Metformin
Contraindicated combinations
Iodine-containing radiocontrast agents: against the background of functional renal failure in patients with diabetes mellitus, radiological examination using iodine-containing X-ray contrast agents can cause the development of lactic acidosis. Treatment with metformin should be discontinued depending on renal function 48 hours before or during an X-ray examination using iodinated contrast agents and not resumed earlier than 48 hours after, provided that during the examination renal function was found to be normal.
Combinations not recommended
Alcohol: with acute alcohol intoxication, the risk of developing lactic acidosis increases, especially in the case of:
- malnutrition;
- following a low-calorie diet;
- liver failure.
While taking the drug, you should avoid drinking alcohol and medications containing ethanol.
Combinations requiring caution
Danazol: simultaneous use of danazol is not recommended to avoid the hyperglycemic effect of the latter. If treatment with danazol is necessary and after stopping the latter, a dose adjustment of metformin is required under the control of blood glucose concentrations.
Chlorpromazine: When taken in large doses (100 mg per day), it increases blood glucose concentrations, reducing insulin release. When treated with antipsychotics and after stopping the latter, dose adjustment of metformin is required under the control of blood glucose concentrations.
Glucocorticosteroids (GCS) of systemic and local action reduce glucose tolerance, increase the concentration of glucose in the blood, sometimes causing ketosis. During treatment with GCS and after stopping the latter, dose adjustment of metformin is required under the control of blood glucose concentrations.
Diuretics: Concomitant use of loop diuretics may lead to the development of lactic acidosis due to possible functional renal failure. Metformin should not be prescribed if creatinine clearance is below 60 ml/min.
Beta2-adrenergic agonists, administered parenterally: increase the concentration of glucose in the blood due to stimulation of beta2-adrenergic receptors. In this case, monitoring of blood glucose concentration is necessary. If necessary, insulin administration is recommended.
When using the above drugs simultaneously, more frequent monitoring of blood glucose may be required, especially at the beginning of treatment. If necessary, the dose of metformin can be adjusted during treatment and after its cessation.
Antihypertensive drugs, with the exception of angiotensin-converting enzyme inhibitors, can reduce blood glucose concentrations. If necessary, the dose of metformin should be adjusted.
When metformin is used simultaneously with sulfonylurea derivatives, insulin, acarbose, and salicylates, hypoglycemia may develop.
Nifedipine increases 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.
The hypoglycemic effect of metformin can be reduced by phenothiazides, glucagon, estrogens, oral contraceptives, phenytoin, sympathomimetics, nicotinic acid, isoniazid, blockers of “slow” calcium channels, sodium levothyroxine.
Concomitant use with cimetidine reduces the rate of elimination of metformin, which can lead to the development of lactic acidosis.
In healthy volunteers, with simultaneous use of metformin and propranolol, as well as with the use of metformin and ibuprofen, no changes in their pharmacokinetic parameters were observed.
Metformin may reduce the effect of indirect anticoagulants.
Organic cation transporter substrates 1 and 2 (OST1 and OST2)
Metformin is a substrate of the organic cations OCT1 and OCT2.
When used together with metformin:
- OCT1 inhibitors (such as verapamil) may reduce the hypoglycemic effect of metformin;
- OCT1 inducers (such as rifampicin) may increase the absorption of metformin in the gastrointestinal tract and enhance its hypoglycemic effect;
- OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin and lead to an increase in its plasma concentration;
- OCT1 and OCT2 inhibitors (such as crizotinib, olaparide) may reduce the hypoglycemic effect of metformin.
Metformin - 50 years in clinical practice
Since 2005, metformin has been a first-line drug for pharmacological intervention in type 2 diabetes mellitus (T2DM) in the recommendations of the International Diabetes Federation (IDF), since 2006 - a first-line drug together with non-pharmacological treatment of T2DM in the framework of the recommendations of the American and European Diabetes Associations (ADA and EASD). Since 2007, metformin is the only drug in the drug prevention of the development of type 2 diabetes in the ADA recommendations. What allowed this well-known drug to occupy a leading position in the treatment of type 2 diabetes and some other metabolic diseases in the new century?
History of creation. From the first experiences of clinical use to the present day
Diabetes mellitus and its manifestations have been known to the world since ancient times. Since then, people began to try to use plants to treat this disease. It has now been established that more than 400 herbs and plant derivatives are used in various regions of the earth for this purpose. Thus, in the first half of the 20th century, the attention of scientists was attracted by the plant Galega officinalis, a rich source of guanidine - a substance that had hypoglycemic activity, but was toxic and therefore did not find further use. However, this helped G. Tanret in the early 20th century to isolate a guanidine-like alkaloid, which in 1927, in a study on rabbits and dogs, demonstrated a significant hypoglycemic effect, but a narrow therapeutic range. Similar data were noted when studying the use of the substance in humans [1]. This served as a basis for further search and study of guanidine derivatives. One of these was decamethyl diguanide, known as Syntalin A, a drug that was even used in medical practice for some time, but according to the observations of researchers, it had an ambiguous clinical effect - a decrease in glycemia in some patients without any effect in others. Phenylethyl biguanide (phenformin), developed in the USA in the 50s. XX century, has not found widespread use due to the high incidence of associated lactic acidosis. Dimethyl biguanide, or metformin, was first synthesized in 1922 by Werner and Bell in Dublin, studied in detail from a chemical point of view in 1929 and evaluated in a series of studies by Stern in 1957 [1] as a potentially promising hypoglycemic drug for patients with hyperglycemia with low toxicity and a wide therapeutic range. Thus, since 1957, the rapid “career growth” of metformin (Glucophage) began, currently occupying a leading position in the initiation of treatment and prevention of type 2 diabetes, as well as making a significant contribution to solving other important problems in medicine.
Briefly dwelling on the significance of the problem under consideration, we note that according to IDF estimates, by 2025 the number of patients with diabetes will reach a terrifying level of 400 million people. As noted above, the recommendations of the American Diabetes Association and the European Diabetes Association define metformin as a drug that is prescribed immediately upon diagnosis of type 2 diabetes mellitus in parallel with lifestyle changes and diet. This is amazing, but a number of factors allow us to give such categorical recommendations: a better (came with time) understanding of the mechanism of action of the drug, its relative safety even when using high doses in various clinical situations, metformin is effective in the treatment of diabetes mellitus (including in children and adolescents ) and its prevention and adverse cardiovascular outcomes, is relatively inexpensive to use. Let's try to understand the above one by one.
Mechanisms of action and clinical efficacy of metformin
The main mechanism of action of metformin is a decrease in the production of glucose by the liver, which, according to numerous studies, correlates with a decrease in glycemic levels [1, 2]. Metformin plays a role in improving the peripheral effects of insulin [3], reducing gluconeogenesis [4] and oxidation of free fatty acids in the liver, increasing the activity of the anaerobic pathway of glucose metabolism with the formation of lactate, and suppressing lipolysis [3, 5]. A number of studies conducted in vivo [6] and in vitro [7] revealed the activating effect of metformin on the cellular enzyme AMP kinase, which plays a role in the transport of glucose across the membrane via GLUT4 and the oxidation of free fatty acids. It is likely that the improvement in the glycemic profile during therapy with this drug is also associated with similar cellular aspects of its mechanism of action. In addition, dimethyl biguanide has demonstrated the ability to reduce cell membrane stiffness [1], which is often observed in patients with diabetes mellitus and may contribute to the development of its complications.
Coming to the question of the effectiveness of metformin, let us mention that numerous trials of this drug took place in England, Germany and France in the 1990s. [1]. A meta-analysis of randomized trials comparing sulfonylureas with metformin by Campbell et al. [8], revealed their equivalent antihyperglycemic effectiveness. During the same period of time, studies were also carried out in the USA, in one of which [9], when comparing placebo and metformin in a population of 289 patients with type 2 diabetes and obesity, during treatment with the latter for 29 weeks, a decrease in HbA1C levels was revealed by 1.4 % (p < 0.001). Another clear evidence of the effectiveness of dimethyl biguanide therapy is the results of the UKPDS 34 study [10]. We note, however, that the progression of diabetes mellitus over time requires correction of approaches to its treatment. The more urgent it becomes to find treatment options that, while improving glycemic control, the most important marker for the prevention of microvascular complications, will not significantly affect the quality of life of patients and their adherence to therapy. Here it is important to note polymorbidity, which is common among this population, requiring the prescription of a number of medications. All the more interesting from this perspective is the dose-dependent effect of metformin, proven in a number of randomized controlled studies [11, 12], demonstrating varying effectiveness of doses from 500 to 3000 mg/day and indicating the possibility of increasing the daily dosage of the drug within a certain range if necessary to tighten glycemic control while maintaining while maintaining adherence to therapy and avoiding polypharmacy. Thus, according to the results of the clinical trials mentioned above, the average effective dose in the USA is considered to be 2000 mg, in Europe - 3000 mg of metformin per day. The frequency of side effects, including gastroenterological ones, is also dose-dependent, which, according to a study by Garber AG et al. [11], higher in the range from 1000 to 2000 mg of the drug per day, however, to prevent their occurrence, a slow titration of the dose of metformin is sufficient. Equally important is the possibility of combining the drug in question with other oral hypoglycemic agents (OHADs) or insulin without losing its hypoglycemic effectiveness. Thus, monotherapy with PSS reduces HbA1C by 1–1.5%, and the combined administration of metformin and sulfonylureas (SMU) in patients subcompensated by diet and physical activity allows doubling the effectiveness of treatment (reduction in HbA1C levels by 1.5–2 .2% of the original) [13, 14]. The combination of metformin with any other class of PSS - thiazolidinediones, drugs of glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, insulin therapy, drugs for weight loss (orlistat, sibutramine, rimonabant) and correction of cardiovascular disorders does not affect the tolerability and safety of combination therapy in general [1]. This, as well as a number of factors that we will consider below, makes it possible to use this drug as a 1st-line drug in the treatment of patients with type 2 diabetes, who often, due to polymorbidity, need to be prescribed several differently acting drugs.
Obesity, especially abdominal obesity, is characterized by insulin resistance and is closely combined with components of the metabolic syndrome [15]. Obesity increases the risk of developing type 2 diabetes [16]. However, most patients with type 2 diabetes are already overweight or obese. Numerous studies evaluating the effect of metformin on body weight show different results - from a significant decrease during this therapy to the absence of any effect. In this regard, the data from the Cochrane review by Saenz A. et al are more interesting. [17], which included clinical trials lasting at least 12 weeks, and an earlier meta-analysis of 9 randomized controlled trials by Johansen K. [18]. In both cases, the results indicate no effect of metformin on body weight compared to placebo and diet therapy regimens. According to the above-mentioned review by Saenz A. et al., as well as a small meta-analysis by Campbel IW et al. [19] a comparison of metformin and sulfonylurea drugs in the same aspects demonstrates the clear advantages of the first - its neutral effect on the recorded increase in body weight during PSM therapy. It is well known and confirmed by the results of a number of clinical trials that the administration of a drug from the group of thiazolidinediones and insulin therapy contribute to weight gain. The addition of metformin to an insulin regimen can reduce these negative effects on weight, as well as improve the glycemic profile, reduce the daily insulin dose and the frequency of hypoglycemic reactions, as demonstrated by Yki-Jarvinen et al. in a clinical randomized placebo-controlled trial [20].
Additional (non-antihyperglycemic effects)
Let us briefly look at determining the effect of metformin on the lipid profile. We present the results of two randomized, double-blind, multicenter studies [9]. In the first, which included 289 obese patients subcompensated for diet therapy, the effect of 2550 mg/day metformin for 29 weeks was compared with placebo. According to the results of the trial, a significant decrease in the level of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) was noted (p = 0.019 and p = 0.001, respectively). In the second, three regimens were compared - monotherapy with metformin 2550 mg/day, monotherapy with glibenclamide 20 mg/day and combinations of both drugs; the number of randomized patients was 632. The results revealed a significant improvement in the lipid profile (decrease in the levels of total cholesterol, LDL-C, triglycerides ; in all cases p < 0.01) in the groups of metformin monotherapy and combination of two drugs. A meta-analysis of 41 randomized controlled trials [21] further confirms the above data.
Of course, the positive effect of metformin on the lipid profile is its additional advantage, but it is not able to fully explain its unique cardioprotective properties, first identified in the largest study UKPDS 34, which became fateful for the drug. We will not dwell on the data obtained regarding microvascular complications of diabetes mellitus, which are strictly related to the level of glycated hemoglobin. More interestingly, the use of metformin compared with dietary therapy was associated with a reduction in the risk of all diabetes-related endpoints by 32% (p = 0.0023), myocardial infarction by 39% (p = 0.01), death from all causes by 35% (p = 0.011) and death from diabetes-related causes by 42% (p = 0.017) [10]. When compared in the group receiving PSM or insulin therapy [10], there were no significant changes in any of the specified principal endpoints. For example, intensive glycemic control in this group reduced the risk of myocardial infarction by only 16% (p = 0.052). As is known, UKPDS 33 and 34 included patients with newly diagnosed diabetes mellitus and not diagnosed with cardiovascular pathology (only 1% had a history of myocardial infarction at baseline). In this regard, the results of the study, in fact, presented the results of primary prevention of cardiovascular complications. However, the data from the following clinical trials, which included people with pre-existing cardiovascular disease, are important. In the randomized, double-blind PRESTO study [22], the design of which we will not dwell on in detail, which studied the frequency of restenosis in patients with type 2 diabetes who underwent coronary angioplasty for occlusive atherosclerosis of the coronary arteries, there was also a significant and significant reduction in the risk of all clinical events - by 28% (p = 0.005), the risk of myocardial infarction by 69% (p = 0.002), death from all causes - by 61% (p = 0.007), at the same time, a decrease in the frequency of necessary revascularizations due to the progression of ischemic heart disease (CHD) did not reach statistical significance. Another study (23) examining the effect of metformin on the risk of recurrent myocardial infarction found an 82% reduction (p = 0.003) compared with other groups. Thus, while tight glycemic control is a critical factor in determining clinical outcomes in patients with type 2 diabetes overall, the significant contribution of dimethyl biguanide in improving cardiovascular endpoints cannot be explained solely by the influence of carbohydrate metabolism and other classical modifiable cardiovascular risk factors. such as dyslipidemia, obesity or hypertension. It is obvious that metformin has its own additional cardioprotective mechanisms of action, including improvement of endothelial function, effect on hemostasis, oxidative stress, protein glycosylation and other cellular processes underlying the progression of atherosclerosis [24, 25]. Further research in this area will provide an even more precise understanding of the unique mechanism of action of this drug.
Safety. Lactic acidosis
Numerous data indicate a low risk of developing lactic acidosis during metformin therapy compared with other bigunides, although metformin does sometimes cause a slight increase in blood lactate levels [26]. This is due to the physicochemical properties of the drug molecule, its ability to interact with the cell membrane and the characteristics of its metabolism. Thus, the risk of developing this complication is practically minimal with strict adherence to these recommendations regarding existing contraindications, especially those related to impaired renal function and conditions accompanied by hypoxia.
Metformin outside the treatment of type 2 diabetes
The socio-economic importance of preventing type 2 diabetes in the era of its growing pandemic is beyond doubt. Lifestyle changes, which have proven effective in a number of key clinical studies (DPP, IDPP, STOPP-NIDDM), unfortunately, due to low patient adherence, are not enough. Thus, medication options in achieving this goal become relevant. Metformin is not inferior to its position in this area. The DPP study noted a reduction in the risk of developing type 2 diabetes by 58% (p < 0.001) with lifestyle changes and by 31% (p < 0.001) with metformin therapy at a dose of 1700 mg/day compared with placebo. The drug was most effective in young patients with significant obesity and glycemic disorders. In the randomized population-based IDPP trial, metformin demonstrated an equivalent 30% reduction in the likelihood of developing type 2 diabetes in both groups, regardless of lifestyle modification, compared with placebo. Currently, the evidence base for drugs that can be used to prevent type 2 diabetes, such as Actos and Rimonabant, is growing. Based on existing data, the consensus of the International and American Diabetes Associations suggested the use of metformin in the stage of impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) in combination with lifestyle changes [27, 28].
Polycystic ovary syndrome (PCOS) is a problem in 5–10% of women of reproductive age and one of the most common causes of infertility. In addition, PCOS is associated with a risk of cardiovascular complications due to severe insulin resistance. The results of clinical trials vary widely, so we refer to two Cochrane reviews [29, 30]. Data from these reviews indicate that when using metformin in this category of patients, there is a decrease in the levels of testosterone, androstenedione, dihydroepiandrosterone sulfate in the blood serum compared to placebo, and the combination of metformin with clomiphene increases the likelihood of ovulation by 4 times with high statistical significance (p < 0 ,00001). Currently, dimethyl biguanide is not included in the international standards of medical care for this disease due to the still insufficient and ambiguous evidence base, however, the convincing results of a number of clinical studies have led to the fact that in recent years some countries in Europe and the USA have developed their own recommendations for prescribing metformin to patients with PCOS, especially women with obesity and clinical manifestations of insulin resistance.
One of the common pathological conditions nowadays, also associated with insulin resistance and the accompanying risk of cardiovascular complications, is non-alcoholic steatohepatosis. A Cochrane analysis of three studies examining metformin in the treatment of the disease [31] revealed the ability of the drug to influence normalization (odds level 7.75, 95% CI 2.37–25.35; p = 0.0007) and even a decrease in transaminase levels (odds level 19 .70, 95% CI 7.09–31.31; p = 0.0002). Another study [32] noted a significant decrease in body mass index, plasma insulin and C-peptide levels, insulin resistance over 6 months of treatment, and by the end of the study, 59% and 75% of patients showed normalization of alanine (ALT) and aspartic acid levels, respectively. (AST) aminotransferases during the use of metformin compared with placebo. The lack of data on clinically significant outcomes (cardiovascular morbidity and mortality) somewhat weakens the impression of the results presented. There is no doubt that further scientific research in this area is needed.
Use of metformin in children and adolescents
Speaking about the enormous prevalence of type 2 diabetes in the world, we must not forget that the proportion of patients in childhood and adolescence is steadily growing. In the United States, recent data indicate that approximately 0.2–0.4% of adolescents aged 12–19 years have type 2 diabetes. It is obvious that in this category of people, normalization of carbohydrate metabolism should be carried out as quickly as possible in order to reduce the likelihood of developing late complications of the disease at a young age. In addition, an additional unfavorable factor that contributes to the development of type 2 diabetes in children and adolescents, along with the classic ones (high-calorie diet, obesity, low physical activity, genetic factors, etc.), is the actual physiological (pubertal) insulin resistance. And in this situation, metformin has found its application - by reducing insulin resistance and thus influencing the key links in pathogenesis, the drug turned out to be effective in treating the disease in this group of patients [33, 34]. Currently, the drug is recommended for use in adolescents and children over 10 years of age with type 2 diabetes in Europe and the USA as monotherapy or in combination with insulin; the maximum dose is 2000 mg/day.
Given that metformin has the ability to improve insulin action in peripheral tissues, it has been suggested that improved glycemic control can be expected in patients with type 1 diabetes when the drug is combined with insulin therapy. A number of small studies [35, 36] indeed noted that the administration of metformin can achieve a reduction in HbA1C levels compared with placebo. Thus, dimethyl biguanide made an attempt to occupy another, seemingly completely inappropriate niche for it.
Conclusion
To conclude this topic, I would like to cite an aphorism written by G. Biger: “Victories that are easily achieved are worth little. Only those we can be proud of are those that are the result of persistent struggle.” Perhaps all the gains of metformin cannot be called “the hand of fortune.” Overcoming a series of endless clinical trials for more than 50 years, it gradually strengthened its position and found more and more new areas of application. Few drugs in medicine are as renowned for their multifaceted clinical effectiveness and safety as metformin. Now, having put into practice the fruits of many years of scientific work on the study of this truly extraordinary drug, I would like to believe that we are yet to witness the discovery of completely new, unique possibilities for the use of metformin in medicine.
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A. L. Terekhova A. V. Zilov , Candidate of Medical Sciences MMA named after I. M. Sechenov , Moscow
Buy Metformin Canon film-coated tablets 500 mg No. 60 in pharmacies
Instructions for use
Metformin tablet p.o 500 mg No. 60
Dosage forms
tablets 500 mg Synonyms Bagomet Vero-Metformin Gliminfor Gliformin Glucophage Glucophage Long Diaformin OD Metfogamma 1000
Metformin
Siofor 1000
Formetin Group Antidiabetic agents - biguanides International nonproprietary name Metformin Composition Active substance - metformin hydrochloride. Manufacturers Kanonpharma Production (Russia) Pharmacological action Hypoglycemic. Reduces the concentration of glucose 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. Does not alter insulin secretion by beta cells of the pancreatic islets. Normalizes the lipid profile of blood plasma in patients with non-insulin-dependent diabetes mellitus: it reduces the content of triglycerides, cholesterol and LDL and does not change the levels of lipoproteins of other densities. Stabilizes or reduces body weight. Rapidly absorbed from the gastrointestinal tract. The maximum concentration is reached after approximately 2 hours. Absorption from the gastrointestinal tract ends after 6 hours and the concentration in the blood begins to gradually decrease. Can accumulate in the salivary glands, liver and kidneys. It is excreted unchanged by the kidneys. The half-life is 6.2 hours (plasma) and 17.6 hours (blood), because accumulates in erythrocytes. Side effects At the beginning of the course of treatment - anorexia, diarrhea, nausea, vomiting, flatulence, abdominal pain (reduced when taken with meals); metallic taste; megaloblastic anemia; lactic acidosis (respiratory disturbances, weakness, drowsiness, hypotension, reflex bradyarrhythmia, abdominal pain, myalgia, hypothermia), hypoglycemia; rashes and dermatitis. Indications for use Diabetes mellitus type 2 with ineffective correction of hyperglycemia by diet therapy, incl. in combination with sulfonylureas; type 1 diabetes mellitus as an adjunct to insulin therapy. Contraindications Hypersensitivity, kidney disease or renal failure, severe liver disorders, cardiac and respiratory failure, acute phase of myocardial infarction, infectious diseases, major operations and injuries, chronic alcoholism, acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma, conducting research using radioactive isotopes of iodine, pregnancy, breastfeeding. Restrictions on use: Children and the elderly (over 65 years of age). Directions for use and dosage : Orally, during or immediately after meals. Monotherapy and combination therapy with other oral hypoglycemic agents. The initial dose is 500-1000 mg 1 time per day in the evening. After 7-15 days, if there are no adverse effects from the gastrointestinal tract, 500-1000 mg is prescribed 2 times a day in the morning and evening. A further gradual increase in the dose is possible depending on the concentration of glucose in the blood. Overdose Symptoms: lactic acidosis. Treatment: hemodialysis, symptomatic therapy. Interaction Phenothiazines, corticosteroids, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium antagonists, isoniazid, thiazide and other diuretics weaken the effect. Insulin, sulfonylurea derivatives, acarbose, NSAIDs, MAO inhibitors, oxytetracycline, ACE inhibitors, clofibrate derivatives, cyclophosphamide, beta-blockers enhance the effect. Furosemide increases the maximum concentration. Nifedipine increases absorption, maximum concentration, and prolongs elimination. Amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene and vancomycin during long-term therapy can increase the maximum concentration by 60%. Incompatible with alcohol. Special instructions It is necessary to constantly monitor renal function, glomerular filtration, and blood glucose levels. Vitamin B12 levels should be determined once a year. When transferring a patient to metformin, it is prescribed immediately after discontinuation of the previous drug, with the exception of replacing chlorpropamide. It should not be used before surgical operations and within 2 days after them, as well as within 2 days before and after diagnostic studies. Should not be prescribed to people performing heavy physical work. Storage conditions List B. In a dry place, protected from light.
