Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins

Abstract

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.

Figure 1

A scheme of the complex effect of incretin activity on postprandial lipids. GLP-1 or GLP-1 receptor agonists acting on the central nervous system increases satiety and therefore reduces nutrient intake. Inhibitory GLP-1 activity on gastric emptying both further increases satiety and slows entry of nutrients including lipids into the intestine. Triglyceride (TG) absorption into intestinal cells is further reduced because of incretin-induced inhibition of gastric lipase. In the intestinal cells, incretins also decrease production of apolipoproteins (Apo) B-48 and A-IV thereby inhibiting intestinal biosynthesis of triglycerides and their secretion into blood. Transport of lipids from intestinal cells to blood may be further reduced by inhibitory effect of incretins on intestinal lymph flow. This combination of effects leads to lowering of postprandial lipid levels in blood.

Figure 2

The effect of exenatide or placebo on postprandial concentrations of triglycerides (panel A) and apolipoprotein B-48 (apoB48, panel B) in serum, and remnant lipoprotein triglycerides (RLP-TG, panel C) and cholesterol (RLP-C, panel D) in plasma. The average effect of study medication (Drug) and the interaction between the effects of meal and drug (Drug*Time) were evaluated by repeated measures ANCOVA (adjusted for test sequence and glucose tolerance status). Symbols denote statistically significant (p < 0.05) difference between exenatide and placebo (‡) and versus pre-meal value (*) at each specified time points tested by post-hoc multiple comparison analyses. Number of subjects included in the analyses: triglycerides, n = 35; RLP-TG, n = 34; RLP-C, n = 31; apoB48, n = 28 (Schwartz et al., Atherosclerosis 2010, 212(1):217-222 [103]).

Figure 3

The effects of exenatide and placebo on postprandial endothelial function. Endothelial function was measured before and after a single high-fat breakfast meal. Participants received placebo and exenatide on separate visits in a cross-over design. Post-meal PAT index was significantly higher (demonstrating improved endothelial function) during the exenatide phase compared with the placebo phase (p = 0.0002, adjusted for pre-meal PAT index, treatment sequence and glucose tolerance status) (Koska et al., Diabetes Care 2010, 33(5):1028-1030 [104]).