Effect of sitagliptin therapy on triglyceride-rich lipoprotein kinetics in patients with type 2 diabetes.

AIM: To investigate the effects of sitagliptin therapy on the kinetics of triglyceride-rich lipoprotein (TRL) apolipoprotein (apo)B-48, VLDL apoB-100, apoE and apoC-III in patients with type 2 diabetes. METHODS: Twenty-two subjects with type 2 diabetes were recruited in this double-blind crossover study, during which the subjects received sitagliptin (100 mg/day) or placebo for a 6-week period each. 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. RESULTS: Sitagliptin therapy significantly reduced fasting plasma triglyceride (-15.4%, p = 0.03), apoB-48 (-16.3%, p = 0.03) and free fatty acid concentrations (-9.5%, p = 0.04), as well as plasma HbA1c (placebo: 7.0% ± 0.8 vs. sitagliptin: 6.6% ± 0.7, p < 0.0001) and plasma glucose levels (-13.5%, p = 0.001), without any significant effect on insulin levels. Kinetic results showed that treatment with sitagliptin significantly reduced the pool size of TRL apoB-48 by -20.8% (p = 0.03), paralleled by a reduction in the production rate of these particles (-16.0%, p = 0.03). The VLDL apoB-100 pool size was also significantly decreased by sitagliptin therapy (-9.3%, p = 0.03), mainly because of a reduction in the hepatic secretion of these lipoproteins, although this difference did not reach statistical significance (-9.2%, p = 0.06). CONCLUSIONS: Treatment with sitagliptin for 6 weeks reduced triglyceride-rich apoB-containing lipoprotein levels by reducing the synthesis of these particles.

Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes.

AIM: Recent studies indicate that type 2 diabetes is associated with an increased secretion of both hepatic and intestinal lipoproteins, leading to the accumulation of atherogenic triglyceride (TG)-rich lipoproteins. 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 presumably through incretin hormone-mediated improvements in islet function. The objective of the present study is to examine the effects of treatment with sitagliptin on postprandial lipid and incretin hormone levels as well as glucose homeostasis in patients with type 2 diabetes. METHODS: Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m(2) ) were recruited in this double-blind cross-over study using sitagliptin 100 mg/day 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, patients underwent an oral lipid tolerance test providing 35 g of fat per m(2) of body surface area and blood samples were taken over an 8-h period. RESULTS: Sitagliptin therapy significantly decreased the postprandial area under the curves (AUCs) for plasma apolipoprotein (apo)B (-5.1%, p = 0.002), apoB-48 (-7.8%, p = 0.03), TG (-9.4%, p = 0.006), very low-density lipoprotein (VLDL)-cholesterol (-9.3%, p = 0.001), free fatty acids (FFAs) (-7.6%, p = 0.005) and glucose (-9.7%, p < 0.0001). Furthermore, the postprandial AUCs for plasma intact glucagon-like peptide-1 (+67.8%, p < 0.0001) and glucose-dependent insulinotropic polypeptide (+67.3%, p < 0.0001) were significantly increased following treatment with sitagliptin, whereas the AUC for plasma glucagon was reduced by -9.7% (p = 0.001) with no significant changes in the AUCs for plasma insulin and C-peptide. Sitagliptin therapy also improved homeostasis model assessment (HOMA) index for insulin resistance (-14.6%, p = 0.01) and ß-cell function (+32.3%, p = 0.007). CONCLUSIONS: Treatment with sitagliptin for 6 weeks reduced postprandial plasma levels of TG-rich lipoproteins of both intestinal and hepatic origin, most likely by increasing incretin hormone levels, reducing circulating plasma FFA concentrations and improving insulin sensitivity and ß-cell function.