Abstract 411: Effect of Sitagliptin Therapy on Triglyceride-Rich Lipoprotein Kinetics in Patients With Type 2 Diabetes

Abstract

Postprandial hyperlipemia is a key metabolic feature of insulin-resistant states and an important risk factor for cardiovascular disease, due to the accumulation of atherogenic triglyceride (TG)-rich lipoproteins (TRL) from both hepatic and intestinal origin. Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 that has been shown to reduce fasting and postprandial glucose levels in patients with type 2 diabetes (T2D) presumably through incretin hormone-mediated improvements in islet function. The objective of the present study was to investigate the effects of sitagliptin therapy on the kinetics of TRL apolipoprotein (apo) B-48, VLDL apoB-100, apoE and apoC-III in patients with type 2 diabetes. Twenty two subjects with T2D (18 men and 4 postmenopausal women, mean age of 58.2±3.8 y) were recruited in this double-blind crossover study using sitagliptin 100 mg/d or placebo for a 6-week period each, with a 4-week washout period between the two phases. At the end of each phase of treatment, the in vivo kinetics of the different apolipoproteins were assessed using a primed-constant infusion of L-[5,5,5-D3]leucine for 12 h with the participants in a constantly fed state. Sitagliptin therapy vs. placebo significantly reduced concentrations of fasting plasma TG (-15.4%, 0.03), apoB-48 (-16.3%, P=0.03), free fatty acids (-9.5%, P= 0.04), HbA1C (placebo: 7.0%±0.8 vs sitagliptin: 6.6%±0.7, P<0.0001), and plasma glucose (-13.5%, P=0.001) without any significant effect on insulin level. Treatment with sitagliptin significantly reduced the pool size of TRL apoB-48 by -20.8% (P=0.03), due to a reduction in the production rate of these particles (-16.0%, P=0.03). VLDL apoB-100 pool size was also significantly decreased by sitagliptin therapy (-9.3%, P=0.03), mainly due to a reduction in the hepatic secretion of these lipoproteins (-9.2%, P=0.06). Finally, sitagliptin treatment had no effect on VLDL apoC-III and apoE levels, but reduced both fractional catabolic and production rates of VLDL apoE (-10.6%, P=0.05 and -12.7%, P=0.04). In conclusion, treatment with sitagliptin for 6 weeks reduces TG-rich apoB-containing lipoproteins levels through a reduction in the synthesis of these particles in patients with T2D.