DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

patients in clinical trials and has been reported equally with pioglitazone
and rosiglitazone. Beyond the effects of edema, treatment
with thiazolidinediones causes an increase in body adiposity and an
average weight gain of 2-4 kg over the first year of treatment.
Importantly, in both preclinical models and in human studies the gain
of body weight occurs peripherally, in subcutaneous adipose tissue,
and visceral fat changes little or is reduced. The use of insulin with
thiazolidinedione treatment roughly doubles the incidence of edema
and amount of weight gain, compared with either drug alone.
Macular edema has been reported in patients using both
rosiglitazone and pioglitazone (Ryan et al., 2006), usually in association
with more general fluid retention. Beyond regular annual retinal
exams, diabetic patients taking thiazolidinediones should be
observed for visual changes.
Of greatest concern among the adverse effects of thiazolidinediones
is the increased incidence of congestive heart failure. This has
generally been attributed to the effect of the drugs to cause plasma
volume expansion in type 2 diabetic patients who have significantly
increased risk for heart failure. There does not appear to be an acute
effect of pioglitazone or rosiglitazone to reduce myocardial contractility
or ejection fraction. Yet exposure to these drugs over several
years in clinical trials has been associated with an increased incidence
of heart failure of up to 2-fold (Home et al., 2009). The use of thiazolidinediones
in diabetic patients without a history of heart failure,
or with compensated heart failure, can be initiated, but monitoring
for signs and symptoms of congestive heart failure is important, especially
when insulin is also used. Thiazolidinediones should not be
used in patients with moderate to severe heart failure, and they should
be discontinued in those who develop clinically apparent heart failure
while being treated (Nesto et al., 2003).
Recent evidence suggests that rosiglitazone, but not pioglitazone,
increases the risk of cardiovascular events (myocardial
infarction, stroke). While the degree of the risk remains controversial,
an expert panel reviewing this question for the FDA recommended
caution in the use of rosiglitazone, but did not recommend
its removal from the market (Rosen, 2010). Rather, as of September,
2010, the FDA requires that new prescriptions for rosiglitazone be
issued under a risk evaluation and mitigation strategy and be limited
to patients whose diabetes could not be adequately controlled by
other medications (including pioglitazone). The European Medicines
Agency has suspended marketing of rosiglitazone-containing formulations
and recommended removal of rosiglitazone and rosiglitazone-containing
formulations from the European market.
Evidence from clinical trials indicates that treatment with thiazolidinediones
can increase the risk of bone fracture in women
(Home et al., 2009; Kahn et al., 2006; Meier et al., 2008). This effect
has been proposed to result from increased shunting of mesenchymal
stem cells into the adipocyte lineage, and away from osteogenesis, as
a result of increased PPARγ activity. Treatment with thiazolidinediones
has also been associated with a small but consistent reduction in the
hematocrit. This has generally been attributed to hemodilution due to
plasma volume expansion, but thiazolidinediones may conceivably
shunt erythroid precursors into adipose tissue development.
The first thiazolidinedione released for treatment of diabetic
patients, troglitazone, was removed from the market because of rare
but severe, and sometimes fatal, hepatic failure. There have been
few cases of severe hepatocellular damage attributable to the newer
thiazolidinediones, and these have not caused death or required
transplantation. In general, pioglitazone and rosiglitazone have been
associated with a lowering of transaminases, probably reflective of
reductions in hepatic steatosis. It is recommended that thiazolidinediones
be withheld from patients with clinically apparent liver disease
and that liver function be monitored intermittently during treatment.
GLP-1-Based Agents
Incretins are GI hormones that are released after meals
and stimulate insulin secretion. The two best known
incretins are GLP-1 and GIP. Although these peptides
share many similarities, they differ in that GIP is not
effective for stimulating insulin release and lowering
blood glucose in persons with type 2 diabetes, whereas
GLP-1 is effective. Consequently, the GLP-1 signaling
system has been a successful drug target.
Both GLP-1 and glucagon are products derived from preproglucagon,
a 180–amino acid precursor with five separately
processed domains (Figure 43–9) (Drucker, 2006). An amino-terminal
signal peptide is followed by glicentin-related pancreatic peptide,
glucagon, GLP-1, and glucagon-like peptide 2 (GLP-2). Processing
of the protein is sequential and occurs in a tissue-specific fashion.
Pancreatic α-cells cleave proglucagon into glucagon and a large
C-terminal peptide that includes both of the GLPs. Intestinal L-cells
and specific hindbrain neurons process proglucagon into a large
N-terminal peptide that includes glucagon or GLP-1 and GLP-2.
GLP-2 impacts the proliferation of epithelial cells lining the GI tract.
Teduglutide, a GLP-2 analog, is under development as a treatment
for short bowel syndrome and has received orphan drug designation
for the treatment of short bowel syndrome from the U.S. FDA and
the European Medicines Agency.
Given intravenously to diabetic subjects in supraphysiologic
amounts, GLP-1 stimulates insulin
secretion, inhibits glucagon release, delays gastric
emptying, reduces food intake, and normalizes fasting
and postprandial insulin secretion. The insulinotropic
effect of GLP-1 is glucose dependent in that insulin
secretion at fasting glucose concentrations, even with
high levels of circulating GLP-1, is minimal. The
effects of GLP-1 to promote glucose homeostasis and
the glucose dependence of these effects are beneficial
aspects of this signaling system for treating type 2 diabetes.
GLP-1 is rapidly inactivated by the enzyme
dipeptidyl peptidase IV (DPP-4), with a plasma t 1/2
of
1-2 minutes; thus, the natural peptide, itself, is not a
useful therapeutic agent.
Two broad strategies have been taken to applying
GLP-1 to therapeutics, the development of injectable,
DPP-4 resistant peptide agonists of the GLP-1 receptor,
and the creation of small molecule inhibitors of
DPP-4 (Figure 43–10; Table 43–6).
GLP-1 Receptor Agonists. There are currently two
GLP-1 receptor agonists that have been approved for
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA