Oral Antidiabetic Agents - Luzimar Teixeira

406 Krentz & Bailey
Table VII. Cautions in the use of thiazolidinediones
Active liver disease
This remains a contraindication to the use of thiazolidinediones
even though neither rosiglitazone nor pioglitazone have been
associated with troglitazone-like hepatotoxicity. In fact, the latter
drugs are under investigation as a potential treatment for nonalcoholic
steatohepatitis. In 2004, the US FDA recommendation
for 2-monthly monitoring of biochemical liver function tests was
relaxed. Instead, periodic biochemical monitoring is now left to
the supervising clinician’s discretion
Heart failure
The precise contraindications differ between countries. In Europe,
current heart failure or a history of heart failure are
contraindications to thiazolidinediones
Insulin treatment
Although rosiglitazone and pioglitazone are licensed in the US for
use in combination with insulin, caution is required. Concerns
about higher rates of heart failure underlie this concern. The
European Agency for the Evaluation of Medicinal Products
considers insulin therapy a contraindication to the use of
thiazolidinediones
Pregnancy and breast-feeding
Thiazolidinediones are classified as pregnancy category C
because of growth retardation in mid-to-late gestation in animal
models. These drugs should only be used during pregnancy if the
potential benefit justifies the potential risk to the fetus
Polycystic ovary syndrome
Thiazolidinediones can cause ovulation to recommence in women
with hyperandrogenism and chronic anovulation; risk of
pregnancy
According to the EU license, rosiglitazone can be
given at a dosage of 4 mg/day in combination with a
sulphonylurea, increasing to 8 mg/day (either once
daily or in divided doses) in combination with met-
formin. Pioglitazone can be given as a once-daily
dosage of 15mg, increasing to 30mg if necessary
(maximum 45mg in the US and Europe). The thera-
peutic response varies markedly between patients
and it can be difficult to predict those most likely to
respond. If no effect is observed after 3 months it is
appropriate to consider the patient as a nonresponder
and to stop the treatment. Rosiglitazone and piog-
litazone can be used in the elderly, provided there
are no contraindications. Both drugs may be used in
patients with mild-to-moderate renal impairment,
although the potential for oedema is a concern. In
women with anovulatory PCOS the improvement in
insulin sensitivity may cause ovulation to resume
during thiazolidinedione therapy. A combination
heart failure is contraindicated. The choice of which
patients to exclude on the basis of cardiac status
varies between the product labelling sheets in the
US and Europe. Consensus guidelines from the
American Heart Association and the American Diabetes
Association have recently been published. [62]
Patients treated with a combination of insulin plus
thiazolidinedione appear to be at highest risk of
oedema, although the absolute rate of cardiac failure
is low despite the fact the diabetes is a major risk
factor for this complication. [62] The guidelines urge a
cautious approach and careful clinical monitoring,
especially for patients likely to be at higher risk of
cardiac failure. The haemogloblin concentration
should be checked before starting a thiazolidinedione,
bearing in mind that reductions of up to 1 g/
dL in haemoglobin concentration may occur during
therapy. No adverse effects on blood pressure have
been noted with the thiazolidinediones, even with
the increase in plasma volume; on the contrary, there
is some evidence for a modest blood pressure-lowering
effect. [63]
As a precautionary measure, liver function
should be assessed by measuring serum ALT before
starting therapy and subsequently at 2-monthly intervals
(or, in the US, as judged necessary by the
prescribing clinician) during the first year of treatment;
thereafter, periodic monitoring of liver function
is prudent. Pre-existing liver disease, the development
of clinical hepatic dysfunction or elevated
ALT levels >2.5 times the upper limit for the laboratory
serve as contraindications to thiazolidinediones.
However, as mentioned earlier, hepatotoxicity
has not been a concern with either rosiglitazone or
pioglitazone. Isolated cases of nonfatal hepatocellular
damage have been reported; however, the issue is
clouded by reports suggesting an intrinsically higher
risk of liver failure in patients with type 2 diabetes.
Nevertheless, precautionary monitoring of liver
function remains advisable. When initiating therapy
with rosiglitazone or pioglitazone, blood glucose
monitoring and titration of drug dosage should be
undertaken while bearing in mind that thiazolidinediones
exert a slowly generated anti-hyperglycaemic
effect that usually requires 2–3 months to
reach maximum effect.
© 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)