Metformin

 
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What is/are Metformin?

Metformin (BP, pronounced /mɛtˈfɔrmɨn/, met-FAWR-min; originally sold as Glucophage) is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns. It is also used in the treatment of polycystic ovary syndrome, and has been investigated for other diseases where insulin resistance may be an important factor. Metformin works by suppressing glucose production by the liver.

Metformin is the only antidiabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes. It helps reduce LDL cholesterol and triglyceride levels, and is not associated with weight gain. As of 2010, metformin is one of only two oral antidiabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide).

When prescribed appropriately, metformin causes few adverse effects (the most common is gastrointestinal upset) and is associated with a low risk of hypoglycemia. Lactic acidosis (a buildup of lactate in the blood) can be a serious concern in overdose and when it is prescribed to people with contraindications, but otherwise, there is no significant risk.

First synthesized and found to reduce blood sugar in the 1920s, metformin was forgotten for the next two decades as research shifted to insulin and other antidiabetic drugs. Interest in metformin was rekindled in the late 1940s after several reports that it could reduce blood sugar levels in people, and in 1957, French physician Jean Sterne published the first clinical trial of metformin as a treatment for diabetes. It was introduced to the United Kingdom in 1958, Canada in 1972, and the United States in 1995. Metformin is now believed to be the most widely prescribed antidiabetic drug in the world; in the United States alone, more than 48 million prescriptions were filled in 2010 for its generic formulations.

Medical uses

Metformin is primarily used for type 2 diabetes, but is increasingly being used in polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD) and premature puberty, three other diseases that feature insulin resistance; these indications are still considered experimental. The benefit of metformin in NAFLD has not been extensively studied and may be only temporary; although some randomized controlled trials have found significant improvement with its use, the evidence is still insufficient.

Type 2 diabetes

The main use for metformin is in the treatment of diabetes mellitus type 2, especially in overweight people. In this group, over 10 years of treatment, metformin reduced diabetes complications and overall mortality by about 30% when compared with insulin and sulfonylureas (glibenclamide and chlorpropamide) and by about 40% when compared with the group only given dietary advice. This difference held in people who were followed up for five to 10 years after the study. Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight people with diabetes, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in this group. In addition, metformin had no effect on body weight: Over the 10-year treatment period, the metformin group gained about 1 kg, the same as the dietary advice group, while the sulfonylureas group gained 3 kg, and the insulin group, 6 kg. As metformin affords a similar level of blood sugar control to insulin and sulfonylureas, it appears to decrease mortality primarily through decreasing heart attacks, strokes and other cardiovascular complications.

Metformin has a lower risk of hypoglycemia than the sulfonylureas, although it has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose.Metformin is also not associated with weight gain, and modestly reduces LDL and triglyceride levels.

 

Prediabetes

Metformin treatment of people at risk for type 2 diabetes may decrease their chances of developing the disease, although intensive physical exercise and dieting work significantly better for this purpose. In a large U.S. study known as the Diabetes Prevention Program, participants were divided into groups and given either placebo, metformin, or lifestyle intervention, and followed for an average of three years. The intensive program of lifestyle modifications included a 16-lesson training on dieting and exercise followed by monthly individualized sessions with the goals to decrease the body weight by 7% and engage in a physical activity for at least 150 minutes per week. The incidence of diabetes was 58% lower in the lifestyle group and 31% lower in those given metformin. Among younger people with a higher body mass index, lifestyle modification was no more effective than metformin, and for older individuals with a lower body mass index, metformin was no better than placebo in preventing diabetes. After ten years, the incidence of diabetes was 34% lower in the group of participants given diet and exercise and 18% lower in those given metformin. It is unclear whether metformin slowed down the progression of prediabetes to diabetes (true preventive effect), or the decrease of diabetes in the treated population was simply due to its glucose-lowering action (treatment effect).

Adverse effects

The most common adverse effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea, vomiting and increased flatulence; metformin is more commonly associated with gastrointestinal side effects than most other antidiabetic drugs.The most serious potential side effect of metformin use is lactic acidosis; this complication is very rare, and the vast majority of these cases seem to be related to comorbid conditions, such as impaired liver or kidney function, rather than to the metformin itself.

Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism, and, in men, testosterone. The clinical significance of these changes is still unknown.

Gastrointestinal

In a clinical trial of 286 subjects, 53.2% of the 141 given immediate-release 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; 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 and prolonged use are associated with increased incidence of vitamin B12 deficiency, and some researchers recommend screening or prevention strategies.

Lactic acidosis

The most serious potential adverse effect of biguanide use is lactic acidosis, the incidence for which is 9 per 100,000 person-years. Phenformin, another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis (rate of 40-64 per 100,000 patient-years) However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication as long as it is not prescribed to known high-risk groups.

Lactate uptake by the liver is diminished with metformin administration because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. In healthy individuals, this slight excess is simply cleared by other mechanisms (including uptake by the kidneys, when their function is unimpaired), and no significant elevation in blood levels of lactate occurs. When there is impaired renal function, however, clearance of metformin and lactate is reduced, leading to increased levels of both, and possibly causing lactic acidosis due to a buildup of lactic acid. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication to its use. Common causes of increased lactic acid production include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate oxygenation of tissues); the most common cause of impaired lactic acid excretion is kidney disease.

Metformin has also been suggested to increase production of lactate in the small intestine; this could potentially contribute to lactic acidosis in those with risk factors. However, the clinical significance of this is unknown, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production.

Mechanism of action

Metformin declines hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis). The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third. Metformin activates AMP-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats; activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Research published in 2008 further elucidated metformin's mechanism of action, showing activation of AMPK is required for an increase in the expression of SHP, which in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase. Metformin is frequently used in research along with AICAR as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, research suggests that metformin increases the amount of cytosolic AMP (as opposed to a change in total AMP or total AMP/ATP). Metformin and other biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by phosphorylating GLUT-4 enhancer factor), increases fatty acid oxidation, and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. The increase in insulin binding after metformin treatment has also been demonstrated in patients with NIDDM  AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; a 2008 study found "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms."

This article uses material from the Wikipedia article Metformin, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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shayna is a member of the Pharmacy Reviewer forum
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Useful for treating PCOS too

I have polycystic ovarian syndrome or PCOS. This condition used to be treated with birth control pills and sometimes still is. However for personal reasons I did not want to use birth control pills. Unfortunately this was not a popular decision with multiple doctors who treated me which caused me to switch doctors several times. I finally found a doctor who shared my fleece and suggested that I try this medication for treatment instead of birth control pills. It took a couple of months before I was sure that I was seeing a difference, but I found this to be an effective treatment that was also in line with my personal beliefs. It does not address all symptoms of PCOS but it certainly helps.

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(Updated: February 02, 2014)
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