Metformin is a tableted hypoglycemic drug of the biguanide class for oral administration. This drug is used in the treatment of type 2 diabetes, especially in people who are overweight and obese, while maintaining normal kidney function. Studies are being conducted on the use of metformin in gestational diabetes and polycystic ovary syndrome. The drug has been investigated for other diseases in which insulin resistance may be an important factor.
With proper administration, metformin causes few side effects (among which gastrointestinal disorders are more frequent) and is associated with a low risk of hypoglycemia. Lactic acidosis (accumulation of lactic acid in the blood) can be a serious problem when overdosing and prescribing for people with contraindications, but otherwise there is no significant risk. Metformin helps to reduce the level of LDL cholesterol and triglycerides and does not cause an increase in body weight. One of the most significant effects of Metformin is a significant reduction in mortality from complications of cardiovascular diseases in diabetes mellitus. Included in the list of the most important drugs of the World Health Organization, along with another oral antidiabetic drug glibenclamide.
Metformin was first described in the scientific literature in 1922 by Emil Werner and James Bell as a product in the synthesis of N, N-dimethylguanidine. In 1929, Slott and Chesche discovered its hypoglycemic effect in rabbits, noting that he was the strongest of the biguanides they studied. These results were forgotten, as well as work on other analogues of guanidine, such as syntalin, amid the popularity of insulin.
Interest in metformin, however, returned in the late 1940s. In 1950, it was found that metformin, unlike some other similar compounds, does not reduce blood pressure and heart rate in animals. In the same year, the Philippine doctor Eusebio Garcia used metformin (who called fluamin) to treat the flu. He noted that the drug "lowers blood sugar to a minimum physiological level" in the treatment of patients and was non-toxic. Garcia also believed that metformin has bacteriostatic, antiviral, antimalarial, antipyretic, and analgesic effects. In a series of articles in 1954, Polish pharmacologist Janusz Supnevsky could not confirm most of these effects, including a decrease in blood sugar levels, but observed some antiviral effects in humans.
At the Salpêtrière hospital, French diabetologist Jean Stern studied the glucose-lowering properties of galegin (an alkaloid isolated from the pharmacy goat's rag) structurally related to metformin and observed its short-term use as an antidiabetic agent before the synthalins were developed. Later, working in the laboratories of Aron in Paris, he re-examined the sugar-lowering activity of metformin and several similar biguanides. Stern was the first to try metformin for the treatment of diabetes in humans; he came up with the name Glucophage (eng. "Glucophage" - "glucose eater") for this drug and published his results in 1957.
Metformin became available in the British National Formulary in 1958 and began to be sold in Great Britain for the first time.
Broad interest in metformin was revived only after the withdrawal from the drug circulation of other biguanides in the 1970s. Metformin was approved in Canada in 1972, and in the USA it was approved by the FDA for the treatment of type 2 diabetes only in 1994. Produced under license from Bristol-Myers Squibb, Glucophagus was the first trade name for Metformin to be sold in the United States since March 3, 1995. Generics are now available in several countries, and metformin is believed to have become the most commonly prescribed antidiabetic drug in the world.
Receipt and properties of matter
Standard metformin synthesis was first described in 1922. It is formed during the reaction of dimethylamine hydrochloride with 2-cyanoguanidine (dicyandiamide) when heated.
In accordance with the procedure described in 1975 in the Aron patent and the Encyclopedia of Pharmaceutical Production (Pharmaceutical Manufacturing Encyclopedia), an equimolar amount of dimethylamine and 2-cyanooguanidine is dissolved in toluene with cooling to achieve a concentrated solution, and then an equimolar amount of hydrogen chloride is slowly added. The mixture begins to boil by itself, and after cooling a precipitate of metformin hydrochloride is formed in 96% yield.
Until 2005, scientists mistakenly assumed that metformin was in protonated tautomeric form. The energy difference between the correct tautomer and the previously represented was about 9 kcal / mol. The drug is used as metformin hydrochloride. The structure of the latter was also clarified.
A recent publication describes an improved (environmentally friendly, using only a few milligrams of reagents and a few drops of solvent) method for the synthesis of metformin, which involves a five-minute reaction in microwave waves.
Metformin reduces the concentration of glucose in the blood by inhibiting the formation of glucose (gluconeogenesis) in the liver. A patient with type 2 diabetes mellitus has a gluconeogenesis rate of 3 times higher than normal. Metformin reduces this by more than one-third. Metformin activates AMP-activated protein kinase (AMPK) - a liver enzyme that plays an important role in insulin signaling, throughout the body's energy balance and in the metabolism of glucose and fat. Activation of AMPA is necessary for the inhibitory effect of metformin on gluconeogenesis in the liver. In a study published in 2008, the mechanism of action of metformin was described in more detail. It showed that activation of AMPK is necessary to increase the expression of the protein SHP (eng. Small heterodimer partner), which in turn suppresses the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, which are involved in gluconeogenesis. Metformin is often used in AICA (English aminoimidazole carboxamide) ribonucleotide as an AMPA agonist. The mechanism by which biguanides activate AMPK remains unclear, but research shows that metformin increases the amount of cytosolic AMP.
It has been shown that metformin has a moderate inhibitory effect of respiratory complex I; Apparently, this property of the drug underlies the mechanism of its action.
In addition to suppressing gluconeogenesis in the liver, metformin increases tissue sensitivity to insulin, increases peripheral glucose uptake (by phosphorylation of the GLUT4 transporter), increases fatty acid oxidation, and decreases glucose absorption from the gastrointestinal tract. The increase in peripheral glucose utilization may be associated with improved insulin binding to insulin receptors. AMPA probably also plays a role in this, since the administration of metformin increases the activity of AMPA in skeletal muscle. AMPA is known to cause embedding of GLUT4 into the plasma membrane, with the result that insulin-independent absorption of glucose occurs. Some metabolic effects of metformin appear to occur by AMPK-independent mechanisms; A study in 2008 showed that "the metabolic effects of metformin in the heart muscle can occur independently of changes in AMPK activity and can be mediated by p38 MAPK (English p38 mitogen-activated protein kinases) and PKC-dependent mechanisms."
The drug reduces the serum concentration of TG, cholesterol and LDL (determined on an empty stomach) and does not alter the concentration of lipoproteins of other densities. Stabilizes or reduces body weight. In the absence of insulin in the blood, the therapeutic effect does not appear. Hypoglycemic reactions does not cause. It improves blood fibrinolytic properties by suppressing tissue-type inhibitor of plasminogen activator profibrinolysin (plasminogen).
With the help of metformin therapy, it is possible to reduce the level of glucose by 20%, and the glycosylated hemoglobin content by 1.5%. Monotherapy with metformin compared with other means to reduce the concentration of glucose in the blood (pioglitazone, acarbose, sulfonylurea drugs), as well as compared with diet, insulin or placebo reduces the risk of myocardial infarction, and also reduces the overall mortality in a population of people with diabetes second type (“insulin-dependent”), which was demonstrated in a systematic review of 29 clinical studies published in the Cochrane Collaboration library in 2005 (source dokta.ru, section on metformin).
Absolute bioavailability (on an empty stomach) is 50-60%, ingestion with food reduces Cmax by 40% and slows its achievement by 35 minutes. The peak concentration in plasma (C max) is reached within one to three hours (1.81-2.69 hours) with immediate release of metformin and from four to eight hours with a sustained release form. The binding of metformin to plasma proteins is insignificant, as evidenced by the very high volume of distribution (654 ± 358 l after a single dose of 850 mg). A stable effect is usually achieved in one or two days.
Metformin is not metabolized. It is excreted in the urine unchanged by tubular secretion; Metformin is not detected in the blood plasma for 24 hours after a single dose. The average half-life in plasma is 6.2 hours (the initial T1 / 2 is from 1.7 to 3 hours, the final is from 9 to 17 hours). Metformin is distributed (and possibly accumulated) in erythrocytes with a much longer half-life: 17.6 hours (values within 18.5-31.5 hours are reported in a single-dose study of people who do not have diabetes).
Absorption - 48-52%. Rapidly absorbed in the gastrointestinal tract. Plasma concentration does not exceed 1 µg / ml (within 24-48 hours).
Unique properties and new uses of Metformin
Metformin is being researched in many countries: the Internet is replete with reports of its newly discovered unique properties. So, what are the uses of metformin and cautions today?
- Metformin prevents and controls type 2 diabetes.
- Metformin does not reduce sugar immediately after taking the first dose. Its action begins after 2.5 hours. Decrease in blood glucose occurs in a few days - from 7 to 14 days.
- Does not cause hypoglycemia in therapeutic doses, with an overdose - extremely rare.
- Metformin can be combined with insulin, mannil, etc.
- Dr. R. Bernstein (USA) claims that metformin reduces the risk of cancer and also suppresses the hunger hormone, thereby helping to stabilize the weight.
- According to research by Craig Kerry, metformin can be successfully used in complex treatment of oncology and cardiovascular diseases.
- Metformin promotes the growth of new neurons in the brain and spinal cord.
- In Alzheimer's disease, the number of nerve cells in the hippocampus, the part of the brain where new memories are formed, is significantly reduced. Experience shows that taking 1000 mg of metformin per day for people weighing 60 kg significantly improves the ability to create new memories.
- There is also an opposite opinion that metformin itself increases the risk of dementia. Taiwanese researchers led by Dr. Ichun Kuan conducted a study of 9,300 patients with type 2 diabetes, analyzing the effects of metformin on the control group of patients. Their conclusion: the longer the patient took Metformin and the higher the dose, the higher the likelihood of developing dementia. This opinion is questioned by many experts.
- Metformin suppresses systemic inflammation - one of the causes of aging, protects the heart and blood vessels from aging.
- The drug improves cholesterol, reducing low-density harmful cholesterol.
- Metformin reduces elevated levels of liver enzymes and can treat non-alcoholic fatty liver in patients with diabetes mellitus.
- Reduces the risk of mortality from a bunch of diabetic complications by about 30%.
- Metformin has no absolute contraindications for diseases of the kidneys, liver, chronic heart failure. If there are any, the doctor adjusts the dose, and the patient continues to take Metformin. However, the decision of the doctor in severe pathologies of the heart, liver and kidneys of the patient may not be in favor of taking this drug.
- Metformin is able to reduce the level of vitamin B12, so when it is used it is necessary to monitor blood counts.
- It is used in the absence of ovulation in patients with infertility.
- Metformin stabilizes weight when recruiting, caused by antipsychotic drugs.
- Can not be combined with alcohol in order to avoid complications such as lactic acidosis (a deadly complication).
- Metformin is a candidate for becoming a cure for old age.
- It is being studied as a potential drug for the possible treatment of rheumatoid arthritis in patients with type 2 diabetes.
From this list, new uses of metformin (except for type 2 diabetes), which have been investigated by scientists, are highlighted. For the sake of justice, it must be said that many of these new indications for use disproved the work of other researchers. So, experts are still arguing - reduces the weight of metformin or not. Some studies indicate successful stimulation of ovulation with metformin, while others tell about the minor effects of the drug on the reproductive system.
Therefore, it is impossible to take this drug as an absolutely healthy remedy for aging and from aging, even though the media advertise metformin as an old drug that is ready to become a new “rejuvenating apple.” Metformin has its own list of indications, which in our country (as well as all over the world) mainly consists in the treatment of type 2 diabetes.