Metformin for Diabetes

Everyone must familiar with diabetes now a days. It is a very common

disease worldwide. Its prevalence is increasing day by day in all the
countries of the world. According to the recent stats, 3.5 million people in
UK are diagnosed with diabetes. It is estimated that around 5.4 million
people in UK have undiagnosed diabetes. Similarly, in the United States,
more than 100 million people are living with diabetes, diagnosed or
undiagnosed.
Diabetes mellitus is a group of metabolic disorders associated with a
number of symptoms. Increased blood glucose level is the most commonly
described symptom to be associated with this disease. Among doctors, it is
known by its famous “three P’s”; Polyphagia (excess eating), Polydipsia
(increased thirst) and Polyuria (excess urination).
Not all people know that there are two types of diabetes; Diabetes
type 1 (Insulin dependent) and Diabetes type 2 (non-insulin dependent).
Type 1 diabetes has much earlier onset and requires permanent insulin
therapy. Type 2 diabetes is adult in onset and doesn’t respond to insulin.
Rather, it requires oral drugs to lower blood glucose levels.
Metformin is a drug of choice to prevent and treat type 2 diabetes
mellitus. It has been successfully used in the patients of diabetes along
with exercise and diet changes to fight against this disease. In this article
we will review various aspects of metformin use in diabetes. Keep reading
the article for further information.

Overview and History:

Metformin is first line drug used in the treatment of type 2 diabetes. It
was discovered in 1922 and was shown to decrease blood glucose levels
in rabbits. In 1950, it was used to treat influenza and was found to
decrease blood glucose levels to the normal physiological limits and was
found to be non-toxic. It was approved for the treatment of diabetes in 1994
and was first marketed in 1995 under the tradename Glucophage. In
several countries, Glucophage has become iconic trade name for
metformin.
Mechanism of Action:
Although various research studies propose different ways how it works, the
mechanism of action of metformin is still not well understood. Following are
the best-known mechanisms till date.
Metformin acts on the liver to improve blood glucose levels. Several studies
provide evidence that metformin plays a role in reducing hepatic
gluconeogenesis (synthesis of glucose from non-carbohydrate sources)
and increasing insulin sensitivity.
Gluconeogenesis is an energy-requiring process, consuming six ATPs per
molecule of the glucose synthesized. Hepatocytes (liver cells) need to
balance the demand for ATP which is primarily provided by the
mitochondria (powerhouse of the cell).
Metformin accumulates within mitochondria up to 1000-fold higher than in
the extracellular medium. It is because metformin carries a positive charge
which drives metformin into the cell and subsequently into the
mitochondria.
Within the mitochondria, metformin inhibits the Complex I of the respiratory
chain which suppresses ATP production. As a result, enough ATP is not
available for the cells to synthesize glucose and thus, gluconeogenesis is
inhibited.
Metformin interacts with nuclear PPAR(peroxisome proliferation activation
receptors) receptors. These receptors induce the insulin responsive genes
and thus increase insulin receptors sensitivity. These receptors also
increase induction of various enzymes including lipoprotein lipase (enzyme
that removes lipids from the blood).
Metformin not only acts on the liver but also on the intestines. Several
researches show that intestines may be a target organ for metformin. It
increases anaerobic glucose metabolism in the enterocytes (cells of the
intestinal walls). As a result, there is a reduced net glucose uptake and
increased lactic acid delivery to the liver. Metformin thus increases glucose
utilization by the gut.
Metabolism and Excretion:
Unlike other drugs, metformin is not metabolized by liver or plasma
enzymes and is excreted unchanged. It is absorbed from the intestines into
the circulation. Blood carries it to the liver where it mainly acts and is then
excreted from the body via kidneys. Kidneys move metformin from the
blood into the urine and it is then removed from the body, along with the
urine.
Drug forms and combinations:
Metformin is available in both immediate release and extended release
forms as oral tablets.
Glucophage is the most common trade name for Immediate release form.
Extended release form of metformin has the advantages of improving GI
tolerability and allows once-daily dosing. It is currently available in multiple
branded and generic formulations; however, it is more expensive than
immediate-release metformin.
Metformin is often used in combination with other diabetes drugs such as
sulfonylureas, glipizide and glimepiride etc.
Therapeutic Uses:
As mentioned earlier, Metformin is a drug of choice in the treatment and
prevention of type 2 diabetes, also called maturity onset diabetes. It can be
used alone or in combination with other anti-hyperglycemic drugs. The use
of this drug is based on more than 20 years of clinical experience. It is
preferred over other drugs because of its minimal side effects, tendency to
weight reduction and almost absence of hypoglycemia. It only lowers
glucose to the normal limits of the body. Because of weight reduction
tendency, it is preferably used in obese people.
In addition to use in diabetes, Metformin is known to have other
beneficial uses. Studies confirm that metformin has antitumor and antiaging
effects. It is also known to have cardiovascular protective and
neuroprotective effects. Its use in polycystic ovary syndrome is also proven.
Side Effects:
Metformin does not have any significant side effects that might be harmful or
fatal. Common side effects include nausea, vomiting and diarrhea. It may also
cause stomach upset and metallic taste in mouth.
Stomach symptoms may occur immediately after the drug is taken or after
few days. If the stomach symptoms occur after the first days of your
treatment, they may be the signs of lactic acidosis.

Metformin does not usually cause low blood glucose levels (hypoglycemia).
It may occur when this drug is prescribed with other diabetes medications.
Symptoms of low blood glucose include sudden sweating, fast heartbeat,
blurred vision, dizziness or tingling hands/feet.

Overdose:

Metformin overdose is not very common but is a serious condition.

Metformin toxicity is associated with development of severe lactic acidosis.
Signs of lactic acidosis include exhaustion or fatigue, muscle cramps or
pain, general body weakness, overall feelings of discomfort, abdominal
pain, diarrhea and headache.
Metformin does not cause insulin release from the pancreatic beta-islet
cells, exposures can infrequently induce disorders of glucose metabolism
such as hypoglycemia and hyperglycemia. Hypoglycemia is much more
commonly seen than hyperglycemia; hypoglycemia is usually associated
with the use of other anti-diabetic medications such as the sulfonylureas.
If hyperglycemia appears, it is a marker of severe toxicity in cases of
metformin poisoning. It may be associated with the patient’s underlying
diabetes or the development of pancreatitis.

Contraindications:

Metformin, favorite drug prescribed in type 2 diabetes, is contraindicated in

some conditions.

Because of the potential risk of causing lactic acidosis, it is contra indicated in

patients who are already having increased level of lactate in their blood due to
some other conditions. Metformin use in this condition can worsen the
symptoms. Its use is contraindicated in acute and chronic metabolic acidosis.

Metformin use is contraindicated in patients of acute myocardial infraction and

congestive cardiac failure that requires drug treatment.
It is contraindicated in case of radiological studies involving iodine.

It should not be given prior to surgical interventions.

As stated earlier, metformin is not metabolized in the body and is solely

excreted via kidneys. Its use is contraindicated in patients having kidney
problems such as renal failure, renal dysfunction and nephritis.

Its use is prohibited in alcoholic patients, a detailed account of which is given

under the subsequent heading.

Drug Interactions:

Drug interaction is defined as an interaction between one or more co-

administered drugs that results in the alteration of the effectiveness or
toxicity of any of the drugs.

Metformin has a number of important drug interactions and can interact

with several other medications. Some drugs can interfere with how well
metformin works, while others can cause increased side effects.

Certain diabetes drugs are used with metformin to decrease blood sugar
levels. Combination of metformin and other diabetes drugs has been
proved more effective in the treatment of diabetes than metformin alone.
However, this combination can sometimes result in severe hypoglycemia
especially early morning hypoglycemia in which the patient wakes up early
with severe sweating, flushing and tingling of hands and feet.

Diuretics are used to lower blood pressure. Taking these drugs with
metformin may interfere with the effectiveness of metformin because they
themselves can increase blood sugar levels.
Nifedipine, a calcium channel blocker used to lower blood pressure, can
increase the amount of metformin in your body. This increases the risk of
side effects from metformin.

Use of metformin with cimetidine, an antihistamine drug used to treat

heartburn and other stomach issues, is associated with increased risk of
lactic acidosis.

Using metformin with certain hormone drugs such as estrogen,

progesterone or corticosteroids may decrease the efficacy of metformin.

Use of isoniazid (a drug used in TB) with metformin may make metformin
less effective.

Use of metformin with certain thyroid drugs such as levothyroxine,

liothyronine, liotrix can make metformin less effective in lowering your blood
sugar.

Metformin and Alcohol Use:

Metformin use can result in buildup of lactic acid in the body. The entire
mechanism of this is explained under the heading mechanism of action.
Alcohol use in patients who are on metformin can cause excessive lactic acid
in the blood. Alcohol prevents lactic acid removal in the urine and thus can
cause serious side effects.

Metformin decreases gluconeogenesis by decreasing ATP production in the

liver cells. As we all know, alcohol use puts stress on the liver. Due to
decreased ATP availability in liver patients who are already on metformin,
stress due to excessive alcohol intake can cause liver injury in such patients.

Studies have also shown that the use of alcohol in diabetes can cause severe
imbalance in blood sugar levels. So, the diabetic patients who are on
metformin are advised not to drink alcohol.

Metformin in Pregnancy and Lactation:

It has been shown that pregnancy may alter the function of drug-
metabolizing enzymes and drug transporters. The activities of several
hepatic cytochrome P450 enzymes are increased, whereas the activity of
some others may be decreased. The activities of some renal transporters
increase during pregnancy.

The pharmacokinetics (the way body handles the drug) of metformin is also
affected by pregnancy, which is related to the changes in renal filtration and
net tubular transport. Studies have shown that at the time of delivery, the
baby is exposed to variable concentrations of metformin from negligible to
as high as maternal concentrations.
However, baby exposure to metformin through the breast milk is low. It is
not present in the breast milk inn significant amounts.
Metformin appears to be effective and safe for the treatment of gestational
diabetes mellitus (diabetes that occur in a pregnant lady).
It has been suggested that metformin is safe for use during pregnancy.
However, as metformin can cross placenta, its use during pregnancy may
cause potential adverse effects on the mother and the fetus.
The use of metformin throughout pregnancy in women with polycystic ovary
syndrome has been shown to decrease the rates of early pregnancy loss
and preterm labor; hence protecting against fetal growth restriction.
Benefits of Metformin over other drugs:
Several drugs are available for the treatment of diabetes mellitus type 2.
There are several reasons why doctors prefer metformin over other drugs.
Some of them are discussed under this section.
First of all, it has been used clinically for several years in the management
of type 2 diabetes.
Contrary to other drugs, metformin is not known to cause any harmful or
lethal side effects.
Metformin is cost effective and patients can purchase it easily without
causing much burden on the budget.
It is a ‘euglycemic’ drug, meaning that it does not decrease blood glucose
level below normal and thus is very unlikely to cause symptoms such as
excessive sweating, flushing and tingling.
Other drugs used in diabetes such as sulfonylureas are very common in
causing these hypoglycemic symptoms. Sulfonylureas can cause severe
toxicity when accidently taken in high doses, however, metformin is devoid
of such severe toxicity.
Other drugs are not safe for use in case the patient is taking antibacterial or
antiviral agents, but metformin is safe even with these drugs.
Metformin is a drug which not only decreases blood glucose levels, but also
increases insulin sensitivity of liver and muscle cells. It is an important plus
point of using metformin instead of other drugs.
Metformin is not metabolized by liver. Thus, it is also safe for use in people
suffering from liver pathologies.
Conclusion:
Metformin is a very effective drug for the treatment of type 2 diabetes. It
has minimal side effects and can be used in all the diabetes patients. It is
also safe for use in pregnancy and lactation as it has no teratogenic effects.
However, it can cause adverse reactions if used in an alcoholic patient.

You must not start the drug on your own whether you have diabetes or not.
Always visit your doctor before starting the drug. A doctor has a better
understanding of how a drug works and interacts with patient’s body. He
knows the past medical history of the patient, is aware of the drugs he is
already taking, his allergies, any drug addiction and other personal history.
Based on this information, a doctor can decide which anti-diabetes drug will
be best for you.

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