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Safety and tolerability

Besides their demonstrated efficacy in lowering blood glucose levels,
DPP-4 inhibitors have proven to be safe and well tolerated, with an
overall incidence of adverse events similar to placebo. 19-21 The inci-
dence of specific adverse events is not increased with DPP-4 inhibitor
treatment compared with placebo, and the dropout rates from studies
due to adverse events are low. 77

In some studies, upper respiratory tract infection, nasopharyngitis and
headache have been reported in patients treated with DPP-4 inhibitors;
a truly enhanced frequency has not been established. Even though
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DPP-4 inhibitors appear to be generally well tolerated, the collective ex-
perience with these drugs in the clinical setting has been relatively short;
therefore, long-term surveillance is critical for the detection of potential
adverse events that may occur rarely or following long-term use. 77
In addition to its role in blood sugar homeostasis, the DPP-4 enzyme may
play a role in the immune system (CD26, a marker of activated T-lymph-
ocytes, is identical to DPP-4) and perhaps also in tumour biology. 78 79
Extensive animal toxicology studies with high doses and long duration,
however, do not provide evidence to support the theory that DPP-4
inhibitors have the potential to cause or promote tumours. A recent
analysis of the FDA adverse events reporting database has been much
debated, with the preliminary conclusion that the findings of an ele-
vated risk for acute pancreatitis and pancreatic carcinoma found in
the case of sitagliptin contradict findings from other analyses, are in
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part biologically implausible, and most likely are the result of reporting
bias. However, a final judgement cannot be made based on findings
currently available, and results from larger and longer duration clinical
trials and other methods of surveillance need to be waited for to allow
firmer conclusions.
Hypoglycaemia

An important consideration in the tolerability of OAD therapy is hypo-
glycaemia; however, compared to some of the OADs on the market,
DPP-4 inhibitors are associated with a low incidence of hypoglycaemia
thanks to their novel mode of action. DPP-4 inhibitors avoid the risk of
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hypoglycaemia in two ways:

z GLP-1, the levels of which are increased by DPP-4 inhibition, suppresses
glucagon release only at euglycaemia, but not at hypoglycaemic plasma
glucose concentrations. 81
z DPP-4 inhibitors may, in addition, enhance α-cell responsiveness to the
suppressive effects of hyperglycaemia and the stimulatory effects of hypo-
glycaemia, as shown for vildagliptin. 82

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