Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice

OBJECTIVE - The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden (E3L) mice with a humanized lipoprotein profile. METHODS AND RESULTS - E3L mice were crossbred with human CETP transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (+43%; P<0.05). To evaluate the effects of CETP on the development of atherosclerosis, mice were fed a Western-type diet containing 0.25% cholesterol, leading to 4.3-fold elevated TC levels in both E3L and CETP.E3L mice (P<0.01). On both diets, CETP expression shifted the distribution of cholesterol from high-density lipoprotein (HDL) toward very-low-density lipoprotein (VLDL)/low-density lipoprotein (LDL). Moreover, plasma of CETP.E3L mice had reduced capacity (-3

A placebo-controlled proof-of-concept study of alirocumab on postprandial lipids and vascular elasticity in insulin-treated patients with type 2 diabetes mellitus

Aim: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear. Material and Methods: Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated. Results: Alirocumab treatment reduced fasting plasma TG levels (between group median change −24.7%; P = 0.018) and fasting apoB48 serum levels (−35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (−26.4%; P = 0.006) and apoB48 AUC (−55.7%; P = 0.046), as well as plasma TG incremental AUC (−21.4%; P = 0.04) and apoB48 incremental AUC (−26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed. Conclusions: In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants

Plasma phospholipid transfer protein activity is decreased in type 2 diabetes during treatment with atorvastatin: A role for apolipoprotein E?

Plasma phospholipid transfer protein (PLTP) plays an important role in lipoprotein metabolism. PLTP activity is elevated in patients with diabetes, a condition with strongly elevated risk for coronary heart disease. The aim of this study was to test the hypothesis that statins reduce PLTP activity and to examine the potential role of apolipoprotein E (apoE). PLTP activity and apoE were measured in patients with type 2 diabetes from the DALI (Diabetes Atorvastatin Lipid Intervention) Study, a 30-week randomized double-blind placebo-controlled trial with atorvastatin (10 and 80 mg daily). At baseline, PLTP activity was positively correlated with waist circumference, HbA 1c, glucose, and apoE (all P < 0.05). Atorvastatin treatment resulted in decreased PLTP activity (10 mg atorvastatin: -8.3%, P < 0.05; 80 mg atorvastatin: -12.1%, P < 0.002). Plasma apoE decreased by 28 and 36%, respectively (P < 0.001). The decrease in apoE was strongly related to the decrease in PLTP activity (r = 0.565, P < 0.001). The change in apoE remained the sole determinant of the change in PLTP activity in