GLP-1 Inhibitors May Have Duel Anti-Atherogenic Action

Results of a small study indicate that glucagon-like peptide (GLP)-1 inhibition may have an anti-atherogenic action that involves both glucose and lipid metabolism. A recent study of exenatide showed that an injection of the GLP-1 receptor agonist in patients with type 2 diabetes (T2DM) inhibited postprandial vascular endothelial dysfunction.

“T2DM is known to be associated with impairment of vascular endothelial function, which plays a major role in atherosclerogenesis,” wrote Keiichi Torimoto and colleagues. “The present study indicated that single-dose exenatide can inhibit postprandial endothelial dysfunction in Japanese patients with T2DM. Furthermore, a single dose of exenatide corrected abnormalities in postprandial lipid metabolism, with particular improvement in postprandial hypertriglyceridemia, which could explain the observed improvement in postprandial vascular endothelial function.”

According to the study, clinical observations have shown that GLP-1 receptor agonists improve glucose metabolism, lipid metabolism, blood pressure, and body weight, as well as having positive long-term effects on vascular endothelial function.

In order to explore these possible effects further, Torimoto and colleagues conducted a small study of 15 patients with T2DM who underwent a meal tolerance test first without exenatide and then after a single subcutaneous injection of the drug. The enrolled patients were “mildly obese” with a mean BMI of 27.1 kg/m². Thirteen of the 15 patients were on an oral hypoglycemic drug.

After the baseline test without exenatide, the researchers observed significant decreases in plasma glucose (P<0.001) and no increase in triglycerides. In contrast, after the meal test with exenatide, plasma glucose was significantly lower (855 vs. 442 mg/dL per hour, P=0.001) and there was a significant improvement in triglycerides (617 vs. 476 mg/dL; P=0.001).

The researchers posited that the mechanism for this improvement could be related to inhibition of oxidative stress and reduced expression of endothelial cell adhesion factors.

“The natural logarithmically-scaled [reactive hyperemia index] RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test,” the researchers wrote. “The change in L_RHI correlated with changes in CV of triglycerides and HDL-cholesterol. Multivariate analysis identified changes in triglyceride CV as the only determinant of changes in L_RHI, contributing to 41% of the observed change.”

Torimoto and colleagues acknowledged several limitations to the study, including the small sample size and the fact that it did not include patients with T2DM and severe obesity, in whom it has been reported the GLP-1 formulation did not improve vascular endothelial function.

Reference: Torimoto K, et al. Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus. Cardiovascular Diabetology.2015;14:25.