1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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available to enable comparison of the efficacies of both DPP-IV inhibitors following
chronic dosing. Preclinical data suggest that sitagliptin may have a longer duration of action
than vildagliptin, since its half-life in monkeys is >2-fold longer than that of vildagliptin.
Thus, in clinical trials with vildagliptin as monotherapy a twice daily dosing has been used
while therapy with sitagliptin an once daily dosing regimen should be indicated. Enzyme
inhibitory data released has shown that sitagliptin has more selectivity for DPP-IV than
vildagliptin. If sitagliptin is superior to vildagliptin in this respect, the biological
consequences of inhibiting DPP-IV related enzymes remains poorly understood. However,
inhibition of DPP VIII/IX may be associated with considerable toxicity in preclinical
studies (247, 248). Given the absence of serious side effects in clinical studies either with
sitagliptin or vildagliptin, any differences in selectivity between inhibitors is likely to be of
more academic, rather than clinical importance (247).
In Table 6 are shown the effects of incretin enhancers on β-cells in animal studies
and in Table 7 the clinical evidences of the effects on β-cell function in humans with DM2.
Table 6. Effects of incretin enhancers (Sitagliptin and Vildagliptin) on β-cells:
animal studies
Table 7. Clinical evidences of incretin enhancers (Sitagliptin and Vildagliptin)
effects on β-cell function in humans with DM2
Summary / Conclusions
Preventing the degradation of native GLP-1 by inhibiting the activity of the DDP-IV
enzyme has emerged as a therapeutic strategy for enhancing endogenous GLP-1 action in
vivo. The effects of DPP-IV inhibition could be mediated not only by GLP-1 but also by
other mediators of the glucose-lowering actions of DPP-IV inhibition in clinical studies,
since it causes little increase in circulating endogenous GLP-1, has little effect on gastric
emptying, does not cause nausea/vomiting like GLP-1 and GLP-1R agonists and it is not
associated with weight loss. In preclinical studies, oral active DDP-IV inhibitors have been
demonstrated to promote beta-cell proliferation, neogenesis and inhibition of apoptosis in
rodents similar to that observed following the administration of GLP-1 or GLP-1R agonists.