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

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in 741 patients with DM2, randomized to placebo or sitagliptin. Post-meal insulin and C-
peptide AUC, ratio of insulin AUC/glucose AUC and HOMA-β, all measures of beta-cell
function were significantly increased with sitagliptin relative to placebo. Moreover,
proinsulin/insulin ratio was significantly reduced with sitagliptin compared to placebo
(230). In the another study,when sitagliptin was added to ongoing metformin
therapy,assessed in 701 patients with DM2 and inadequate glycemic control on metformin
who were randomized to to receive either placebo or sitagliptin, a significant reduction in
HbA1c, fasting plasma glucose and 2-hour post-meal plasma glucose was observed after 24
weeks .The same indices of beta-cell function evaluated as in the above indicated report,
were also significantly increased and the proinsulin/insulin ratio significantly decreased,
with sitagliptin relative to placebo (231).
The effect of sitagliptin on beta-cell function in DM2 was assessed using frequently
sampled (9 points) meal tolerance tests in sub-studies from 3 phase III trials (2
monotherapy studies and an add-on to metformin study) using the C-peptide minimal
model,which allowed for the estimation of the insulin secretion rate and the
characterization of the insulin secretion response into basal (beta-cell responsiveness to
basal glucose concentrations), static (beta-cell responsiveness to above-basal glucose
concentrations following a meal) and dynamic (beta-cell responsiveness to the rate of
increase in above–basal glucose concentrations following a meal) components.Insulin
sensitivity was assessed with a validated composite index (ISI). The disposition indices
were also assessed. When used as monotherapy or added to on-going metformin therapy,
sitagliptin produced improvements in basal and static components and overall
responsiveness to the beta-cell to glucose. The dynamic component showed numerical, but
not statistically significant improvements with sitagliptin. Disposition indices were also
broadly improved with the DPP-IV inhibitor relative to placebo. Despite enhanced beta-cell
sensitivity to glucose, the low rate of hypoglycemia observed in clinical trials with
sitagliptin indicated, according to the AA, that the increase in beta-cell function remained
glucose-dependent (232).
Finally, the addition of sitagliptin to 353 DM2 patients who were not well
controlled with pioglitazone monotherapy and were randomized to placebo or
sitagliptin(100mg qd) to ongoing pioglitazone, produced a significant placebo–subtracted