control in type 2 diabetes. Ingestion of food stimulates production of incretin peptides by
neuroendocrine cells in the intestine. The incretin peptides GLP-1 and GIP are rapidly
cleaved and inactivated by DPP-4. Inhibition of DPP-4 increases postprandial levels of
GLP-1 by approximately two- to threefold. This postprandial increase in GLP-1
mediates an increase in Insulin secretion by the pancreatic beta cell and also mediates a
decrease in glucagon secretion by the pancreatic alpha cell in a glucose dependent
fashion. The net effect is the reduced blood glucose. As Dr. Chen will describe,
Saxagliptin significantly reduces both postprandial and fasting levels of glucose. Some
of the properties of Saxagliptin are described on the next slide.
(GIP) are both secreted in response to feeding and are largely responsible for the
incretin effect in humans. Both peptides are inactivated by dipeptidyl-peptidase 4
The pharmacodynamic properties of Saxagliptin are consistent with once
daily administration when given as a 5 mg dose. It is rapidly and extensively absorbed
after oral administration, can be taken without regard to meals, and has predictable dose
The next slide summarizes how inhibition of DPP-4 can improve glycemia
magnitude, or greater, selectivity for DPP-4 versus other proteases. It has an active,
monohydroxy metabolite that is a twofold less potent inhibitor of DPP-4 than
Saxagliptin. It is present in fourfold greater exposure and therefore contributes to in vivo
DPP-4 inhibition activity.
proportional pharmacokinetic behavior. Clearance of Saxagliptin and its active
metabolite occur via metabolism in renal and non-renal routes of elimination.
Saxagliptin is a potent competitive inhibitor of DPP-4 with two orders of
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