Metformin is one of the main drugs in the treatment diabetes mellitus 2 types.

Historical background

Metformin is a biguanide. Before metformin, other drugs in this group were invented, but in studies they turned out to be unsafe and were soon discontinued. Metformin was synthesized in 1957, and already in the 60s of the last century it began to be actively used for the treatment of type 2 diabetes.

In the well-known and very important study UKPDS (United Kingdom Prospective Diabetes Study - a prospective multicenter randomized study of diabetes mellitus), which was conducted in Great Britain from 1977 to 1997 and included more than 11 thousand participants, the safety of its use and positive effect on cardiovascular system, namely reducing the risk of developing myocardial infarction.

Over 50 years, a huge number of studies (more than 5 thousand) have been conducted in which the various effects of metformin, as well as the safety of its action, have been studied. Recently, its effect on reducing the risk of developing cancer in people with type 2 diabetes has been actively studied.

How does metformin work?

• Reduces glucose absorption in the intestine
• Reduces the formation of glucose in the liver. The liver stores glucose in the form of a special substance, glycogen. In addition, glucose can be formed from proteins and fats, which is why you may see a higher blood sugar number on your glucometer in the morning than before going to bed.
• Improves sensitivity to insulin: cells begin to be more active and better perceive insulin - both their own and those introduced externally in the form of injections. This means that metformin reduces insulin resistance (resistance to the action of insulin), which underlies type 2 diabetes.
• Does not affect insulin production, and therefore cannot cause glucose levels to fall below normal (hypoglycemia)
• Does not affect weight or promote weight loss

Who is prescribed metformin?

• All patients with type 2 diabetes mellitus in the absence of contraindications
• People with prediabetes
• Women with polycystic ovary syndrome (PCOS)

When should metformin not be used?

• With a pronounced decrease in kidney function. The doctor determines how the kidneys are working by the level of blood creatinine and a special indicator - the glomerular filtration rate.
• In case of severe heart disease, severe heart failure, including the first time after a myocardial infarction, as well as after a stroke
• For anemia (decreased hemoglobin)
• If you have a respiratory disease that has led to respiratory failure
• With the development of ketoacidosis
• For severe liver dysfunction
• During pregnancy
• If there is individual intolerance (for example, severe side effects)

Consult your doctor about all contraindications; do not stop taking metformin on your own! For example, if you had a myocardial infarction several years ago and now there are no signs of cardiac dysfunction, or if you have bronchial asthma, but it responds well to treatment, this does not indicate the need to discontinue this drug.

What side effects might there be?

• The most common are nausea, discomfort and pain in the abdomen, frequent bowel movements, bloating
• Skin rash
• Excessive accumulation of lactic acid - lactic acidosis (possible when taking metformin if there are contraindications)

How to take metformin?

• Taking the drug with food is believed to reduce the risk of side effects
• Metformin is taken 1 to 3 times a day
• There is a special form of the drug with a long action (extended), in which case the name contains the prefix “long”. This type of metformin is taken 1 time per day
• Maximum daily dose for regular tablets - 3000 mg, and for extended-release metformin - 2000 mg. Therefore, do not be afraid if the doctor prescribed three huge 1000 mg tablets. But you shouldn’t take more either!
• Metformin can be produced in the form of ready-made combinations, that is, one tablet can contain two substances at once - metformin and some other drug. These tablets must be taken according to the instructions.
• Metformin can be taken together with other tablets if there are no special instructions for their use

Resume

Metformin belongs to the group of biguanides. It increases tissue sensitivity to insulin and reduces blood sugar levels. There are concerns that metformin may lead to the development of lactic acidosis in patients undergoing diagnostic procedures requiring the administration of iodinated contrast agents and in patients with renal or heart failure. Numerous studies have reviewed the evidence underlying these concerns, concluding that metformin is rarely a cause of lactic acidosis. The generally accepted view that all patients should stop taking metformin 48 hours before and 48 hours after contrast media procedures is illogical, lacks evidence, and is not consistent with acceptable clinical practice. In patients with heart failure, this disease may predispose to the development of lactic acidosis, and the administration of metformin leads to an improvement in observed outcomes rather than an increase in possible risks.

Keywords

Metformin, lactic acidosis, risk.

Metformin, a drug from the biguanide group, increases tissue sensitivity to insulin, inhibits gluconeogenesis in the liver and, as a result, lowers blood sugar levels. It can be prescribed in combination with any other oral antidiabetic agent and insulin. It is characterized by a short half-life of about 6 hours; 90% of the drug is excreted by the kidneys within 24 hours. When using metformin, the same concerns exist as when using its biguanide precursor, phenformin: the latter was found to have a strong relationship with the development of lactic acidosis, and therefore in 1978 it was prohibited for clinical use.

Among doctors, there is an opinion that metformin causes lactic acidosis in patients with diabetes or renal dysfunction. Therefore, the possibility of its use in patients with cardiac disease during intravenous or intra-arterial administration of contrast agents, as well as in patients with heart failure, is controversial. Many cardiac catheterization protocols stipulate that metformin should be discontinued 48 hours before and 48 hours after any elective diagnostic or therapeutic procedure. In patients who do not stop taking metformin, the intervention is often delayed, compromising the expected outcome.

Metformin is not nephrotoxic and does not interact with iodinated contrast agents. Recommendations for discontinuation of this drug are based on the theoretical risk of developing lactic acidosis in patients predisposed to acute renal impairment after administration of contrast agents. In this case, accumulation of metformin is possible, which can increase the concentration of lactic acid in the blood plasma. However, how verified is this concept?

Risks associated with stopping metformin

The presence of hyperglycemia in itself can be harmful during fairly delicate coronary and carotid interventions. In addition, no specific studies have been conducted to evaluate the long-term effects of rebound hyperglycemia in patients after temporary discontinuation of metformin. However, it should be noted that the effects of stopping metformin for 1-2 weeks were studied in the Diabetes Prevention Program, in which 3234 patients with impaired glucose tolerance were randomly assigned to placebo, metformin, or lifestyle modification; the follow-up period averaged 2.8 years. It was found that during this time period, the likelihood of developing diabetes (measured by impaired oral glucose tolerance test) increased by 50% in the metformin group compared with the placebo group, although the difference did not reach statistical significance (p = 0.098).

Risks associated with continuing metformin use

Lactic acidosis in patients without diabetes mellitus develops in the presence of infections, cancer, liver and kidney failure and, if these diseases are not corrected, always leads to death. Risk factors for the development of lactic acidosis are largely similar and independent of diabetic status. Risk factors predisposing to the development of lactic acidosis:

— age > 80 years;

— tissue hypoxia;

— reduction cardiac output;

- respiratory failure;

- liver failure;

- renal failure;

- sepsis;

— surgery;

- ethanol intoxication;

- diabetic ketoacidosis;

— fasting/reduced nutrition;

— short small bowel syndrome (jejunoileal anastomosis, small bowel resection);

- antiretroviral therapy;

- high doses (deliberate overdosage) of metformin > 2 g/day.

Metformin was approved for use in the United States in May 1995, and over the next 12 months, lactic acidosis was reported to the Food and Drug Administration (FDA) in 66 patients. receiving metformin. In 47 patients, the diagnosis was established on the basis of an increase in plasma lactate concentration (> 5 mmol/l), in accordance with the accepted diagnostic criteria for lactic acidosis. Of these, 43 patients had one or more risk factors for the development of lactic acidosis: 30 had heart disease (18 suffered from heart failure), 13 had renal failure (2 patients were undergoing hemodialysis). 3 patients had chronic obstructive pulmonary disease, 8 patients were over 80 years of age. Only 4 of 47 patients had no visible risk factors for the development of lactic acidosis at the time of initiation of metformin therapy; they all recovered from lactic acidosis. Since these data, the association between metformin use and lactic acidosis has generated considerable controversy, based primarily on anecdotal reports, with an incidence currently estimated at 2–5 cases per 100,000 patient-years.

The incidence of lactic acidosis in patients with type 2 diabetes mellitus was similar among patients taking and not taking metformin, after excluding risk factors associated with the development of lactic acidosis. The mortality rate among patients with lactic acidosis attributable to metformin is approximately 40% and appears to be related to heart failure. It appears that in most cases metformin was not the original cause of lactic acidosis, but may have contributed to its severity. The etiology of lactic acidosis is quite complex and is believed to be associated with a shift in the intracellular redox potential from an aerobic to an anaerobic mechanism, which leads to intracellular lactate production.

An interesting retrospective study was carried out that attempted to answer the question of whether the contraindications published in the literature were taken into account when prescribing metformin and whether the required precautions were followed. It was found that physicians (presumably aware of the potential of metformin to cause lactic acidosis) rarely followed the instructions exactly and prescribed metformin to patients with diseases that could potentially lead to the development of lactic acidosis. Despite this “minus”, no cases of lactic acidosis were noted. In another similar study carried out in Scotland and including 1847 patients taking metformin, the drug was prescribed against instructions in 24.5% of patients, but despite this, lactic acidosis developed during 30 months of follow-up in only 1 patient, who died of heart failure.

Metformin and heart failure

Diabetes is a common comorbidity in patients with heart failure and is associated with a poorer prognosis. Metformin is “contraindicated” in heart failure due to the theoretical risk of lactic acidosis, although appropriate long-term studies have not been performed. On the other hand, the literature on heart failure has accumulated a significant amount of data confirming the safety of metformin. Findings from large retrospective registry analyzes suggest that, paradoxically, metformin is the only antidiabetic agent that reduces morbidity (reduced readmission rates for heart failure) and mortality in patients with heart failure, including older patients. Moreover, no cases of lactic acidosis were noted in these studies.

A mechanism has been proposed that could explain the observed improvements. In a mouse model of heart failure, it was shown that the cardioprotective properties of metformin are independent of its hypoglycemic effects and are mediated by activation of AMP-activated protein kinase.

A pilot study was recently undertaken to evaluate the feasibility of a large randomized controlled trial with endpoints aimed at assessing the safety of metformin in heart failure. The randomization design involved receiving either metformin 1500 mg/day or matched placebo for 6 months. As a result, the study was unable to recruit patients because all 58 patients screened were excluded from the study. The main reasons for exclusion from the study were the use of insulin, the presence of glycosylated hemoglobin levels< 7 % и приему высоких доз метформина. Пилотное исследование было прервано, а шансы на проведение крупного исследования стали почти безнадежными.

Many questions also arise regarding the validity of “contraindications” for metformin in patients with diabetic cardiomyopathy, based on outdated and unconfirmed concerns about the drug’s ability to cause lactic acidosis.

Safety Data

To reduce tensions around the safety of metformin, the pharmaceutical company Bristol-Myers Squibb (New York, USA) initiated a large study, COSMIC (the Comparative Outcomes Study of Metformin Intervention versus Conventional approach - a comparative study of the safety of metformin and other antidiabetic drugs) lasting 1 year, which compared treatment with metformin and “usual care” with other antidiabetic agents. The results found no difference in safety between the 7,227 patients taking metformin and the 1,505 patients taking “usual care.” None of the groups developed lactic acidosis.

Two large, pharmaceutical company-independent clinical studies provided very impressive evidence of the safety and effectiveness of metformin. First, as part of the large UKPDS (UK Prospective Diabetes Study), a subpopulation of 753 overweight patients was randomized to either treatment traditional method including diet alone (n = 342) or intensive glycemic control with metformin (n = 411). Metformin demonstrated greater efficacy in reducing the incidence of diabetes-related endpoints, including macrovascular complications, without negative influence safety in both this randomized cohort and the entire UKPDS study population (n = 4075) over a median follow-up of 10.7 years. It should be noted that metformin also leads to weight loss, which has a positive effect on cardiovascular risks in patients with diabetes and obesity. The safety and effectiveness of metformin was confirmed by the Diabetes Prevention Program (n = 2155), which showed that the drug reduced the risk of developing diabetes by 31% compared with placebo.

Recently, the results of a Cochrane meta-analysis were published, which examined the incidence of fatal and non-fatal cases of lactic acidosis with metformin compared with placebo and other types of glucose-lowering therapy in patients with type 2 diabetes. Pooled data from 206 comparative and cohort studies found no cases of fatal or nonfatal lactic acidosis per 47,846 patient-years in the metformin group and 38,221 patient-years in the non-metformin group. The researchers concluded that data from prospective comparative studies and observational cohort studies do not support the finding that metformin use is associated with an increased risk of lactic acidosis.

Despite the results of controlled trials, registry analyses, and meta-analyses, the risk of metformin-related lactic acidosis has become firmly established through anecdotal published reports and typical guidelines issued by major professional associations (Table 1).

One recently completed review of similar anecdotal reports found that the vast majority of metformin-associated cases of lactic acidosis (especially fatal ones) were more likely due to the presence of comorbidities or to the fact that patients with diabetes mellitus are prone to developing serious medical complications, which can lead to the development of lactic acidosis than with taking metformin itself. Another review, which analyzed all cases of lactic acidosis that developed after intravenous contrast administration, indicated that patients had poor renal function or other contraindications to the use of metformin. The lack of correlation between lactate and metformin in the blood plasma in these patients also indicated the “innocence” of metformin. In such patients, the need for contrast administration should once again be carefully considered and, if a positive decision is made, an aggressive hydration regime should be used to minimize the risk of developing contrast-induced nephropathy.

Conclusions

When analyzing the large clinical experience with metformin, it was found that the actual number of confirmed cases of metformin-associated lactic acidosis was very small. The causal relationship is weak and owes its appearance to cases of overestimation of the dose of metformin. In patients with heart failure, this disease may predispose to the development of lactic acidosis, and the administration of metformin leads to an improvement in observed outcomes rather than an increase in possible risks. Accumulation of metformin in cases of renal failure may increase the risk of developing lactic acidosis in high-risk patient groups - for example, elderly patients and those receiving high doses of metformin ≥ 2 g/day. The risk of developing lactic acidosis due to metformin in patients undergoing cardiac catheterization has not been determined; There are no published studies or registry data on this topic. The generally accepted view that all patients should stop taking metformin 48 hours before and 48 hours after contrast-enhanced procedures is illogical, lacks any evidence base and does not correspond to the principles of acceptable clinical practice. Even in patients with impaired renal function, the causal relationship between metformin use and the development of lactic acidosis is weak. In connection with all of the above, it is proposed to use a pragmatic approach when prescribing metformin.

Financial support: Biomedical Research Council (BRC).

Conflict of interest: not declared.

Customer and review: the article was not ordered; No external review was performed.

Translation by A.V. Savustyanenko
The original article was published in Postgrad. Med. J. - 2010. - 86. - 371-373

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Catad_tema Diabetes mellitus type II - articles

Metformin's place in modern treatment and prevention of type 2 diabetes mellitus

Smirnova O.M.
FGU Endocrinological science 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.
Key words: 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. Results of multicentre studied 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 more than 50 years. Professor Lefebvre P. writes that today we can treat, but not cure diabetes mellitus (DM). Type 2 diabetes (T2DM) constitutes the main form of the disease. According to WHO forecasts, by 2025 the number of patients suffering from diabetes will exceed 380 million people. Presenters medical organizations It is recommended today to begin treatment for T2DM with a combination of lifestyle changes and metformin. In this regard, new results concerning the newly discovered properties of metformine 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. Currently, metformin is the most commonly prescribed oral hypoglycemic drug in Europe, the USA and other countries. The mechanism of the antihyperglycemic action of metformin has been well studied. 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 into 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;
• reduction in triglyceride (TG) and low-density lipoprotein (LDL) levels;
• increase in high-density lipoprotein (HDL) content (Fig. 1).

Rice. 1. Antihyperglycemic effect of metformin

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

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

Metformin increases the fluidity of plasma membranes 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 red blood cells were noted in individuals who had previously received metformin. The schematic action of metformin on membranes and their components is presented 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 the double-blind, randomized, crossover study are presented in Figure 3.

Rice. 3. The effect of metformin and placebo on glycemia and selected indicators of glucose metabolism in patients with newly diagnosed type 2 diabetes mellitus (double-blind randomized crossover study)

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

Another double-blind, randomized study comparing hepatic glucose production between metformin and rosiglitazone under conditions of controlled hyperinsulinemia showed that metformin significantly suppresses hepatic glucose production compared with 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, have been well studied. They were first introduced after the completion of the multi-year UKPDS (United Kingdom Prospective Diabetes Study) 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 completely rehabilitated as a safe and useful antihyperglycemic 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

Key findings from research over 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 obtained in the UKPDS.

Data obtained in subsequent years confirmed the positive effects 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, or any event of cardiovascular event compared with those receiving other treatment (Fig. 5).

Rice. 5. Cardiovascular disease outcomes during 3 years of follow-up

One of the current sections of discussions about the effectiveness of modern trends in the treatment of T2DM is the safety of both individual glucose-lowering drugs and their combinations. Various 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 presented figure we see that metformin is present in all treatment options. 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, simultaneously with lifestyle changes? Because for the majority of people with T2DM, lifestyle interventions do not achieve or maintain glycemic targets, which may be due to the following factors:

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

In addition to the fact that some patients experience intolerance to the drug (according to various authors - from 10 to 20%), there are also clear contraindications to the use of metformin.

Contraindications to taking metformin

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

Table 3
Special instructions when taking metformin

The frequency of contraindications to the use of metformin, according to different authors, varies significantly. Thus, 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, according to various authors, is 3 cases per 100,000 patient-years treated with metformin.

Lactic acidosis is clinically very dangerous. A study conducted by Stacpool P.W. et al. , was performed by evaluating 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, 80% of these patients were diagnosed with circulatory shock. Sepsis, liver failure and respiratory diseases were the main factors leading to the development of lactic acidosis. Survival rates were 59% at 24 hours, 41% at 3 days, and 17% at 30 days.

Cases of lactic acidosis associated with taking 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).

The question of the possibility of using metformin in chronic heart failure (CHF) remains important and actively discussed. To date, quite a lot of experience has been accumulated indicating the benefits of using metformin in the treatment of patients with T2DM and CHF. One such study is the work. The aim of the study was to evaluate the relationship between metformin use and clinical outcomes in patients with CHF and T2DM. Using health care databases (Canada), 12,272 patients with T2DM who received glucose-lowering drugs from 1991 to 1996 were examined. Among them, 1,833 patients with CHF were identified. 208 people received metformin monotherapy, 773 sulfonylurea derivatives (SU) and 852 people received combination therapy. The average age of the patients was 72 years. There were 57% men, the average follow-up was 2.5 years. CHF was first diagnosed during hospitalization, that is, at the beginning of the study. The observation period was 9 years (1991 – 1999). Fatal outcomes among persons receiving: SM - 404 (52%), metformin - 69 (33%), combination therapy - 263 cases (31%). Mortality from all causes after 1 year in persons receiving SM was 200 people. (26%), in persons receiving 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 individuals not receiving antidiabetic medications, metformin use was associated with a lower risk of mortality compared with other antidiabetic medications, even including potentially adverse factors such as poor glycemic control, decreased renal function, excess weight, and arterial hypertension. These data are consistent with previous work that 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 studying the properties of metformin is its anti-oncogenic effect. A number of clinical studies have been published that have shown a reduction in the incidence of cancer among patients using metformin. One is a population-based retrospective cohort study using a database from the state of Saskatchewan, Canada, 1995–2006. The aim of the study was to examine cancer mortality and the relationship with antidiabetic therapy in T2DM. We studied 10,309 patients with T2DM newly prescribed metformin, sulfonylureas (SUs) and insulin. The average 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, and insulin was added to 1,443 patients. The duration of observation was 5.4±1.9 years.

Overall, cancer mortality was 4.9% (162 of 3,340) in those receiving SM, 3.5% (245 of 6,969) in metformin, and 5.8% (84 of 1,443) in insulin. Data presented by Bowker show a twofold increase in the incidence of cancer in the insulin group 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 T2DM depending on the type of therapy performed. The study included 62,809 patients with T2DM over 40 years of age who were divided into four treatment groups: metformin or SU monotherapy, combination therapy with metformin and SU, and insulin therapy. The group of patients receiving insulin was divided into subclasses: monotherapy with insulin glargine, NPH insulin, biphasic insulin. Data on the manifestation or progression during the period of treatment (insulin therapy since 2000) of any malignant tumors were also assessed; Special attention was paid to breast, colon, pancreas and prostate cancer.

When analyzing the data obtained, it was revealed 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 during metformin monotherapy was 0.54 (95% CI 0.43-0.66). Even when metformin was added to any glucose-lowering therapy, the risk of malignancy decreased 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 risks (RR) were:

• 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 most recently 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 examine the association between specific T2DM treatments and cancer-related mortality. This case study examined the association between metformin use and cancer-related mortality in a prospective cohort. Patients were recruited from 1998 to 1999. A total of 1,353 patients with T2DM were included. The study was completed in 2009. Patient characteristics:

• on metformin – 289;
• without metformin – 1,064;
• 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 were excluded.

At the 9.6-year assessment, a total of 570 patients (42%) had 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 receiving metformin compared with patients not receiving metformin, the RR for cancer mortality was 0.43 (95% CL 0.230.80). The RR increased with increasing metformin dose. For each gram of metformin added, the RR was 0.58 (0.95% CL 0.36–0.93).

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

Of undoubted interest are studies by 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 follow-up, 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 breast.

Antitumor effect of metformin

Evident antitumor effect metformin is most likely associated with activation of cyclic adenosine monophosphate-dependent protein kinase (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. The activation of AMPK in a healthy cell is caused by various metabolic processes, such as hypoxia, hypoglycemia, oxidative and hyperosmolar stress, which allows us to consider the activation of AMPK as an adaptive process that preserves energy reserves in the cell. AMPK is a heterotrimeric protein consisting of catalytic α and regulatory β and γ units in the absence of cAMP (Fig. 8).

Rice. 8. AMPK activation scheme

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

mTOR kinases belong to the phosphatidylinositol kinase (PIKK) family, their C-terminus is similar to the catalytic region of phosphatidylinositol 3-kinases (PI3K), and their N-terminus binds the FKBP12 (rapamycin) complex. Numerous studies 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-sensitive mTORC1 regulates several pathways that determine cell size. Rapamycin-insensitive mTORC2 regulates actin scaffold functions by determining shape. Both complexes integrate various signals to regulate 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 lipid metabolism, playing an essential role in adipogenesis and lipid accumulation. Thus, mTOR kinase integrates 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 positive effects. During a study among patients with prostate cancer, evidence was obtained of 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 in 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 biochemically important protein LKB1, known as a tumor suppressor. Loss of function contributes to the formation of benign tumors, hamartomas 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 pathway mediates the molecular link between DM and cancer. Metformin activates AMPK and affects LKB1-dependent tumorigenesis. Another anti-oncogenic effect of metformin is thought to be based on the study's finding of CD8+ T cells that were deficient in tumor necrosis factor receptor-associated factor 6 (TRAF6) and unable to generate memory T cells. This deficiency was 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 studying the possibilities of other uses of metformin is work 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 an abnormal accumulation of fatty liver droplets that is not associated with alcohol consumption. NAFLD is a component of metabolic syndrome, T2DM, and obesity. NAFLD can be referred to in the literature by different 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 unexplained existence of persistent hepatomegaly, which is confirmed by radiological examination, subject to the exclusion of all other causes leading to hepatomegaly (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 studies devoted to the study of the pathogenesis and effectiveness of treatment of NAFLD. 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 increases more than 2 times compared to normal. The course of NAFLD can be benign or malignant. In the second case, the outcome is cirrhosis and liver failure or hepatocellular carcinoma.

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

Rice. 9. Target tissues for metformin and thiazolidinediones

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

Table 4
Studies of 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
Areas of application of metformin in the present and future

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

Rice. 10. Slow-release metformin, prescribed once daily. GelShield Diffusion System

This extended-release form of the drug is intended to overcome such side effects as a function disorder gastrointestinal tract, simplifying the drug dosage regimen 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 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 must be emphasized that metformin is one of the oldest drugs, and many of its properties have been studied quite well, but this drug rightfully occupies a leading position in the treatment of T2DM today. Clinical studies are ongoing, and many new beneficial properties may be discovered.

Literature

1. Metformin. The Gold Standard. A Scientific Handbook. /Ed. Bailey C.J., Campbell J.W., Chan J.C.N. Wiley. – 2007. – P. 1.
2. Metformin. The Gold Standard. A Scientific Handbook. /Ed. Bailey C.J., Campbell J.W., Chan J.C.N. Wiley. – 2007. – P. 37.
3. Metformin. The Gold Standard. A Scientific Handbook. /Ed. Bailey C.J., Campbell J.W., Chan J.C.N. Wiley. – 2007. – P. 77–88.
4. Muller S., Denet S., Candiloros H. Action of metformin on erythrocyte membrane fluidity in vitro and in vivo // European Journal of Pharmacology. – 1997. – 337. – R. 103–110.
5. Jonson A.B., Webster J.M., SUM C.F. The impact of metformin therapy on hepatic glucose production and sceletal muscle glycogen synthase activity in overweight type 2 diabetes patients // Metabolism. – 1993. – 42. – R. 1217–1222.
6. Tiikkainen M., Hakkinen A.M., Korsheninnikova E., Nyman T. Effect of Rosiglitazone and Metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes / Diabetes 2004. – 53. – R. 2169–2176.
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9. Emsley-Smith A.M., Boyle D.I., Evance J.M., Sullivan F., Morris A.D. Contraindication to metformin therapy in patients with type 2 diabetes – a population-based study of adherence to prescribing quidelines // Diabetic Medicine. – 2003. – 18. – R. 483–488.
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14. Currie C.J., Pool C.D., Gale E.A.M. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes // Diabetology. DOI: 10. 1007/s00125-009-1440-6.
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16. Bernstein L.M. Lipid-lowering and antidiabetic drugs as a means of prevention and therapy malignant tumors: clinical data. Research Institute of Oncology named after. prof. N.N. Petrova Ministry of Health of the Russian Federation, St. Petersburg // Collection of abstracts of the VIII Russian Oncological Congress. – M., 2004. – P. 106–108.

This material discusses mechanism of action of metformin- a popular oral hypoglycemic drug that is prescribed for the treatment of type 2 diabetes mellitus, as well as for persons with overweight and obesity. 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 has not been fully studied. also called “a bestseller not read to the end.” To this day, various studies are actively being carried out and scientists are discovering new facets of this drug, identifying its additional beneficial properties and side effects.

It is known that the World Health Organization has recognized it as 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 only began to be used in the United States in 1995. And in Germany, metformin is still not a prescription drug and German doctors do not prescribe it.

Mechanism of action of metformin

Metformin activates the release of the liver enzyme AMP-activated protein kinase (AMPK), which is responsible for the metabolic processes of glucose and fat. Activation of AMPK is necessary 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 glucose absorption from the gastrointestinal tract.

In simpler terms, after a high carbohydrate meal enters the body, pancreatic insulin begins to be secreted to maintain blood sugar levels within normal limits. Carbohydrates contained in food products, 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 and also 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).

Most important effect The action of metformin is to inhibit (suppress) the production of glucose by the liver, which is typical for type 2 diabetes mellitus.

Another effect of the drug is expressed in delayed absorption of glucose in the intestine, which allows for lower blood glucose levels after meals (postprandial blood sugar) and also increases cell sensitivity to insulin (target cells begin to respond more quickly to the insulin that is released when glucose is absorbed).

How does metformin affect pregnant women with gestational diabetes?

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

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

In animal experiments, no adverse effects of metformin on fetal development were observed.

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

Metformin should be avoided during lactation, because it passes into breast milk. Treatment with metformin should be discontinued during breastfeeding.

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. Polycystic ovary syndrome is often associated with insulin resistance.

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

In the UK, metformin is not recommended as first-line treatment for polycystic ovary syndrome. The recommendation is to prescribe clomiphene and emphasize the need for lifestyle changes, regardless of drug therapy.

Taking metformin for female infertility

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

Another study recommends the use of metformin without reservation as a primary treatment option, as it has a positive effect not only on anovulation, but also on hirsutism and obesity, which are often observed in PCOS.

Prediabetes and metformin

Metformin may be prescribed for prediabetes (people at risk of developing type 2 diabetes), which reduces their chances of developing the disease, although intensive physical activity and a carbohydrate-restricted diet is much preferable for this purpose.

A study was conducted in the United States in which one group of subjects was given metformin, while the other played sports and followed a diet. As a result, the incidence of diabetes mellitus in the healthy lifestyle group was 31% lower than in prediabetics taking metformin.

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

“People with high blood sugar levels who do not have diabetes are at risk of developing clinical type 2 diabetes, called prediabetes.” prediabetes usually applicable to border level fasting plasma glucose (impaired fasting glucose levels) and/or to the level of plasma glucose taken 2 hours after an oral glucose tolerance test with 75 g. sugar (impaired glucose tolerance). In the United States, even the upper limit level of glycated hemoglobin (HbA1c) began to be considered prediabetes.
Individuals with prediabetes have an increased risk of microvascular damage and development of macrovascular complications, similar to long-term complications of diabetes. Pausing or reversing the progression of decreased insulin sensitivity and destruction of β-cell function is the key to achieving prevention of type 2 diabetes.

Many interventions have been developed to promote weight loss: pharmacological treatments (metformin, thiazolidinediones, acarbose, basal insulin injections and weight loss medications), as well as bariatric surgery. These measures are aimed at reducing the risk of developing type 2 diabetes in people with prediabetes, although positive results are not always achieved.

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

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

Is it possible to take Metformin for weight loss? Research results

Research suggests 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, causing weight loss. Although metformin helps you lose weight, the 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 amount of kilograms lost also varies from person to person and is associated with many other factors - body composition, the number of calories consumed daily, and lifestyle. According to the results of the study, 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 a more than modest result.

Mindlessly taking 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 you burn calories during exercise. If you don't exercise, then you probably won't have this advantage.

Is metformin prescribed to children?

Taking metformin by children and adolescents over ten years of age is acceptable - this has been tested by various clinical studies. They did not identify any specific side effects related to the child's development, but treatment should be carried out under the supervision of a doctor.

Conclusions

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

Sources:

1. Petunina N.A., Kuzina I.A. Long-acting metformin analogues // Attending physician. 2012. No. 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.

Metformin hydrochloride (metformin)

Composition and release form of the drug

Film-coated tablets white, oblong, biconvex, with a notch on one side; on a cross section there is a homogeneous white or almost white mass.

The profile of adverse reactions in children aged 10 years and older is the same as in adults.

Drug interactions

When used simultaneously with sulfonylurea derivatives, acarbose, insulin, salicylates, MAO inhibitors, oxytetracycline, ACE inhibitors, clofibrate, cyclophosphamide, the hypoglycemic effect of metformin may be enhanced.

When used simultaneously with GCS, hormonal contraceptives for oral administration, danazol, epinephrine, glucagon, hormones thyroid gland, phenothiazine derivatives, thiazide diuretics, derivatives may reduce the hypoglycemic effect of metformin.

In patients receiving metformin, the use of iodinated contrast agents to diagnostic studies(including IV urography, IV cholangiography, angiography, CT) increases the risk of developing acute renal dysfunction and lactic acidosis. These combinations are contraindicated.

Injectable beta 2 adrenergic agonists increase blood glucose concentrations due to stimulation of beta 2 adrenergic receptors. In this case, monitoring of blood glucose concentration is necessary. If necessary, it is recommended to prescribe insulin.

Concomitant use of cimetidine may increase the risk of developing lactic acidosis.

Concomitant use of loop diuretics may lead to the development of lactic acidosis due to possible functional renal failure.

When taken simultaneously with ethanol, the risk of developing lactic acidosis increases.

Nifedipine increases the absorption and Cmax of metformin.

Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) secreted in the renal tubules compete with metformin for tubular transport systems and may lead to an increase in its Cmax.

Special instructions

Do not use before surgery and within 2 days after surgery.

Metformin should be used with caution in elderly patients and people performing heavy physical work, which is associated with an increased risk of developing lactic acidosis. In patients old age Asymptomatic renal dysfunction is often observed. Particular caution is required if renal dysfunction is caused by taking either diuretics or NSAIDs.

If during treatment the patient develops muscle cramps, indigestion (abdominal pain) and severe asthenia, it should be borne in mind that these symptoms may indicate the onset of lactic acidosis.

During treatment, it is necessary to monitor renal function; Determination of lactate content in plasma should be carried out at least 2 times a year, as well as when myalgia appears.

When metformin is used as monotherapy in accordance with the dosage regimen, hypoglycemia, as a rule, does not occur. However, when combined with insulin or sulfonylurea derivatives, there is a risk of developing hypoglycemia. In such cases, particularly careful monitoring of blood glucose concentrations is necessary.

During treatment, patients should avoid drinking alcohol due to the risk of developing lactic acidosis.

IN preclinical studies Metformin has been shown to have no carcinogenic potential.

Pregnancy and lactation

There have been no adequate and strictly controlled studies of the safety of metformin during pregnancy. Use during pregnancy is possible in cases of extreme necessity, when the expected benefit of therapy for the mother outweighs the possible risk to the fetus. Metformin penetrates the placental barrier.

Metformin is excreted in small quantities into breast milk, with the concentration of metformin in breast milk may be 1/3 of the maternal plasma concentration. No side effects were observed in breastfeeding newborns while taking metformin. However, due to limited data, use during breastfeeding is not recommended. The decision to stop breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of side effects for the baby.

Preclinical studies have shown that metformin does not have a teratogenic effect at doses that are 2-3 times higher than therapeutic doses used in humans. Metformin does not have mutagenic potential and does not affect fertility.

For impaired renal function

Contraindicated in cases of severe renal impairment.

For liver dysfunction

Contraindicated in cases of severe liver dysfunction.

Use in old age