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Chapter 4 Summary

z Eating promotes a much greater degree of insulin secretion compared with
intravenous injection of glucose. This is the incretin effect, a physiological
phenomenon mediated by the incretin hormones, notably glucagon-like
peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).
z Incretin hormones elicit an increase in glucose-dependent insulin secretion
and suppress glucagon secretion as well as increasing sensitivity to insulin
and glucose uptake in the peripheral tissues, independent of insulin secretion.

z GLP-1 may stimulate increases in β-cell mass and function (animal and cell
line studies).
z In people with T2DM there are several defects in the incretin effect:
◦ Decreased potency of GLP-1 in stimulating the production and release
of insulin.
◦ An almost complete loss of late-phase insulin secretion in response to GIP.
◦ Suppression of glucagon secretion is impaired during oral glucose tolerance
tests (OGTTs) as opposed to isoglycaemic intravenous glucose infusion.
z DPP-4 inhibitors can enhance and prolong the effects of endogenous GLP-1
by inhibiting the enzyme that rapidly degrades this incretin hormone.
z These DPP-4 inhibitors are orally active, do not require a dose-finding pe-
riod and two of the three types currently available only have to be taken
once a day.
z DPP-4 inhibitors can significantly reduce HBA , FPG and PPG. There is also
1c
some evidence to suggest they may preserve β-cell function and provide
some degree of cardiovascular protection. However, studies proving a
lasting improvement in the course of diabetes progression still have to be
initiated.

z Generally, DPP-4 inhibitors have proven to be safe and well tolerated, with
an overall incidence of adverse events similar to placebo.
◦ DPP-4 inhibitor treatment is associated with a low incidence of hypogly-
caemia due to their glucose-dependent mode of action (as derived from
studies with GLP-1).
◦ DPP-4 inhibitors are body-weight neutral.
◦ Specific issues with vildagliptin may be angioedema, skin lesions and el-
evation in liver enzymes (with uncertain impact on the spectrum of ad-
verse events observed with clinical use). Saxagliptin has been associated
with a minor decrease in absolute mean lymphocyte count, again with
uncertain clinical significance.
◦ All the currently available DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin
and alogliptin) are primarily excreted via the kidneys with implications for
their use in people with renal impairment (dose reduction or avoidance of
use in that particular population).
◦ The suspicion has been raised based on analyses from an adverse events
reporting database located at the FDA that pancreatitis and pancreatic
carcinoma may be observed more often with sitagliptin treatment, but
this evidence is considered non-convincing due to the nature of this data-
base and the high likelihood for reporting bias.

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