Endogenous GLP-1 concentrations can be raised two- to threefold by inhibiting GLP-1 degradation via DPP-4. Support for this approach to therapy also comes from the observations that glucose tolerance is improved in animals in which the enzyme has been genetically deleted (75) and in animals treated with DPP-4 inhibitors (76). Various substances with DPP-4 inhibition properties are currently being tested in preclinical and clinical trials. The two compounds have reached approval in several countries are sitagliptin (MK0431, Januvia ; Merck Pharmaceuticals, Whitehouse Station, NJ, U.S.A.) and vildagliptin (LAF 237, Galvus®; Novartis Pharmaceticals, Basel, Switzerland) (77). Saxagliptin and further substances are presently also in clinical studies (78). In clinical studies, vildagliptin lowered HbA1c, fasting and postprandial glucose in type 2 diabetic patients not sufficiently treated with metformin and other oral antidiabetic drugs (79). In monotherapy, vildaglitpin lead to a sustained HbA1 reduction almost similar to metformin. Sitagliptin also effectively lowers the HbA1c and reduces diurnal fluctuations in glucose concentrations (58,80). In clinical studies, DPP-4 inhibitors improve beta-cell secretory capacity and suppress glucagon secretion from the alpha cells. In contrast to incretin mimetics, DPP-4 inhibitors have been weight neutral in clinical studies so far (58,79) (Fig. 3).
The application of DPP-4 inhibitors retards endogenous GLP-1 degradation, but there is still some uncertainty, whether all effects of DPP-4 inhibitors are exclusively mediated by the prolongation of the biological half-life of the peptide (81-83). One puzzling finding might support this: in patients with type 2 diabetes, concentrations of active GLP-1 after meal ingestion are doubled by DPP-4 inhibition (compared with placebo), and glucose control improves (79). In contrast, when similar increases in GLP-1
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