CETP-driven cholesterol enrichment of remnant particles worsens atherosclerosis risk in diabetic dyslipidaemia (Eur Heart J 1998)

In patients with insulin resistant or type II diabetes, changes in the composition of lipoprotein occur in the absence of large changes in the absolute levels of cholesterol and triglycerides. A small increase in serum cholesterol reflects both a reduction in high density lipoprotein (HDL) cholesterol and an increase in very low density lipoprotein (VLDL) cholesterol. There are also increases in the triglyceride content of HDL and low density lipoprotein (LDL). Overproduction of VLDL occurs partly due to the resistance to insulin and also because of lower lipoprotein lipase activity. Furthermore, the lipoprotein phenotype in patients with type II diabetes is similar to that in familial combined dyslipidaemia. This is associated with an increased residence time for triglyceride rich particles and exposure to cholesterol ester transfer protein (CETP) which facilitates the transfer of cholesterol to VLDL and chylomicrons in exchange for triglyceride. CETP can also have an atherogenic effect by reducing the cholesterol in HDL. These factors combine to increase the degree of cholesterol enrichment in remnant particles and thereby exacerbate the atherosclerotic process. The high levels of circulating LDL, which result from the overproduction of VLDL and impaired lipoprotein lipase activity, are glycated in the presence of elevated blood glucose. These glycated particles are primarily removed by a non-receptor mediated pathway that results in the formation of foam cells. These changes in lipoprotein profile markedly increase the risk of coronary events and treatment that can reduce triglycerides and VLDL cholesterol and increase HDL cholesterol has clear benefits.