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Metformin in Diabetes: Uses, Side Effects

Metformin in Diabetes: Uses, Side Effects

metformin and alcohol

Everyone must be familiar with diabetes nowadays. 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 the UK are diagnosed with diabetes. It is estimated that around 5.4 million people in the 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 a much earlier onset and requires permanent insulin therapy. Type 2 diabetes is an 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 the 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 to 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 (the 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 insulin-responsive genes and thus increase insulin receptors sensitivity. These receptors also increase induction of various enzymes including lipoprotein lipase (an enzyme that removes lipids from the blood).

Metformin not only acts on the liver but also on the intestines. Several types of research 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. The 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, the 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 the mouth. Stomach symptoms may occur immediately after the drug is taken or after a 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 the 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, a favorite drug prescribed in type 2 diabetes, is contraindicated in some conditions.

Because of the potential risk of causing lactic acidosis, it is contraindicated in patients who are already having an 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 inadvisable in patients of acute heart attack 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 coadministered 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 the 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 a 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 the body handles the drug) of metformin is also affected by a pregnancy, which is related to the changes in the 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 breast milk is low. It is not present in breast milk in significant amounts.

Metformin appears to be effective and safe for the treatment of gestational diabetes mellitus (diabetes that occurs in a pregnant lady).

It has been suggested that metformin is safe for use during pregnancy. However, as metformin can cross the 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 in 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 accidentally 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 the 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 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 the 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 histories. Based on this information, a doctor can decide which anti-diabetes drug will be best for you

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I am Sohaib Asghar, a medical student from King Edward Medical University, Lahore. The facts stated by me are all authentic and are based on various research articles. Be confident, because the information you get from my articles is 100% true.

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