β-Cell Stimulation by Saxagliptin in Patients with T2D
Abstract Number: 447-P
Authors: ROBERT HENRY, STEVEN SMITH, SHERWYN SCHWARTZ, JAMES LIST, RAINA YUYAN DUAN, ROLAND CHEN
Institutions: San Diego, CA, Baton Rouge, LA, San Antonio, TX, Princeton, NJ
Results: Saxagliptin (SAXA) is a potent, selective DPP-4 inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme. DPP-4 inactivates incretins that stimulate glucose-dependent insulin secretion and inhibit glucagon secretion. A proposed MOA of SAXA involves protecting incretins from DPP-4 degradation, thus improving β-cell response. This randomized, parallel-group, double-blind, PBO-controlled study (CV181-041) assessed SAXA's effect on β-cell function by intravenous hyperglycemic clamp (IV HC) in T2D patients. Patients were assessed at baseline (BL) and wk 12 in the fasting state (0-180min, IV HC) and after stimulating incretin secretion by orally ingesting 75g glucose (180-480min, IV-oral HC). HC infusions were adjusted to maintain plasma glucose at 280mg/dL. Insulin secretion was calculated by C-peptide deconvolution. Primary endpoint was %Δ from BL in total insulin secretion (%Δ insulin) during IV-oral HC (180-480min). Secondary endpoint was %Δ insulin during IV HC (120-180min). Patients were drug-naïve with T2D aged 43-69yrs with BL A1C range 5.9%-8.1%. Twenty patients received SAXA 5mg od; 16 received PBO. After 12 wks, SAXA significantly increased %Δ insulin from BL during IV-oral HC (adj% difference of 18.5% vs PBO, p=.035). In the fasting state during IV HC SAXA significantly increased %Δ insulin from BL (adj% difference of 27.9% vs PBO, p=.020). At wk 12 insulin secretion increased from BL with SAXA but not with PBO. [figure1] Glucagon AUC during IV-oral HC also improved from BL with SAXA, (adj% difference of –21.8% vs PBO, p=.031). SAXA was generally safe and well-tolerated. In conclusion, SAXA improved pancreatic β-cell function in the postprandial and fasting states and decreased postprandial glucagon concentration.