β-cell stimulation by saxagliptin in patients with type 2 diabetes

Diabetes is Australia’s fastest growing chronic disease with approximately 890,000 patients currently diagnosed with diabetes.1By 2031 it is predicted that 3.3 million Australians will have type 2 diabetes2thus increasing the demand for prevention strategies and an emphasis on early diagnosis and treatment. 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 randomised, parallel-group, double-blind, PBO-controlled study (CV181-041) assessed SAXA’s effect on β-cell function by intravenous hyperglycaemic clamp (IV HC) in T2DM 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 %Δfrom BL in total insulin secretion (%Δinsulin) during IV-oral HC (180-480min). Secondary endpoint was %Δinsulin during IV HC (120-180min). Patients were drug-naive with T2DM 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 %Δinsulin 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 %Δinsulin 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 (Fig). 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.