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1 Metformin;
trade names
Glucophage, Diabex, Diaformin, Fortamet,
Riomet, Glumetza and others) is an
anti-diabetic
drug from the biguanide class of
oral antihyperglycemic agents.
Other biguanides include the
withdrawn agents phenformin and
buformin.
Metformin is
the
most popular anti-diabetic drug in the United States and one of
the most prescribed drugs overall, with nearly 35 million
prescriptions filled
in 2006 for generic metformin alone.
2
History
The biguanide class of
anti-diabetic drugs originates from
the French lilac (Galega officinalis), a plant
known for
several centuries to
reduce the symptoms of diabetes mellitus.
Metformin
was
first described in the
scientific
literature in 1957. It was
first marketed in France in 1979, but
did not receive approval
by the U.S. Food and Drug Administration (FDA) for Type 2
diabetes until 1994.
Bristol-Myers
Squibb's Glucophage was the first presentation of metformin
to
be marketed in the United States, on March 3, 1995.
Generic
formulations
are now available.
3
Indications
The main use for metformin is
in the treatment of diabetes
mellitus type 2, especially
when this accompanies obesity and
insulin resistance.
It is also being
used increasingly
in polycystic ovarian syndrome (PCOS),
non-alcoholic fatty liver disease (NAFLD) and
premature puberty,
three other diseases that
feature insulin resistance; these
indications are
still considered experimental.
Although
metformin is not licenced for use in PCOS, the United Kingdom's
National Institute for Health and Clinical Excellence recommends
that women with PCOS and a body mass index above 25 be given
metformin when other therapy has failed to produce results.
The benefit of
metformin in NAFLD has not been extensively studied and may be
only temporary.
Metformin is the
only anti-diabetic drug that
has been proven to reduce
the
cardiovascular complications of diabetes, as
shown in a large
study of overweight patients with diabetes.
Unlike the other
most-commonly prescribed oral diabetes drugs, the sulfonylureas,
metformin monotherapy
will not induce hypoglycemia.
4 Mechanism of action
The
exact
mechanism of action of metformin
is uncertain despite
its known therapeutic benefits. Its
mode of action
appears to be reduction of hepatic
gluconeogenesis, decreased
absorption of glucose from the gastrointestinal
tract, and increased insulin sensitivity.
The 'average'
person with type 2 diabetes has
three times the normal rate of
gluconeogenesis; metformin treatment
reduces this by
over one third.
It has also been
shown to decrease intestinal absorption
of glucose, and may also improve insulin sensitivity
by increasing peripheral glucose
uptake and utilization, although
such an effect will occur nonspecifically
following the lowering of glucose levels,
regardless
of how this lowering
was achieved.
A 2001 study
showed that metformin stimulates the hepatic
enzyme AMP-activated protein kinase (AMPK), which
plays an important
role in the metabolism of fats and glucose. The
molecular
target which metformin
directly interacts with
remains
elusive.
5 Adverse effects
[Lactic
acidosis
The
most serious side effect
of metformin is lactic acidosis;
this complication is rare, as
it seems limited to those with
impaired liver or kidney function.
Phenformin, another biguanide,
was withdrawn because
of an increased
risk of lactic acidosis (up to 60 cases per million
patient-years). However, metformin is safer and the risk of
developing lactic acidosis is not changed by the medication,
so
long as it is not prescribed to the
known high-risk groups.
Gastrointestinal
The most common side effect
of metformin is gastrointestinal
upset, including diarrhea, cramps, nausea and vomiting. In
a
clinical trial of 286 subjects, 53.2% of the 141 who were given
Metformin (as opposed to placebo) reported diarrhea, versus
11.7% for placebo, and 25.5% reported nausea/vomiting, versus
8.3% for those on placebo.
Gastrointestinal upset
can cause severe discomfort for
patients; it is most common
when metformin is first
administered, or when
the dose is increased. The discomfort
can
often be avoided by beginning at a low dose (1 to 1.7 grams per
day) and increasing the dose gradually. Gastrointestinal upset
after prolonged, steady use is
less common.
Long-term use of metformin has been associated with increased
homocysteine levels and malabsorption of vitamin B12.
Higher doses are associated with increased
incidence of B12 deficiency, and
some researchers
recommend
screening or prevention strategies.
6 Contraindications
Metformin is
contraindicated in
any condition
that may increase the risk of lactic acidosis, including
heart failure, kidney disorders (creatinine
levels over 150 µmol/l, although this is an arbitrary limit),
lung disease and liver disease.
It is recommended
that metformin be temporarily discontinued
before any radiographic procedure
involving iodinated contrast (such
as a CT scan or angiogram) as contrast may temporarily
impair kidney function and indirectly
lead to lactic acidosis.
7
Formulations
Metformin IR (immediate release) is available in 500 mg, 850
mg, and 1000 mg tablets.
Metformin SR (slow release) or XR (extended release) was
introduced in 2004, in 500 mg and 750 mg strengths, mainly to
counteract the most common side effects, as well as
increase
patient compliance (e.g. taking one tablet once a day instead of
one tablet multiple times per day). No difference in glycemic
control exists between the two preparations.
Combinations
Metformin is often prescribed to type 2 diabetes patients
in
combination with rosiglitazone. This drug actively reduces
insulin resistance,
complementing the action of the metformin.
In 2002, the two drugs were
combined into a single product,
Avandamet, marketed by GlaxoSmithKline. In 2005,
all current
stock of Avandamet
was seized by the FDA and
removed
from the market, after inspections showed the
factory where it was produced was violating Good Manufacturing
Practices.
The drug pair
continued to be prescribed
separately in the absence of Avandamet, which was available
again by the end of that year.
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