termed glitazones) are a novel class of drugs that were initially identified
for their insulin-sensitizing properties. They all act to de-crease insulin
resistance and enhance insulin action in target tissues. Thiazolidinediones
activate the nuclear peroxisome proliferator–activated receptor (PPAR) , a
nuclear orphan receptor that is predominantly ex-pressed in adipose tissue and
to a lesser extent in mus-cle, liver, and other tissues. The endogenous ligand
for the PPAR-γ receptor is postulated to be prostaglandin J2, and it appears to
work by heterodimerizing with other nuclear receptors to modulate the
expression of insulin-sensitive genes.
readily absorbed from the gastrointestinal tract following oral administration
and are rapidly metabolized by the liver. Plasma elimination half-life is 2 to
3 hours for rosiglitazone (Avandia)
and slightly longer for pioglitazone (Actos).
About two-thirds of conjugated metabolites appear in the urine and the
remainder in the feces. The biological effect of these drugs takes several
weeks to develop, although patients may see some benefit within a few days to a
week. Generally, however, the insulin-sensitizing action of the
thiazolidinediones takes a while to develop. For that reason, upward
adjustments in dosage are made gradually to avoid hypoglycemia.
The patient who would benefit
the most from a thi-azolidinedione is a type II diabetic with a substantial
amount of insulin resistance (e.g., one who does not re-spond to other oral
therapies or who requires excessive amounts of insulin [ >100 units/day]).
Improvements in diabetic control are variable, ranging from a 1% reduc-tion in
hemoglobin A1c when used as monotherapy to greater reductions (> 2%
reduction in hemoglobin A1c) when used in combinations with other agents, such
as sulfonylureas or metformin.
Rosiglitazone is approved for
use as monotherapy and in conjunction with metformin, though it is some-times
combined with a sulfonylurea or insulin. It is usu-ally taken once or twice a
day with or without food. Rosiglitazone may cause a modest increase in
low-density lipoprotein and triglyceride concentrations, but it is unclear
whether this effect has any clinical signifi-cance or persists in the long
Pioglitazone is approved for
use as monotherapy and in conjunction with metformin, sulfonylureas, and
insulin. It is taken once a day with or without food. Though pioglitazone may
also cause a small increase in low-density lipoprotein concentrations, there is
usually a modest decrease in triglyceride levels, but it unclear whether this
has any clinical significance or persists in the long term.
The original prototype of
this class of drugs, trogli-tazone (Rezulin),
was taken off the U.S. market in 2000 because of increasing concerns about
idiosyncratic he-patic toxicity that resulted in several deaths worldwide.
Consequently, frequent monitoring of liver transami-nases is recommended for
rosiglitazone and pioglita-zone, and these drugs should be stopped if
transami-nases rise to more than two to three times the upper limit of normal.
To date, rosiglitazone and pioglitazone seem to be associated with far fewer
incidents of he-patic toxicity.
cause edema that can be quite severe, sometimes requiring cessation of the
drug, but mild cases of lower extremity edema can be treated with a low dose of
a diuretic. There is often a modest amount of weight gain that is independent
of water-retaining effects. In laboratory animals, thiazo-lidinediones at high
doses are associated with ultrastruc-tural histopathological changes in cardiac
tissue; there-fore, thiazolidinedione use is contraindicated in patients with
significant heart failure. Thiazolidinediones can also cause mild anemia.
Safety in pregnancy is not estab-lished.
Hypoglycemia is rare with
thiazolidinedione mono-therapy; however, these drugs may potentiate the
hypo-glycemic effects of concurrent sulfonylurea or insulin therapy. If a
thiazolidinedione is to be added to a dia-betic’s regimen, the sulfonylurea or
insulin dosage should be decreased to compensate for any enhanced insulin
sensitivity. Occasionally a small portion of in-sulin-treated type II diabetics
may be capable of coming off their insulin altogether, depending on their
respon-siveness to thiazolidinedione action.