactions with n-3 PUFA supplementation were also analyzed.
Results: There were 383 participants (92.3%) completed the 14-month intervention and 358 patients (86.3%) completed carotid ultrasound exams. Fish oil supplementation was significantly associated with reduced prevalence of carotid plaques (P=0.023). Compared to the placebo group, the adjusted odds ratio (95% CI) was 0.41 (0.19-0.88) for the high-dose group and 0.86 (0.42-1.79) for the low-dose group. High-dose fish oil intervention significantly reduced remnant cholesterol, LDL-1-triglycerides (TG), HDL-4-TG, and HDL-3-TG, which largely mediated the anti-atherosclerotic effects. Additionally, the anti-atherosclerotic effect on carotid plaques was most prominent among patients with low genetic risk of remnant cholesterol and LDL. Variants of ELOVL2 (rs2295602, rs4711171 and rs3734398) significantly modified the protective effects of high-dose marine n-3 PUFAs on carotid plaques.
Conclusions: Long-term supplementation with high-dose marine n-3 PUFAs was associated with a reduced risk of carotid artery plaques among T2D patients, potentially mediated by improvements in lipoprotein subclasses, particularly remnant cholesterol and TG-rich particles. Our findings support the use of high-dose dietary n-3 PUFA supplements for atherosclerosis protection and also highlight the potential for personalized n-3 PUFA treatment based on genetic risk.