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Even though DPP-4 inhibitor treatment by itself is associated with a min-
imal risk of hypoglycaemia, caution is required when they are added to
agents, which themselves can cause hypoglycaemia, such as SUs or in-
sulin. Recently updated prescribing information in the US recommends
that when sitagliptin is used with insulinotropic agents, a lower dose of
the latter may be required to reduce the risk of hypoglycaemia. If at
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all possible, this combination should be avoided.

Weight gain

Weight gain is another important concern in OAD therapy as some
compounds, such as SUs, non-SU secretagogues and TZDs are associ-
ated with significant increases in weight. Clinical studies have demon-
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strated that DPP-4 inhibitors are body-weight neutral.
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Other safety issues

Angioedema has been reported in patients receiving vildagliptin and
concomitant ACE inhibitors. Also, there have been incidences of skin
lesions with vildagliptin, including blistering and ulceration, in non-
clinical toxicology studies. Vildagliptin has not been approved in the U.S.
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due to a lack of studies in patients with renal impairment. In addition, in
those markets where vildagliptin is approved, liver function monitoring
is recommended with vildagliptin at three-month intervals during the
first year and periodically thereafter. With saxagliptin, a dose-related
21
mean decrease in absolute lymphocyte count was observed during
clinical development, but the clinical relevance of this is unknown.
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Post-marketing reports of serious hypersensitivity reactions in patients
treated with sitagliptin have been reported. These reactions include
anaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome. Pending approval and the appropriate
20
dose reduction, sitagliptin and saxagliptin may be used in patients with
renal impairment. Alogliptin has been withdrawn from the FDA ap-
proval process due to insufficient cardiovascular safety data, but it has
been approved in Japan.

Elimination and implications for renal impairment

The DPP-4 inhibitors, sitagliptin, vildagliptin, saxagliptin and alogliptin
are primarily excreted via the kidneys. This route of elimination has
obvious implications for the use of these agents in patients with renal
impairment. Consequently, the prescribing information for sitagliptin,
vildagliptin and saxagliptin in the EU recommend these agents should
not be used in patients with moderate or severe renal impairment. 19-21
The equivalent information in the US recommends these agents can be
used in patients with moderate and severe renal impairment with the
appropriate dose adjustment.
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