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The effect of vildagliptin therapy on atherogenic postprandial remnant particles and LDL particle size in subjects with Type 2 diabetes

Dipeptidylpeptidase 4 (DPP-4) inhibitors are recommended as second-line anti-hyperglycaemic therapy after metformin. Cardiovascular endpoint studies with DPP-4 inhibitors are ongoing, but so far a variety of surrogate markers are used to assess cardiovascular benefits of these agents [1]. Our previous study was the first to demonstrate that a DPP-4 inhibitor vildagliptin reduces postprandial plasma triglycerides and chylomicron triglycerides, chylomicron apolipoprotein (apo) B-48 and chylomicron cholesterol, suggesting improvement in the metabolism of postprandial intestinal triglyceride-rich lipoprotein particles [2]. Recently, our findings have been confirmed with sitagliptin [3] and alogliptin [4] therapies suggesting a class effect. It is, however, not known if DPP-4 inhibitors alleviate the atherogenic properties of small postprandial triglyceriderich lipoprotein remnants and if the changes in triglyceriderich lipoprotein metabolism are reflected to LDL particle size. We studied 23 drug-naive subjects with diabetes who underwent an oral fat load before and during vildagliptin 50 mg or placebo twice daily. The fat-rich test meal contained 1000 kcal, 72 g fat (saturated fat 64.5%, monounsaturated fat 30.4%, polyunsaturated fat 5.1%) with a polyunsaturated/saturated fatty acid (P/S) ratio of 0.08, 490 mg cholesterol, 50 g carbohydrate and 35 g protein. We measured remnant-like particle cholesterol, remnant-like particle triglycerides, apoA5 and apoCIII preprandially and 3, 4, 6 and 8 h postprandially and LDL particle size preprandially and 4 h postprandially at week 0 and week 4 during vildagliptin or placebo. ApoA5 and apoCIII were quantified in total plasma by commercial ELISA kits (Millipore Corporation, Bedford, MA, USA and Assaypro, St Charles, MO, USA, respectively). Plasma remnant-like particle cholesterol and remnant-like particle triglycerides were analysed with commercial immunoseparation assay (Otsuka Pharmaceutical, Osaka, Japan). Gradient gel analysis was used to assess LDL particle size [5]. An analysis of covariance (ANCOVA) model including terms for treatment, baseline value and treatment 9 baseline interaction was used for statistical comparisons. Treatment with vildagliptin produced significant reduction in postprandial triglyceride area under the curve by –32% (P = 0.001) and remnant-like particle triglyceride area under the curve by –38% (P = 0.01) from week 0 to week 4, while no change occurred with placebo (+9% and