Abstract 247: Dipeptidyl Peptidase-4 Inhibition With Sitagliptin Acutely Inhibits Intestinal Lipoprotein Particle Secretion in Healthy Humans

Abstract

Postprandial dyslipidemia, in part due to overproduction of triglyceride-rich lipoprotein (TRL) particles from the liver and the intestine, contributes to increased CVD risk. The DPP-4 inhibitor sitagliptin, an anti-diabetic agent, has been shown to reduce postprandial lipid excursion following a mixed meal. The underlying mechanism of this effect, however, has not been examined in humans. This study was designed to examine intestinal and hepatic TRL particle production and clearance in response to a single oral dose of sitagliptin. 15 lean, healthy male volunteers were studied in two occasions, 4-6 weeks apart, receiving sitagliptin (100 mg) or placebo in random order. Kinetics of TRL particles of intestinal and hepatic origin were measured using stable isotope tracer infusion techniques and with control of pancreatic hormone levels. Sitagliptin decreased TRL apoB-48 concentration (-32%, P<0.05) by reducing production rate (sitagliptin 47.2+/- 11.0 vs placebo 93.9 +/- 25.2 ug/kg/d, P<0.05). Fractional catabolic rate was not significantly affected. TRL apoB-100 concentration, production rate and fractional catabolic rate were not significantly different between sitagliptin and placebo. Plasma TG, free fatty acids, glucose, pancreatic hormones, and TRL TG were similar between treatments. In conclusion, sitagliptin acutely inhibits intestinal, but not hepatic, lipoprotein particle production, independent of changes in pancreatic hormones and circulating glucose and free fatty acids. This pleotropic effect of sitagliptin explains in part the reduction in postprandial lipemia seen in clinical trials and may provide metabolic benefits beyond glucose lowering.