Efficacy of DPP-IV inhibitors
Clinical proof-of concept was provided in 2001 by Ahren et al. when they demonstrated significant glucose-lowering effect and reduction of fasting blood glucose and HbA1c upon oral administration of an early inhibitor from Novartis in a 4-week study in patients with type 2 diabetes. Subsequent studies with a more long-acting inhibitor (vildagliptin) documented sustained effects on HbA1c (about 1% reduction compared to placebo) for 52 weeks when the inhibitor was added to existing metformin treatment.
Although the DPP-4 inhibitors are all competitive reversible inhibitors, it can be difficult to compare them using data reported in individual studies, because these are influenced by differences in the assay conditions used to estimate the extent of DPP-4 inhibition. However, one study in which the inhibitors were directly compared under identical experimental conditions reported that all available inhibitors showed similar efficacy (i.e. maximal effect) for inhibition of DPP-4 in vitro. With regard to half-life, there are also differences between the various inhibitors. These differences are reflected in the therapeutic doses, which range from 5 mg (saxagliptin) to 100 mg (sitagliptin), and in the dosing frequency (once daily for most of them, twice daily for vildagliptin). Nevertheless, despite the differences in potency, when used at their therapeutic doses, the effects of the inhibitors, in terms of the extent of DPP-4 inhibition in vivo, are broadly similar. Over 90% inhibition is attained within 15 min of inhibitor administration, with around 70–90% inhibition being sustained at 24 h postdose. However, it should be pointed out that plasma DPP-4 activity is assessed ex vivo (i.e. in plasma samples taken after in vivo dosing) and is generally not corrected for the inherent dilution of the sample in the assay. Hence, the true extent of DPP-4 inhibition in vivo is probably higher than the measured values suggests.