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