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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
12
VOLUME 9 NUMBER 1 • MARCH 2012
In the USA both sitagliptin and saxagliptin can be used in severe
renal impairment, with dose adjustments.
22
It would be expected
that linagliptin should be safe in the renally impaired because it
is not renally excreted, but too little data are available to make
a recommendation. This drug is currently not available in South
Africa.
41
In patients with hepatic impairment, it seems that the
pharmacokinetics is not clinically significantly changed. However,
vildagliptin is not recommended in these patients.
12
The effects
of hepatic impairment on sitagliptin and alogliptin were very mild
and not significant.
15,24
Saxagliptin exposure increased with hepatic
impairment and its active metabolite decreased.
17
Therefore,
saxagliptin should be used with caution in these patients and it is
preferable to use one of the safer DPP-4 inhibitors (sita-, alogliptin).
Linagliptin is primarily hepatically eliminated and should therefore
not be recommended in liver disease. The characteristics of the
DPP-4 inhibitors are summarised in Table 2.
12,15,17,24,25
Side effects
These drugs are in general well toleratedwith few side effects, largely
comparable to placebo in trials.
22
Hypoglycaemic risk is low, which
make these drugs safe in the elderly and those with cardiovascular
disease. Hypoglycaemia only becomes a risk when the drugs are
combined with sulphonylureas. They are all weight neutral, which
is a further benefit compared to the sulphonylureas.
Vildagliptin was the first of these drugs on the market in South
Africa and had been shown to cause increased liver transaminases
in some of the trials, especially with the 100-mg once-daily dose,
resulting in dose alteration to 50 mg bd. Hence the recommendation
of liver-function tests prior to initiation of treatment, and three
monthly thereafter for the first year. Liver disease is a contra-
indication for its use, although no evidence of adverse liver
outcomes were proven.
12,42,43
Although earlier reports suggested increased urinary tract
infections and nasopharyngitis, this was not confirmed by later
analyses.
22
No links to cancer or metabolic bone disease could be
found. These drugs have also shown no negative cardiovascular
symptoms in the available data.
43-45
There are no current data to
suggest increased risk of pancreatitis.
22,43,47,48
Efficacy and use
From the pharmacodynamic data, we expected to see similar
lowering of HbA
1c
and fasting blood glucose levels when these
drugs were compared to each other. The reasons for this include
their comparative effects on DPP-4 inhibition. The data are mostly
from different trials, not directly comparing the drugs, and showed
very little difference between them. There is only one head-to-head
study comparing sitagliptin to saxagliptin as add-on therapy, which
showed similar HbA
1c
lowering, with sitagliptin being slightly better
at lowering fasting blood glucose levels. This is probably related to
the longer half-life of sitagliptin.
49
The DPP-4 inhibitors showed significant lowering of HbA
1c
,
postprandial and fasting blood glucose levels in multiple trials
across the board. These trials showed the same trends already
established with other drugs, i.e. that greater reduction in HbA
1c
levels is seen in patients with higher baseline levels. Some studies
also showed equivalent HbA
1c
lowering compared to metformin,
50,51
sulphonylureas
52,53
and the glitazones.
54,55
In general, the expected
lowering of HbA
1c
levels from 8% baseline would be about 0.5–
1.0%. If, however, the baseline was 8.5–9.0%, the drugs could
lower HbA
1c
levels by about 1% or more.
22
These drugs are very safe and should be used early in type 2
diabetes. When used early, these agents are more efficacious. Their
hypoglycaemic risk is very low, side effects are minimal and they
are weight neutral. They are fairly well priced. Their well-described
mode of action and correction of pathophysiology in type 2 diabetes
gives further peace of mind. We are keenly awaiting cardiovascular
disease outcome trials.
Our South African/SEMDSA guidelines are currently being
rewritten and should be published early in 2012. This will include
DPP-4 inhibitors as second-line treatment at primary level, after
metformin and lifestyle changes, which will always be first-line
treatment. If, however, metformin is not tolerated, DPP-4 inhibitors
should be seriously considered as first-line therapy.
Conclusion
The DPP-4 inhibitors are a new class of antidiabetic agents which
are here to stay and will probably be used as first- or second-line
therapy. The different agents are very similar where safety, tolerability
and efficacy are concerned. They do differ in structure, selectivity,
half-life, route of elimination, dosing and use in patients with organ
dysfunction. Currently we are limited by those registered by the
Medicines Control Council, but I am sure that most, if not all, will
eventually reach our shores.
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