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Metformin (Glucophage®)?
Why has it become so popular?
Metformin
was originally developed in 1957 and used worldwide
before finally being introduced to the US in 1994. Metformin
is approved by the FDA for treatment of type 2 diabetes.
Metformin is a biguanide oral antihyperglycemic.
Metformin has many
actions, the main being suppression of endogenous glucose
production by the liver. Among oral antihyperglycemic
medications it is unique, unlike the sulfonlyureas such
as Diabinese® it does not cause hypoglycemia, weight
gain, unfavorable alteration of lipids, nor increase
insulin secretion.
Unlike thiazolidinediones
such as Avandia® metformin does not cause weight
gain, fluid retention, or potential idiosyncratic hepatotoxicity.
Instead, metformin improves the effectiveness of insulin
while maintaining or even decreasing insulin levels.
Metformin decreases both basal and postprandial glucose
levels, without the danger of hypoglycemia. Glucophage
promotes weight loss and favorable changes in the lipid
profile.
Metformin's effects
are beneficial to women with type 2 diabetes. Metformin's
unique properties have already established it as the
initial medication of choice for type 2 diabetes treatment
and produced many studies advocating other possible
indications:
- Metformin may decrease
the progression from IGT to type 2 diabetes. In a
prospective RCT, 3,234 women with IGT were followed
for an average of 2.8 years. With placebo treatment,
11% per year progressed to type 2 diabetes. With a
weight loss and exercise program, 4.8% per year progressed
(a 58% improvement vs. placebo). With Glucophage treatment,
7.8% per year progressed (a 31% improvement vs. placebo).
Weight loss and exercise remain the best hedge against
developing IGT or type 2 diabetes. The usefulness
of Metformin treatment in women simply with PCOS to
prevent the development of IGT or type 2 diabetes
is unknown.
- In women with infertility due to PCOS,
three randomized, placebo controlled trials found
metformin plus Clomid
to be more effective than Clomid alone in ovulation
induction. Glucophage may also improve the quality
of ovulation
induced by recombinant FSH administration. Sustained
metformin administration may establish regular menses
in women with PCOS.
- Metformin may decrease the miscarriage
risk associated with PCOS. These findings are
preliminary, based on two small studies. PCOS is not
associated with the most incessant forms of recurrent
miscarriage. One small study found metformin may also
decrease the incidence of gestational diabetes in
PCOS
women. The safety of Glucophage's use in pregnancy
has not been established.
- Metformin's effectiveness as
a treatment for hirsutism have been mixed.
Metformin
is chemically related to phenformin, which was withdrawn
from the US market in 1976 because of a high association
with lactic acidosis. With normal metformin dosing and
normal renal function, development of lactic acidosis
is very rare. It is prudent to verify a normal serum
creatinine level before starting Metformin and to stop
metformin treatment before conditions of relative renal
compromise such as the administration of IV iodinated
contrast agents and during fluid restriction. Cationic
medications, such as cimetidine, compete with metformin
for renal clearance thus increasing the risk of lactic
acidosis.
Metformin's
other contraindications are liver dysfunction, excessive
alcohol intake, severe illness. The main side effects
of metformin are GI: diarrhea, nausea. These effects
can be mitigated by taking Glucophage with food and
slowly building up to the target dosage of 1,500 to
2,000 mg total per day.
Metformin Summary:
- PCOS is a
syndrome, defined by unexplained hyperandrogenism
and associated ovulatory dysfunction. Although not
essential to its definition, PCOS will usually be
accompanied by polycystic ovaries, and in about half
the women, IR .
- IR is suggested clinically by
central obesity
and acanthosis nigricans. IR is a given with IGT or
Type 2 Diabetes. Because of its high prevalence in
PCOS, a strong case can be made for all women with
PCOS to undergo an OGTT to detect IGT and Type 2 Diabetes.
Unfortunately, proven practical means to screen for
less advanced forms of IR are not established. Elevated
fasting insulin levels and decreased fasting glucose
insulin ratios (G/I < 4.5) are consistent with
early IR, before beta cell exhaustion. With IGT or
Type 2 Diabetes, the best intervention is weight loss
and exercise. Metformin is generally the first choice
among pharmacologic agents.
- For most women with PCOS
trying to conceive, the first medication option to
induce ovulation is still Clomid. However, metformin
is arguably the first choice in women with IGT and
certainly in women with type 2 diabetes. The combination
of metformin and Clomid
is effective. Weight loss and exercise promote
ovulation.
- In women with PCOS not trying
to conceive, menstrual irregularity is usually best
treated with an estrogen-progestin contraceptive.
In some women, it is possible that sustained metformin
treatment may induce regular, ovulatory menstruation.
- In women with PCOS not trying
to conceive, hirsutism treatment initially usually
consists of an estrogen-progestin contraceptive, an
anti-androgen such as spironolactone, and mechanical
cosmetic treatment.
- Metformin is a very safe medication
when used properly and given to healthy women. It
is contraindicated in women with renal compromise,
liver disease, and at risk for lactic acidosis. GI
side effects are initially very common, but usually
are not
Interview with Dr. Daniel Potter on PCOS
Other Fertility Drugs
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