N-3 polyunsaturated fatty acids improve lipoprotein particle size and concentration in Japanese patients with type 2 diabetes and hypertriglyceridemia: a pilot study

Abstract

Background: Patients with type 2 diabetes are at high risk for cardiovascular disease. Although hydroxymethylglutaryl-CoA reductase inhibitors (statins) can reduce cardiovascular events, residual risk remains even after target low-density lipoprotein cholesterol (LDL-C) levels have been achieved. Lipoprotein particle size and fraction changes are thought to contribute to such risks. The purpose of this study was to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid and docosahexaenoic acid, on lipoprotein particle size, concentration, and glycemic control in Japanese patients with type 2 diabetes and hypertriglyceridemia.

Methods: This was a multicenter, prospective, open-label, single arm study. We enrolled 14 patients with type 2 diabetes and hypertriglyceridemia treated with statins and dipeptidyl peptidase-4 inhibitors with glycated hemoglobin (HbA1c) < 8.0%, LDL-C < 120 mg/dL, and fasting triglyceride ≥150 mg/dL. After a 12-week observation period, they were treated with 4 g/day n-3 PUFAs for 12 weeks. Lipoprotein particle sizes, concentrations, lipoprotein insulin resistance (LPIR) scores, lipid profiles, HbA1c, and fasting plasma glucose (FPG) were measured before and after treatment. Lipoprotein profiles were measured by nuclear magnetic resonance spectroscopy. Data were analyzed using Wilcoxon signed-rank tests.

Results: Concentrations of total cholesterol (P < 0.001), LDL-C (P = 0.003), and triglyceride (P < 0.001) decreased following n-3 PUFA administration. N-3 PUFAs decreased the size of very low-density lipoprotein (VLDL; P < 0.001) particles, but did not affect LDL or high-density lipoprotein (HDL) particles. The concentration of large LDL increased, whereas small LDL decreased, causing the large to small LDL ratio to increase significantly (P = 0.042). Large VLDL and chylomicron concentrations significantly decreased, as did the large to small VLDL ratio (all P < 0.001). FPG levels unchanged, whereas HbA1c levels slightly increased. LPIR scores improved significantly (P = 0.001).

Conclusions: N-3 PUFAs partly improved atherogenic lipoprotein particle size and concentration, and produced less atherogenic lipoprotein subclass ratios in patients that achieved target LDL-C levels and glycemic control. These results suggest that n-3 PUFAs may reduce residual cardiovascular risk factors in statin-treated patients with type 2 diabetes and hypertriglyceridemia.

Trial registration: The study was registered at UMIN-ID: UMIN000013776 .

Keywords: Cardiovascular risk; Dipeptidyl peptidase-4 inhibitor; Hydroxymethylglutaryl-CoA reductase inhibitor; Hypertriglyceridemia; Lipoprotein; Low-density lipoprotein cholesterol size; N-3 polyunsaturated fatty acids; Small dense low-density lipoprotein cholesterol; Type 2 diabetes.

Fig. 1

Lipoprotein particle size correlations using nuclear magnetic resonance (NMR) and high performance liquid chromatography (HPLC)

Fig. 2

Changes in lipoprotein subclass ratios after n-3 PUFA treatment. Panels show the subclass percentages for (a) very low-density lipoprotein (VLDL), (b) low-density lipoprotein (LDL), and (c) high-density lipoprotein (HDL). IDL, intermediate density lipoprotein

Fig. 3

Correlations between the EPA/AA and DHA/AA ratios and (a) small LDL concentration, (b) large VLDL concentration, (c) lipoprotein insulin resistance (LPIR) score. LDL, low-density lipoprotein; VLDL, very low-density lipoprotein