Metformin. Metformin (Metformin) What group of drugs does Metformin belong to?

Catad_tema Type II diabetes mellitus - articles

The place of metformin in the modern treatment and prevention of type 2 diabetes mellitus

Smirnova O.M.
Federal State Institution Endocrinological Research Center, Moscow (Director - Academician of the Russian Academy of Sciences and Russian Academy of Medical Sciences I.I. Dedov) Metformin is the main antihyperglycemic drug in the treatment of type 2 diabetes mellitus. An analysis of the mechanism of its action is given. Cardioprotective and anti-oncological properties are described. Data from multicenter studies using metformin are presented.
Keywords: type 2 diabetes mellitus, metformin, lactic acidosis, chronic heart failure, anti-oncogenic effect

The role of metformin in the modern strategy of treatment and prevention of type 2 diabetes mellitus

O.M.Smirnova
Endocrinological Research Center Metformin is a major antihyperglycemic agent used for the treatment of DM2. Analysis of the mechanism of its action is presented. Cardioprotective and anticancer activities of metformin are discussed. The results of multicentre studies of metformin are described.
key words: type 2 diabetes mellitus, metformin, lactacidosis, chronic cardiac failure, antioncogenic activity

Biguanides have been used in medical practice for over 50 years. Professor Lefebvre P. writes that today we can treat but not cure diabetes mellitus (DM). Type 2 diabetes (DM2) is the main form of the disease. According to WHO forecasts, by 2025 the number of patients suffering from diabetes will exceed 380 million people. Leading medical organizations today recommend starting treatment for type 2 diabetes with a combination of lifestyle changes and metformin. In this regard, new results concerning the newly discovered properties of metformin are of particular interest.

Metformin was introduced into clinical practice for the treatment of T2DM in 1957 in Europe and in 1995 in the USA. Metformin is currently the most commonly prescribed oral antihyperglycemic drug in Europe, the US and other countries. The mechanism of the antihyperglycemic action of metformin is well understood. Numerous studies have found that metformin does not affect insulin secretion by the β-cell, but has an extrapancreatic effect. It calls:

• decreased absorption of carbohydrates in the intestine;
• increased conversion of glucose to lactate in the gastrointestinal tract;
• increased binding of insulin to receptors;
• expression of the GLUT 1 transporter gene (secretion);
• increased transport of glucose across the membrane in muscles;
• movement (translocation) of GLUT 1 and GLUT 4 from the plasma membrane to the surface membrane in the muscles;
• decreased gluconeogenesis;
• decreased glycogenolysis;
• lowering the level of triglycerides (TG) and low density lipoproteins (LDL);
• an increase in the content of high-density lipoproteins (HDL) (Fig. 1).

Rice. 1. Antihyperglycemic action of metformin

The main mechanism of action of metformin is aimed at overcoming the resistance of peripheral tissues to the action of insulin, especially in muscle and liver tissue (Table 1).

Table 1
Potential clinical mechanisms of action of metformin in relation to its antihyperglycemic action (IW Campbell, P Ritz, 2007) [3]

Metformin increases plasma membrane fluidity in humans. The physiological functions of the plasma membrane depend on the ability of their protein components to move freely within the phospholipid bilayer. A decrease in membrane fluidity (increased rigidity or viscosity) is often observed in experimental and clinical diabetes, which leads to the development of complications. Small changes in the properties of erythrocytes were noted in individuals who previously received metformin. The schematic effect of metformin on membranes and their components is shown in Figure 2.

Rice. 2. Effect of metformin on the plasma membrane and its components

A number of clinical studies with different designs have been published, confirming the effect of metformin on hepatic glucose metabolism. The results of a double-blind, randomized cross-over study are presented in Figure 3.

Rice. 3. Effect of metformin and placebo on glycemia and selected parameters of glucose metabolism in patients with newly diagnosed type 2 diabetes mellitus (double-blind, randomized, cross-over study)

In this study, a significant difference between groups was obtained, proving the suppression of glucose production by the liver when metformin was added.

In another double-blind, randomized trial comparing hepatic glucose production with metformin and rosiglitazone in controlled hyperinsulinemia, metformin significantly suppressed hepatic glucose production compared to rosiglitazone (Fig. 4) .

Rice. 4. Suppression of hepatic glucose production by metformin in controlled hyperinsulinemia (double-blind, randomized trial)

The clinical effects of metformin, in addition to its antihyperglycemic properties, are fairly well understood. They were first presented after the completion of the long-term study UKPDS (United Kingdom Prospective Diabetes Study) in 1998, which showed that metformin therapy in obese individuals reduces the risk of complications:

• vascular complications - 32%;
• mortality from diabetes - 42%;
• overall mortality - 36%;
• myocardial infarction - 39%.

These data were so convincing that metformin was fully rehabilitated as a safe and useful antidiabetic drug.

Subsequently, numerous cardioprotective properties of metformin were proven (Table 2).

It is believed that it is the presence of these properties that explains the additional positive and preventive effect of metformin in T2DM.

table 2
Cardioprotective properties of metformin

The main conclusions of the studies of the last decade

Glucophage (metformin) has direct angioprotective properties that do not depend on the hypoglycemic effect of the drug. These effects are unique.

The dual action of Glucophage explains the mortality reduction results reported by the UKPDS.

The data obtained in subsequent years confirmed the positive effect of metformin in a number of studies. Thus, treatment with metformin compared with any other treatment was associated with lower all-cause mortality, myocardial infarction, symptoms of angina pectoris, or any event of cardiovascular manifestation compared with individuals receiving other treatment (Fig. 5).

Rice. 5. Outcomes of cardiovascular disease during 3 years of follow-up

One of the topical sections of discussions about the effectiveness of modern trends in the treatment of type 2 diabetes is the safety of both individual hypoglycemic drugs and their combinations. Different treatment regimens were considered, one of which was the consensus algorithm of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), presented in Figure 6.

Rice. 6. ADA/EASD Consensus Algorithm

In the figure below, we can see that metformin is present in all therapies. In this regard, it is advisable to consider the issue of indications and contraindications for the use of metformin, based on the available modern data.

First, it is necessary to answer the question, why should metformin treatment be started right from the moment of diagnosis, along with lifestyle changes? Because for the majority of people with T2DM, lifestyle interventions do not achieve or maintain target glycemic levels, which may be due to the following factors:

• ineffectiveness of measures to reduce body weight;
• re-gaining body weight;
• disease progression;
• a combination of these factors.

In addition to the fact that some patients have intolerance to the drug (according to different authors - from 10 to 20%), there are clear contraindications to the appointment of metformin.

Contraindications to taking Metformin

• Acute or chronic diseases that can cause tissue hypoxia (for example, heart or lung failure, myocardial infarction, shock).
• Liver failure, acute alcohol intoxication, alcoholism.
• Renal failure or impaired renal function (creatinine clearance) Acute conditions that may impair kidney function (dehydration, acute infection, shock, intravascular administration of radiopaque agents).
• Lactation, diabetic ketoacidosis, diabetic precoma, hypersensitivity to metformin or its components (Table 3).

Table 3
Special instructions for taking Metformin

The frequency of contraindications to the appointment of metformin, according to different authors, differs significantly. So, according to the data presented in Figure 7, chronic heart failure (CHF) is 87%.

One of the main reasons for concern when prescribing metformin is the risk of developing lactic acidosis in the presence of any conditions accompanied by hypoxia. Lactic acidosis is a very rare but potentially fatal complication. Its frequency is, according to different authors, 3 cases per 100,000 patient-years treated with metformin.

Lactic acidosis is clinically very dangerous. A study by Stacpool P.W. et al. , was performed by examining and treating 126 patients admitted to the intensive care unit who had a lactate level ≥5 mmol/l, an arterial blood pH ≥7.35, or a base deficiency >6 mmol/l. During hospitalization, circulatory shock was diagnosed in 80% of these patients. Sepsis, liver failure and respiratory diseases were the main factors leading to the development of lactic acidosis. Survival was 59% at 24 hours, 41% at 3 days, and 17% at 30 days.

Cases of lactic acidosis associated with the intake of biguanides have been studied in detail. It has been reliably established that the risk of developing lactic acidosis when prescribing Phenformin is 20 times higher than that when using Metformin. For this reason, the use of Phenformin is prohibited in most countries of the world, including Russia. In order to prevent this formidable complication, it is necessary to carefully examine patients before prescribing the drug (see above).

Still important and actively discussed is the question of the possibility of using metformin in chronic heart failure (CHF). To date, quite a lot of experience has been accumulated, indicating the benefits of using metformin in the treatment of patients with DM2 and CHF. One of these studies is the work. The aim of the study was to evaluate the relationship between metformin intake and clinical outcomes in patients with CHF and T2DM. With the help of health databases (Canada), 12,272 patients with type 2 diabetes who received hypoglycemic drugs from 1991 to 1996 were examined. Among them, 1,833 patients with CHF were identified. Monotherapy with metformin was received by 208, sulfonylurea derivatives (SM) - 773 and combination therapy - 852 people. The mean age of the patients was 72 years. There were 57% of men, the average duration of observation was 2.5 years. CHF was first diagnosed during hospitalization, that is, at the beginning of the study. The follow-up period was 9 years (1991-1999). Lethal outcomes among persons who received: SM - 404 (52%), metformin - 69 (33%), combined therapy - 263 cases (31%). Mortality from all causes after 1 year was 200 people in people who received SM. (26%), in persons treated with metformin - 29 people. (14%), on combination therapy - 97 (11%). It was concluded that metformin, both as monotherapy and as part of combination therapy, is associated with lower mortality and morbidity in patients with CHF and T2DM compared with SM.

The 2010 British Study included 8,404 patients with new-onset T2DM and new-onset heart failure (1988 to 2007). A comparative analysis of the causes of death was carried out in two groups (1,633 deaths in each). The results concluded that, when comparing people who did not receive antidiabetic drugs, the use of metformin was associated with a lower risk of mortality compared with other antidiabetic drugs, including even potentially adverse factors such as poor glycemic control, decreased kidney function, overweight and arterial hypertension. These data are consistent with previous work, which showed that people with CHF using metformin had a lower risk of death than people using other antidiabetic drugs.

Another important and very promising direction in the study of the properties of metformin is its anti-oncogenic effect. A number of clinical studies have been published that have shown a reduction in the growth of cancer among patients using metformin. One is a population-based retrospective cohort study using the Saskatchewan, Canada 1995–2006 database. The aim of the study was to study cancer mortality and the relationship with antidiabetic therapy in T2DM. We examined 10,309 patients with DM2 who were newly prescribed metformin, sulfonylurea derivatives (SM) and insulin. The mean age of the patients was 63.4±13.3 years, among them 55% were men. Metformin was prescribed to 1,229 patients as monotherapy, SM - to 3,340 patients as monotherapy, combination therapy - to 5,740, 1,443 patients added insulin. The follow-up period was 5.4±1.9 years.

Overall, cancer mortality was 4.9% (162 out of 3340) in those treated with SM, 3.5% (245 out of 6969) with metformin and 5.8% (84 out of 1443) with insulin. The data presented by Bowker demonstrate a two-fold increase in the incidence of cancer in the group of patients on insulin therapy relative to the metformin group 1.9 (95% CI 1.5-2.4, p<0,0001). В группе пациентов, находящихся на терапии препаратами СМ, риск возникновения раковых опухолей был также значительно выше показателей в группе метформина и составлял 1,3 (95% ДИ 1,1-1,6, p=0,012) .

Currie C.J. et al. also studied the risk of developing malignant tumors in patients with type 2 diabetes, depending on the type of therapy. The study included 62,809 patients with type 2 diabetes over 40 years of age, who were divided into four treatment groups: metformin monotherapy or SM, combination therapy with metformin and SM, and insulin therapy. The group of patients receiving insulin was divided into subclasses: insulin glargine monotherapy, NPH insulin, biphasic insulin. Data on the manifestation or progression during the treatment period (insulin therapy since 2000) of any malignant tumors were also evaluated; special attention was paid to cancer of the breast, colon, pancreas and prostate.

When analyzing the data obtained, it was found that in the group of patients receiving metformin, there was a significant reduction in the risk of developing colon and pancreatic cancer (however, a similar pattern was not observed for prostate and breast cancer). The reduction in the growth of malignant cells against the background of metformin monotherapy was 0.54 (95% CI 0.43-0.66). Even when metformin was added to any hypoglycemic therapy, the risk of malignancy was reduced to 0.54 (95% CI 0.43-0.66).

Results and conclusion

Metformin monotherapy was associated with the lowest risk of cancer. For comparison, the relative risk (RR) was:

• for metformin + SM - 1.08;
• for SM monotherapy - 1.36;
• when using insulin - 1.42;
• adding metformin to insulin - 0.54;
• compared with metformin, insulin therapy increased the risk of colorectal cancer (RR 1.69) and pancreatic cancer (RR 4.63);
• insulin therapy did not affect the risks of prostate and breast cancer.

One of the latest published studies is the ZODIAC-16 (Zwolle Outpatient Diabetes project Integrating Available Care) study completed in the Netherlands and published in 2010. The aim of the study was to investigate the association between specific treatment for type 2 diabetes and cancer mortality. In this case, we studied the association between metformin use and cancer mortality in a prospective cohort. The recruitment of patients was carried out from 1998 to 1999. 1,353 patients with T2DM were included. The study was completed in 2009. Characteristics of patients:

• on metformin - 289;
• without metformin – 1064;
• mean age 67.8±11.7 years;
• duration of diabetes – 6.0 years;
• body mass index (BMI) – 28.9±4.8 kg/m2;
• HbA1c - 7.5±1.2%;
• glomerular filtration rate (GFR) – 73.9±28.1 ml/min;
• insulin therapy - 16.5%;
• SM - 55.0%;
• diet (only) - 13.0%;
• those with active cancer, cognitive impairment, and very short life expectancy are excluded.

When assessed after 9.6 years, only 570 patients (42%) died. Of these, 122 (21%) died from cancer, among them 26 (21%) from lung cancer, 21 (17%) from abdominal cancer, 238 patients (41%) died from cardiovascular diseases. The causes of death of 541 (94%) patients are known. In patients treated with metformin, compared with patients not treated with metformin, the RR of cancer mortality was 0.43 (95% CL 0.230.80). The RR increased with an increase in the dose of metformin. For each gram of metformin added, the RR was 0.58 (0.95% CL 0.36-0.93).

It is worth mentioning that the appointment of metformin in polycystic ovary syndrome, characterized by insulin resistance (IR) and acting as a risk factor for the development of uterine cancer, also contributes to the leveling of possible atypical endometrial hyperplasia.

Of undoubted interest are the studies of Russian scientists, in which biguanides, along with lipid-lowering drugs and diet, were prescribed for a long period of time to more than 300 patients with breast and colon cancer undergoing surgical treatment. As a result, by 37 years of observation, an increase in cumulative survival was found, as well as a slight decrease in the frequency of detection of primary multiple tumors and metachronous tumors of the second mammary gland.

Antitumor effect of metformin

The apparent antitumor effect of metformin is most likely associated with the activation of cyclic adenosine monophosphate-dependent protein kinase (AMPK (AMP-activated protein kinase)), which controls glucose and lipid metabolism. AMPK activates the AMP/ATP pathway, which plays a key role in cellular energy balance by increasing ATP levels. AMPK activation in a healthy cell is caused by various metabolic processes, such as hypoxia, hypoglycemia, oxidative and hyperosmolar stress, which allows us to consider AMPK activation as an adaptive process that preserves energy reserves in the cell. AMPK is a heterotrimeric protein consisting in the absence of cAMP of catalytic α- and regulatory β- and γ-units (Fig. 8).

Rice. 8. AMPK activation scheme

It is known that many metabolic effects of metformin are carried out in the presence of AMPK, including inhibition of mTOR (mammalian target of rapamycin) with subsequent restoration of cell sensitivity to insulin and a decrease in hyperinsulinemia as a tumor development factor.

mTOR kinases belong to the phosphatidylinositol kinase (PIKK) family, their C-terminus is similar to the catalytic region of phosphatidylinositol-3-kinases (PI3K), and the N-terminus binds the FKBP12 (rapamycin) complex. Numerous works have shown that mTOR plays a key role in cell growth and cell energy metabolism. mTOR signaling consists of two branches, each of which contains a specific complex (mTORC1 or mTORC2). Rapamycin-responsive mTORC1 regulates several pathways that determine cell size. Rapamycin-insensitive mTORC2 regulates the functions of the actin skeleton, determining the shape. Both complexes integrate various signals for the regulation of cell growth, the main ones being: growth factors (insulin/IGF), energy status, amino acids and stress. In addition, mTOR regulates many aspects of cellular metabolism, including amino acid biosynthesis, glucose homeostasis, and fat metabolism, playing a significant role in adipogenesis and lipid storage. Thus, mTOR kinase combines cellular signals from growth factors, nutrition, and metabolic rate to regulate protein synthesis and cell growth.

The use of rapamycin, an mTOR inhibitor, and its derivatives in the treatment of certain cancers has shown a positive effect. In the course of the study among patients with prostate cancer, data were obtained on the presence of a strong antiproliferative effect of metformin. In this case, the effect of the drug was associated to a greater extent with the freezing of the cell cycle at the G0 \ G1 phase and the suppression of the level of cyclin D1, that is, with the inhibition of cell proliferation.

The activity of the AMPK enzyme is regulated by the LKB1 protein, which is important from a biochemical point of view and is known as a tumor growth suppressor. Loss of function contributes to the formation of benign hamartoma tumors and some types of lung and colon cancer. Most of these tumors are characterized by high levels of unregulated mTOR protein activity. The LKB1/AMPK mechanism provides a molecular link between DM and cancer. Metformin activates AMPK and affects LKB1-dependent tumorigenesis. Another anti-oncogenic effect of metformin is presumably based on CD8+ T-lymphocytes found in the study, which lacked tumor necrosis factor receptor-associated factor 6 (TRAF6) and were unable to generate memory T cells. This deficiency has been associated with a defect in fatty acid oxidation. Metformin restored both the metabolic defect and the generation of memory T cells.

One of the current directions in the study of the possibilities of other uses of metformin are works related to the possibility of treating non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease is a common chronic liver disease characterized by the abnormal accumulation of fatty droplets not associated with alcohol consumption. NAFLD is a component of the metabolic syndrome, type 2 diabetes, and obesity. NAFLD can be referred to in the literature by various names: non-alcoholic Laennec disease, fatty liver hepatitis, diabetic hepatitis, alcohol-like liver disease, non-alcoholic steatohepatitis.

Steatohepatitis is a stage in the development of non-alcoholic fatty liver disease.

The diagnosis of "NAFLD" is made on the basis of an asymptomatic increase in aminotransferase levels, the inexplicable existence of persistent hepatomegaly, which is confirmed by radiological examination, provided that all other causes leading to hepatomegaly are excluded (alcohol, drugs, lack of protein nutrition, poisonous mushrooms, organic solvents, etc.) .

The only reliable diagnostic criterion is a liver biopsy. It is the lack of available non-invasive diagnostic methods that explains the small number of works devoted to the study of the pathogenesis and effectiveness of NAFLD treatment. The diagnosis can be confirmed by the following laboratory data: an increase in the level of Aspartate aminotransferase (AST), an increase in the level of Alanine aminotransferase (ALT), an increase in enzymes by more than 4 times. ALT>AST; alkaline phosphatase increased by more than 2 times compared with the norm. The course of NAFLD can be benign or malignant. In the second case, there is an outcome in cirrhosis and liver failure or in hepatocellular carcinoma.

It has been established that target tissues for drugs that reduce the resistance of peripheral tissues to insulin are different. Thus, thiazolidinediones (TZD) act mainly at the level of muscle and adipose tissue, and metformin to a greater extent at the level of the liver (Fig. 9).

Rice. 9. Target tissues for metformin and thiazolidinediones

Therefore, it is advisable to use metformin in the first place for the treatment of NAFLD. The results of the use of metformin in a number of completed studies in patients without DM are presented in Table 4.

Table 4
Studies on the effectiveness of Metformin in patients with NAFLD

In conclusion, it is necessary to summarize the enormous work that has already been done and present the prospects that can be determined for metformin today (Table 5).

Table 5
Current and Future Uses of Metformin

In the near future, a new dosage form of metformin, Glucophage® Long, will appear in clinical practice in Russia (Fig. 10).

Rice. 10. Metformin slow release once daily. GelShield Diffusion System

This form of extended-release drug is designed to overcome side effects such as gastrointestinal dysfunction, simplify the regimen of the drug for the elderly, to increase compliance and maintain the effectiveness of the treatment. This drug has already been successfully used in European countries and is included as an initial therapy in the clinical recommendations of a number of countries. The drug has been tested in international multicenter studies and has proven its effectiveness and safety.

In conclusion, it should be emphasized that metformin is one of the oldest drugs, and many of its properties are well studied, but this drug rightfully occupies a leading position in the treatment of type 2 diabetes today. Clinical research is ongoing and many new beneficial properties may be discovered.

Literature

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For citation: Aleksandrov A.A. Metformin and cardiovascular complications of diabetes mellitus: "Reflections at the front door" // RMJ. 2008. No. 11. S. 1544

Currently, metformin is positioned as one of the main drugs of choice in the treatment of type 2 diabetes mellitus (DM). At least, this is the opinion of the authors of many articles based on the recommendations of the IFD and ADA. One gets the impression that metformin is a kind of "front door" of type 2 diabetes, through which it is recommended to go through almost every patient in the treatment of this disease.

It's not even that the hypoglycemic ability of metformin monotherapy is quite comparable with the effectiveness of other groups of hypoglycemic agents (Fig. 1). And, perhaps, not even that the combination of metformin with most other hypoglycemic drugs significantly expands the possibilities of achieving target levels of carbohydrate metabolism compensation in patients with type 2 diabetes mellitus.
It seems that the opinion about metformin as the drug of first choice is primarily based on data from the UKPDS study on the unique property of metformin (Glucophage®) for hypoglycemic drugs, to significantly reduce the incidence of myocardial infarction and cerebrovascular accidents in patients with type 2 diabetes mellitus (Table 2). 1).
Ideas about the unique cardio-so-su-di-with properties of metformin are especially impressive against the background of data on the special safety of the use of metformin. This is manifested, on the one hand, in the almost complete absence of dangerous hypoglycemia when using it, and on the other hand, in the fact that such a serious complication as lactic acidosis, which develops in a number of patients when taking drugs of the biguanide group, is extremely rare when using metformin. . All this irrefutably indicates the need for the widest possible introduction of this drug into the therapeutic practice of patients with type 2 diabetes mellitus.
However, medical practice every time confronts the doctor with an individual, specific patient. And therefore, when planning to use recommendations based on the experience of the conducted studies, every time you try to remember again in which patients such attractive results were obtained. And, of course, to compare the patient who now, today turned to you for help, with those patients from the cited study.
In fact, you are faced with the need to answer a few simple questions. First of all: does the use of metformin really lead to the desired results in all patients without exception? Will all those waiting in front of this “front door” receive the promised benefit? Or is it still not worth it for some of them to enter this “entrance”? Are there many? How to recognize them? And can we answer these questions now?
In the European guidelines for the treatment of diabetes mellitus, prediabetes and cardiovascular complications, published in January 2007, developed by a special joint group of the European Society of Cardiology and the European Society for the Study of Diabetes Mellitus, metformin is presented as the drug of first choice. with excess weight in patients with type 2 diabetes.
It is known that about 60-80% of patients with type 2 diabetes are overweight. This means that only in about 20% of diabetic patients, the use of metformin as the drug of first choice is not very justified. True, it is by no means contraindicated. Simply normal and even less weight in patients with type 2 diabetes often indicates that they already have a fairly pronounced insulin deficiency. In such patients, of course, it is more expedient to start therapy with the appointment of sulfonylurea drugs.
There is an opinion that additional indications for the use of metformin in patients with type 2 diabetes may be the presence of hyperinsulinemia or hyperlipidemia. So far, these are separate, private opinions that have not been reflected in official recommendations.
When prescribing metformin to overweight individuals, those who have serious contraindications to taking metformin should be excluded from their number. Here is how it is stated in the last European recommendations already mentioned: “Metformin is an important component of both mono- and combination therapy, provided that there are no contraindications for its use.”
The most serious contraindication to the use of metformin is the high risk of developing lactic acidosis.
From the point of view of the clinic, the most important diagnostic criteria for the above situations are the following indicators:
- Lack of kidney function. Metformin is contraindicated in serum creatinine levels >130 µmol/l in men and >120 µmol/l in women and creatinine clearance<60 мл/мин. Известно, что введение йодированных рентгеноконтрастных средств больным с почечной недостаточностью может привести к острому функциональному ухудшению функции почек. Если больной при этом страдает диабетом и принимает метформин, велик риск развития лактат-ацидоза. Описаны случаи лактат-аци-доза с летальным исходом, развившиеся как следствие острой почечной недостаточности после введения йодсодержащего контраста. Поэтому существуют определенные правила терапии метформином в этой ситуации.
. In each patient with diabetes mellitus receiving metformin, it is necessary to determine the serum creatinine concentration before the intravenous administration of iodine-containing contrast agents.
. If the creatinine level is normal, the test can be performed, and metformin is suspended for 48 hours and can be resumed if the kidney function/creatinine concentration remains normal.
. If renal function is impaired, metformin is suspended and contrast studies can be performed no earlier than 48 hours later. Restarting metformin is only possible if there is no change in renal function/creatinine concentration (ESUR, 2006).
Considering that in 80-90% of cases lactic acidosis develops with renal failure, this is one of the most important contraindications.
- Chronic dysfunction of the lungs. It is believed that metformin is contraindicated if there are symptoms confirming a violation of the function of external respiration, pronounced radiological signs of pathology of the bronchopulmonary system, constant drug therapy, except for inhaled bronchodilators.
- Heart failure. Ejection fraction less than 50%, radiographic evidence of pulmonary congestion, chronic diuretic or ACE inhibitor therapy.
- Chronic liver dysfunction. More than 2-fold increase in the level of transaminases and alkaline phosphatase.
- Alcoholism.
- Acute infections, injuries, operations under general anesthesia.
Thus, strictly speaking, it is absolutely safe to use metformin in the first place in patients without obvious cardiovascular and renal complications of type 2 diabetes mellitus.
At the same time, according to many European studies, metformin is used much more widely in practice. Thus, more than half of outpatients receiving metformin actually have one or more contraindications to taking it. Among hospitalized patients taking metformin, the proportion of patients with at least one contraindication to its use reaches almost 75%. In reality, every tenth outpatient and every second inpatient who takes metformin has several contraindications.
The situation is explained quite simply. The fact is that although the above conditions do dramatically increase the risk of developing lactic acidosis, lactic acidosis itself develops very rarely when taking metformin (in 0.03 cases / 1000 patient-years). Thus, in practice, the attending physician encounters such a situation extremely rarely. Undoubtedly, this creates a feeling of "imaginary" security. “Imaginary” due to the fact that the doctor does not have exact criteria in his hands to calculate which particular patient with a high risk of lactic acidosis will “carry over”, and which one will suddenly develop it. Mortality associated with lactic acidosis is 0-0.039 per 1000 patient-years. That is, if lactic acidosis suddenly "unexpectedly" develops, then the probability of death is 40-50% for such a particular "loser". A kind of "Russian roulette" with a large number of blank charges.
However, every effort must be made to minimize its danger. First, by regularly and consistently evaluating possible contraindications not only before prescribing metformin, but also in the process of taking the drug. Reassessment of contraindications should be carried out at least once a year, as well as when any concomitant and intercurrent diseases are added, especially if cardiovascular complications occur. Secondly, it is necessary to unconditionally cancel the use of metformin in the most common situations in everyday practice, such as upcoming general anesthesia (metformin is canceled at least 72 hours in advance), the perioperative period, acute infectious diseases and exacerbations of chronic ones, upcoming radiopaque studies, acute coronary syndrome. You should be aware that taking a number of cardiac drugs (digoxin, procainamide, quinine, amiloride, triamterene, furosemide) can slow down the excretion of metformin and increase blood lactate levels.
In addition, during metformin therapy, regular laboratory monitoring of hemoglobin (once every six months) and at least once a year - urea, creatinine, liver enzymes - are necessary. If possible, then it is planned, twice a year, to determine the content of lactate in the blood, and also to conduct this study when complaints of muscle pain appear (!). The patient should also be strictly warned about the danger of alcohol abuse, which, when taken simultaneously with metformin, can increase lactate production, as well as contribute to the development of hypoglycemia.
By following these fairly simple rules, you can fully realize the potential safety of metformin.
The game is definitely worth the candle! No hypoglycemic drug reduces cardiovascular and myocardial infarction mortality as powerfully as metformin can. It is only necessary to remember that doctors can expect such impressive results first of all when using metformin as monotherapy in overweight patients with newly diagnosed type 2 diabetes mellitus.
From 2000 to 2010, the number of diabetic patients in the world will increase from 151 to 221 million, and then to 300 million by 2025 (an increase of about 6 million patients per year). It is these patients who should first of all be treated with metformin monotherapy. And more than half of them will remain effective for up to 6 years, and for 25% - up to 9 years. And every next year, 6 million more patients will be added. A huge, constantly growing, hardly conscious range of metformin, which already now accounts for 25% of all hypoglycemic tablets.
It is with this huge increase in the predicted use of metformin that, in my opinion, the call of international experts for more persistent dissemination of knowledge about contraindications to metformin and for their careful compliance with the conditions for its safe use is connected. With such a massive use of metformin, its negligible ability to stimulate lactic acidosis may be clinically significant.
The use of metformin in 65% of cases is associated with its use in combination with other sugar-lowering drugs, primarily with sulfonylurea drugs. And here there is one problem that arose after the publication of the results of the UKPDS. It is not related to the hypoglycemic potential of such combinations. Sulfanilamides + Metformin is a hypoglycemic classic. Its effectiveness in achieving target blood glucose levels has made this combination the most used in patients with type 2 diabetes.
The problem is different. Since 1998, the following UKPDS data has been widely discussed: "In diabetic patients intensively treated with a combination of sulfonamides and metformin, total mortality and diabetes-related mortality are 96% and 60% higher, respectively, than those patients treated with sulfonamides alone." The group of such patients in the UKPDS was small - 480 patients. This was one of the explanations for the shocking results obtained.
Perhaps the criticism of the UKPDS is well founded. However, other, less well-known studies can be cited, in which mortality among patients with type 2 diabetes mellitus treated with a combination of sulfonylurea drugs and metformin was higher than among people on sulfonamide monotherapy. A number of critical remarks can also be made there. It is more fruitful to doubt the absolute correctness of criticism and look for a possible reason for such coincidences.
Now, in 2008, a possible explanation is fairly easy to find. In the literature, the results of several well-organized studies on the use of combination drugs containing both sulfonylurea and metformin are quite available. In the vast majority of these studies, it was found that when taking certain dose combinations of glibenclamide and metformin, the number of recorded hypoglycemic complications is not much, but still significantly higher than the same indicator when taking similar doses with glibenclamide monotherapy.
Undoubtedly, the increase in the number of hypoglycemia is an increase in the risk of cardiovascular mortality among diabetics. I am not sure if evidence of a definite increase in the risk of hypoglycaemia with sulfonylurea and metformin combination therapy can be used to explain the UKPDS results described above? Something else is important. Now that it has been proven that the risk of hypoglycemia in such patients is actually increased, awareness of doctors and patients about it will help to minimize its consequences. Once again confirmed: hypoglycemic efficacy and efficacy in preventing cardiovascular complications are not the same thing.
Nevertheless, the increase in the risk of hypoglycemia in combination therapy with metfarmin and sulfonylurea drugs, apparently, if it poses a real cardiovascular risk, is only for a small group of patients with type 2 diabetes mellitus. This is evidenced by the results of a Canadian retrospective study that analyzed the 5-year intake of hypoglycemic agents in 12,000 patients with type 2 diabetes. It was found that in general among patients with type 2 diabetes mellitus treated with metformin as monotherapy or in the form of its combination with other antidiabetic drugs, overall and cardiovascular mortality was approximately 40% lower than in patients on therapy. sulfonylurea drugs. The European recommendations of 2007, emphasizing the benefits of using metformin in combination with other hypoglycemic agents to control the development of cardiovascular complications in patients with type 2 diabetes, thus quite objectively reflect the level of today's knowledge on this problem.
There is, however, another very tempting prospect for the use of metformin. This is a prospect for the targeted use of metformin in solving the problems of interventional treatment of coronary heart disease in patients with diabetes mellitus.
As is known, the results of revascularization of the coronary vessels of the heart in patients with diabetes mellitus are significantly worse than in persons without impaired carbohydrate metabolism. Even with complete restoration of the lumen of the affected coronary vessels, the resumption of clinical signs of coronary heart disease in patients with diabetes mellitus occurs more often and after a shorter period of time after the intervention. This is largely due to the fact that in patients with diabetes in a large percentage of cases (up to 40%), the restoration of blood flow in large coronary vessels is not accompanied by a full improvement in tissue microvascular blood circulation.
The initial disturbance of microvascular blood flow, not associated with the process of revascularization, is a characteristic feature of the lesion of the coronary basin in diabetes mellitus. Significant - 30-40% decrease in microvascular coronary reserve is observed in diabetic patients long before the appearance of hemodynamically significant narrowing of the lumen of large coronary arteries. In many ways, this is why after successful restoration of the lumen of large coronary vessels in patients with diabetes mellitus, clinical signs of coronary heart disease more often persist or reappear after a shorter time: angina pectoris, heart rhythm disturbances, signs of congestive heart failure.
Unfortunately, to date there are no single generally recognized effective methods that can positively solve this problem. That is why the results of the PRESTO (Prevention of Restenosis with Tranilast and its Outcomes) study, published in California in 2004, are attracting close attention.
PRESTO is the largest prospective, randomized study in which long-term close follow-up of patients undergoing percutaneous interventional intervention on the coronary vessels of the heart was carried out. The study included 11484 patients. When analyzing their case histories, it was found that 2772 of these patients suffer from diabetes mellitus. Specific therapy for diabetic patients included sulfonylurea drugs, metformin (Glucophage®), thiazolidinediones, or insulin injections. At the same time, 1110 patients received metformin or its combination with other hypoglycemic drugs, and in 887 patients, metformin and thiazolidinediones were absent in their hypoglycemic therapy.
Multivariate comparison of the results of percutaneous interventional revascularization in patients on insulin synsetizers (metformin + its combination with other drugs) and patients without insulin synsetizers revealed significant significant differences. It turned out that metformin therapy (Glucophage®) is accompanied by a significantly rarer onset of death in patients with diabetes mellitus in the late post-revascularization period and a significantly rarer development of myocardial infarction in the subsequent period. Interestingly, there was no significant difference in repeated revascularizations of interested vessels between these groups of patients.
The data obtained suggest that the mechanism of action of metformin in these patients is not related to its effect on post-revascularization intimal proliferation in the affected coronary vessel. Rather, the favorable effect of metformin can be associated with its absolutely unique recently discovered ability to dramatically reduce hemodynamic disturbances at the level of the microvasculature, especially developing during post-ischemic reperfusion. Considering that this ability of metformin (Glucophage) is manifested both in the presence of diabetes mellitus and in its absence, the possible potential for its use in interventional interventions may be unusually wide.
However, in order for this to become a reality, of course, more studies are needed to confirm the results of PRESTO. But if this happens, then millions of patients undergoing interventional coronary revascularization and, possibly, many other patients in whom the occurrence of microcirculatory disorders makes a significant contribution to progression of their disease.

This material discusses mechanism of action of metformin- a popular oral antidiabetic drug, which is prescribed for the treatment of type 2 diabetes, as well as for people who are overweight and obese. prevents the development of cardiovascular diseases and complications of diabetes, helps the body increase sensitivity to insulin.

Despite the popularity the effect of metformin on the human body is not fully understood. also called "the bestseller, not read to the end." To this day, various studies are being actively conducted and scientists are discovering new facets of this drug, revealing its additional beneficial properties and side effects.

It is known that the World Health Organization has recognized one of the most effective and safe medicines used in the healthcare system.

On the other hand, although metformin was discovered back in 1922, it was only in 1995 that it began to be used in the United States. And in Germany, metformin is still not a prescription drug and German doctors do not prescribe it.

The mechanism of action of metformin

Metformin activates the secretion of the liver enzyme AMP-activated protein kinase (AMPK), which is responsible for the metabolism of glucose and fat. AMPK activation is required for inhibitory effect of metformin on gluconeogenesis in the liver.

In addition to suppressing the process of gluconeogenesis in the liver metformin increases tissue sensitivity to insulin, increases peripheral glucose uptake, increases fatty acid oxidation, while reducing the absorption of glucose from the gastrointestinal tract.

In simpler terms, after a high-carbohydrate meal is ingested, pancreatic insulin begins to be secreted to keep blood sugar levels within normal limits. Carbohydrates found in foods are digested in the intestines and converted into glucose, which enters the bloodstream. With the help of insulin, it is delivered to the cells and becomes available for energy.

The liver and muscles have the ability to store excess glucose, as well as easily release it into the bloodstream if necessary (for example, during exercise). In addition, the liver can store glucose from other nutrients, such as fats and amino acids (the building blocks of proteins).

The most important effect of metformin is the inhibition (suppression) of glucose production by the liver, which is characteristic of type 2 diabetes.

Another effect of the drug is expressed inhibition of glucose absorption in the intestine, which allows you to get lower blood glucose levels after meals (postprandial blood sugar), as well as increase cell sensitivity to insulin (target cells begin to respond more quickly to insulin, which is released when glucose is absorbed).

How does metformin work in pregnant women with gestational diabetes?

Prescribing metformin to pregnant women is not an absolute contraindication, uncompensated is much more harmful to the child. However, Insulin is more often prescribed for the treatment of gestational diabetes. This is explained by the conflicting results of studies on the effects of metformin on pregnant patients.

One US study found metformin to be safe during pregnancy. Women with gestational diabetes who took metformin had less weight gain during pregnancy than patients on insulin. Children born to women treated with metformin had less visceral fat gain, making them less prone to insulin resistance later in life.

In animal experiments, no adverse effect of metformin on fetal development was observed.

Despite this, in some countries metformin is not recommended for pregnant women. For example, in Germany, the prescription of this drug during pregnancy and gestational diabetes is officially prohibited, and patients who want to take it take all the risks and pay for it themselves. According to German doctors, metformin can have a harmful effect on the fetus and forms its predisposition to insulin resistance.

When lactating, metformin should be abandoned., because it passes into breast milk. Treatment with metformin while breastfeeding should be discontinued.

How does metformin affect the ovaries?

Metformin is most often used to treat type 2 diabetes, but it is also prescribed for polycystic ovary syndrome (PCOS) due to the relationship between these diseases, because Polycystic ovary syndrome is often associated with insulin resistance.

Clinical studies completed in 2006-2007 concluded that the efficacy of metformin in PCOS is no better than placebo, and the combination of metformin with clomiphene is no better than clomiphene alone.

In the UK, metformin is not recommended as first-line therapy for polycystic ovary syndrome. As a recommendation, clomiphene is indicated and the need for lifestyle changes is emphasized, regardless of drug therapy.

Metformin for female infertility

A number of clinical studies have shown the effectiveness of metformin in infertility, along with clomiphene. Metformin should be used as a second-line drug if clomiphene treatment has shown to be ineffective.

Another study recommends unqualified metformin as the primary treatment option, as it has a positive effect not only on anovulation, but also on thyroiditis, hirsutism, and obesity, which is often seen in PCOS.

prediabetes and metformin

Metformin may be given to pre-diabetics (those at risk of developing type 2 diabetes), which reduces their chances of developing the disease, although intense exercise and a carbohydrate-restricted diet are much preferable for this purpose.

In the United States, a study was conducted according to which one group of subjects was given metformin, while the other went in for sports and dieted. As a result, in the healthy lifestyle group, the incidence of diabetes mellitus was 31% less than in prediabetics taking metformin.

Here is what they write about prediabetes and metformin in one scientific review published on PubMed— English-language database of medical and biological publications ( PMC4498279):

"People with elevated blood sugar levels who do not have diabetes are at risk of developing clinical type 2 diabetes, the so-called" pre-diabetes ". prediabetes usually applicable to boundary level fasting plasma glucose (impaired fasting glucose levels) and / or to the level of glucose in the blood plasma, donated 2 hours after the oral glucose tolerance test with 75 g. sugar (impaired glucose tolerance). In the United States, even the upper borderline level of glycated hemoglobin (HbA1c) has come to be considered prediabetes.
Individuals with prediabetes have an increased risk of microvascular injury and macrovascular complications. similar to long-term complications of diabetes. Halting or reversing the progression of decreased insulin sensitivity and destruction of β-cell function is the key to achieving type 2 diabetes prevention.

Many weight loss interventions have been developed: pharmacological treatment (metformin, thiazolidinediones, acarbose, basal insulin injections and weight loss drugs) and bariatric surgery. These measures aim to reduce the risk of developing type 2 diabetes in people with prediabetes, although positive results are not always achieved.

Metformin enhances insulin action in the liver and skeletal muscle, and its effectiveness in delaying or preventing the onset of diabetes has been proven in various large, well-designed, randomized trials,

including programs for the prevention of diabetes. Decades of clinical use have shown that Metformin is generally well tolerated and safe."

Can Metformin be taken for weight loss? Research results

According to research, metformin may help some people lose weight. Nevertheless, it is still not clear how metformin leads to weight loss.

One theory is that metformin reduces appetite, which leads to weight loss. Despite the fact that metformin helps to lose weight, this drug is not directly intended for this purpose.

According to randomized long-term study(cm.: PubMed, PMCID: PMC3308305), weight loss from metformin use tends to occur gradually over one to two years. The number of kilograms dropped also varies from person to person and is associated with many other factors - with the constitution of the body, with the number of calories consumed daily, with lifestyle. According to the results of the study, the subjects, on average, lost from 1.8 to 3.1 kg after two or more years of taking metformin. When compared with other methods of losing weight (low-carbohydrate diets, high physical activity, fasting), this is more than a modest result.

Thoughtless use of the drug without observing other aspects of a healthy lifestyle does not lead to weight loss. People who eat a healthy diet and exercise while taking metformin tend to lose more weight. This is because metformin increases the rate at which calories are burned during exercise. If you don't exercise, then you probably won't have this benefit.

Is metformin given to children?

Reception of Metformin by children and adolescents over ten years of age is acceptable - this has been verified by various clinical studies. They did not reveal any specific side effects related to the development of the child, but the treatment should be carried out under the supervision of a physician.

conclusions

• Metformin reduces the production of glucose in the liver (gluconeogenesis) and increases the sensitivity of body tissues to insulin.
• Despite the high marketability of the drug in the world, its mechanism of action is not fully understood, and many studies contradict each other.
• Taking metformin in more than 10% of cases causes problems with the intestines. To solve this problem, long-acting metformin was developed (original - Glucophage Long), which slows down the absorption of the active substance and makes its effect on the stomach more gentle.
• Metformin should not be taken in severe liver diseases (chronic hepatitis, cirrhosis) and kidneys (chronic renal failure, acute nephritis).
• In combination with alcohol, metformin can cause the deadly disease lactic acidosis, so it is strictly forbidden to take it to alcoholics and when drinking large doses of alcohol.
• Long-term use of metformin causes a lack of vitamin B12, so it is advisable to take supplements of this vitamin in addition.
• Metformin is not recommended during pregnancy and gestational diabetes, as well as during breastfeeding, because. it passes into milk.
• Metformin is not a "magic pill" for weight loss. The best way to lose weight is by following a healthy diet (including carbohydrate restriction) along with physical activity.

Sources:

1. Petunina N.A., Kuzina I.A. Metformin analogues of prolonged action // The attending physician. 2012. №3.
2. Does metformin cause lactic acidosis? / Cochrane systematic review: main provisions // News of Medicine and Pharmacy. 2011. No. 11-12.
3. Long-Term Safety, Tolerability, and Weight Loss Associated With Metformin in the Diabetes Prevention Program Outcomes Study // Diabetes Care. 2012 Apr; 35(4): 731-737. PMCID: PMC3308305.

Gross formula

Pharmacological group of the substance Metformin

Nosological classification (ICD-10)

CAS code

Characteristics of the substance Metformin

Metformin hydrochloride is a white or colorless crystalline powder. Let's well dissolve in water and practically insoluble in acetone, ether and chloroform. Molecular weight 165.63.

Pharmacology

Lowers the concentration of glucose (on an empty stomach and after eating) in the blood and the level of glycosylated hemoglobin, increases glucose tolerance. Reduces intestinal absorption of glucose, its production in the liver, potentiates sensitivity to insulin in peripheral tissues (increased absorption of glucose and its metabolism). Does not alter insulin secretion by pancreatic islet beta cells (fasting insulin levels and daily insulin response may even decrease). Normalizes the lipid profile of blood plasma in patients with non-insulin dependent diabetes mellitus: reduces the content of triglycerides, cholesterol and LDL (determined on an empty stomach) and does not change the levels of lipoproteins of other densities. Stabilizes or reduces body weight.

Experimental studies in animals at doses 3 times the MRDC in terms of body surface area did not reveal mutagenic, carcinogenic, teratogenic properties and effects on fertility.

Rapidly absorbed from the gastrointestinal tract. Absolute bioavailability (on an empty stomach) is 50-60%. C max in plasma is achieved after 2 hours. Food intake lowers C max by 40% and slows down its achievement by 35 minutes. The equilibrium concentration of metformin in the blood is reached within 24-48 hours and does not exceed 1 μg / ml. The volume of distribution (for a single dose of 850 mg) is (654 ± 358) liters. Slightly binds to plasma proteins, can accumulate in the salivary glands, liver and kidneys. It is excreted by the kidneys (mainly by tubular secretion) unchanged (90% per day). Renal Cl - 350-550 ml / min. T 1/2 is 6.2 h (plasma) and 17.6 h (blood) (the difference is due to the ability to accumulate in erythrocytes). In the elderly, T 1/2 is prolonged and C max increases. In case of impaired renal function, T 1/2 is prolonged and renal clearance decreases.

The use of the substance Metformin

Type 2 diabetes mellitus (especially in cases accompanied by obesity) with ineffective correction of hyperglycemia by diet therapy, incl. in combination with sulfonylurea drugs.

Contraindications

Hypersensitivity, kidney disease or renal insufficiency (creatinine level is more than 0.132 mmol / l in men and 0.123 mmol / l in women), severe liver dysfunction; conditions accompanied by hypoxia (including heart and respiratory failure, acute phase of myocardial infarction, acute cerebrovascular insufficiency, anemia); dehydration, infectious diseases, major surgery and trauma, chronic alcoholism, acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma, history of lactic acidosis, adherence to a low-calorie diet (less than 1000 kcal / day), research using radioactive iodine isotopes , pregnancy, breastfeeding.

Application restrictions

Children's age (efficacy and safety of use in children have not been determined), elderly (over 65 years old) age (due to slow metabolism, it is necessary to evaluate the benefit / risk ratio). It should not be given to people doing heavy physical work (increased risk of developing lactic acidosis).

Use during pregnancy and lactation

During pregnancy, it is possible if the expected effect of therapy outweighs the potential risk to the fetus (adequate and strictly controlled studies on the use during pregnancy have not been conducted).

At the time of treatment should stop breastfeeding.

Side effects of Metformin

From the digestive tract: at the beginning of the course of treatment - anorexia, diarrhea, nausea, vomiting, flatulence, abdominal pain (reduce when taken with food); metallic taste in the mouth (3%).

From the side of the cardiovascular system and blood (hematopoiesis, hemostasis): in isolated cases - megaloblastic anemia (the result of malabsorption of vitamin B 12 and folic acid).

From the side of metabolism: hypoglycemia; in rare cases, lactic acidosis (weakness, drowsiness, hypotension, resistant bradyarrhythmia, respiratory disorders, abdominal pain, myalgia, hypothermia).

From the side of the skin: rash, dermatitis.

Interaction

The effect of metformin is weakened by thiazide and other diuretics, corticosteroids, phenothiazines, glucagon, thyroid hormones, estrogens, incl. as part of oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium antagonists, isoniazid. In a single dose in healthy volunteers, nifedipine increased absorption, C max (by 20%), AUC (by 9%) of metformin, T max and T 1/2 did not change. The hypoglycemic effect is enhanced by insulin, sulfonylurea derivatives, acarbose, NSAIDs, MAO inhibitors, oxytetracycline, ACE inhibitors, clofibrate derivatives, cyclophosphamide, beta-blockers.

In a single dose interaction study in healthy volunteers, furosemide has been shown to increase Cmax (by 22%) and AUC (by 15%) of metformin (without significant changes in renal clearance of metformin); metformin reduces C max (by 31%), AUC (by 12%) and T 1/2 (by 32%) of furosemide (without significant changes in the renal clearance of furosemide). There are no data on the interaction of metformin and furosemide with long-term use. Drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, and vancomycin) secreted in the tubules compete for tubular transport systems and, with long-term therapy, can increase Cmax of metformin by 60%. Cimetidine slows down the elimination of metformin, resulting in an increased risk of developing lactic acidosis. Incompatible with alcohol (increased risk of lactic acidosis).

Overdose

Symptoms: lactic acidosis.

Treatment: hemodialysis, symptomatic therapy.

Routes of administration

inside.

Metformin Substance Precautions

It is necessary to constantly monitor kidney function, glomerular filtration, blood glucose levels. Especially careful monitoring of blood glucose levels is necessary when using metformin in combination with sulfonylurea drugs or insulin (risk of hypoglycemia). Combined treatment with metformin and insulin should be carried out in a hospital until an adequate dose of each drug is established. In patients on continuous metformin therapy, it is necessary to determine the content of vitamin B 12 once a year due to a possible decrease in its absorption. It is necessary to determine the level of lactate in plasma at least 2 times a year, as well as with the appearance of myalgia. With an increase in the content of lactate, the drug is canceled. Do not apply before surgical operations and within 2 days after they are carried out, as well as within 2 days before and after performing diagnostic studies (in / in urography, angiography, etc.).

Interactions with other active substances

Trade names

A. S. Ametov, M. A. Prudnikova

SBEE DPO "Russian Medical Academy of Postgraduate Education" of the Ministry of Health of Russia, Moscow

Today, metformin is central to all current recommendations for the management of type 2 diabetes mellitus (T2DM). Given the epidemic nature of the prevalence of the disease, the number of patients receiving metformin is steadily increasing day by day. The article describes the cellular and molecular mechanisms of action of metformin, the advantages of its choice as a hypoglycemic therapy in patients with type 2 diabetes, argues in favor of the use of metformin for the prevention of type 2 diabetes, considers the possibility of prescribing metformin to patients with moderate hepatic and renal dysfunction. Recently, a new dosage form of the sustained release drug has been developed. Against the background of taking sustained release metformin, the risk of developing gastrointestinal disorders is reduced by 2 times and the adherence of patients to treatment increases significantly. The article presents the advantages and disadvantages of using a prolonged form in comparison with immediate release metformin.

type 2 diabetes mellitus, metformin, sustained release metformin, metformin and cancer, metformin pharmacokinetics

Endocrinology: analytical reviews. 2015. No. 1.

The prevalence of type 2 diabetes mellitus (T2DM) is constantly growing, ahead of all existing forecasts. According to the epidemiological data of the International Diabetes Federation, in 2014 every 12th inhabitant of the planet suffered from DM. By 2035, the number of cases is expected to increase to 592 million people.

The epidemic nature of the spread of the disease was the reason for the development of clear algorithms for managing DM2. The drug of choice in all current clinical recommendations is a drug used to treat carbohydrate metabolism disorders for more than half a century.

Cellular and molecular mechanisms of action of metformin

According to modern ideas about the cellular and molecular mechanisms of action of the drug, it shows the greatest activity in the liver. The uptake of the drug by hepatocytes is mediated by the activity of organic cation transporter 1.