Type 2 diabetes is often treated today with metformin. This is the main indication for this drug. The full composition of the product and detailed information on its indications are indicated in the manufacturer's instructions.
The release form of the drug is oval biconvex tablets in a white or beige shell, which contain the active drug - metformin hydrochloride (500 g, 850, 1000 mg). Their appearance is the presence of marks and embossing of the symbol “f” on different sides. The outline blister packs contain 10, 15, 20 tablets. The medicine is sold in cardboard packs, which contain 3 or 6 contour packs, as well as instructions for using the medicine.
Features of the impact
Metformin is a hypoglycemic agent that belongs to the biguanide group. The active substance of the same name is distinguished by its ability to reduce glucose synthesis. In addition, the drug increases sensitivity to insulin and improves the processing of glucose by cells. When taking metmorphine, it is possible to stabilize the patient’s body weight, and in some cases even reduce it.
After oral administration, the drug is slowly absorbed into the gastrointestinal tract. The maximum amount of active substance in the blood is observed after approximately a couple of hours. In this case, the bioavailability of the drug is 50-60%. If the medicine is taken with fatty foods, the absorption of the active substance slows down.
Is Metformin a cure for everything? Yes, but no
We are here, in the editorial office of “XX2 Century”
, we love metformin very much and talk about it at every opportunity. Today it suppresses the growth of cancer cells, tomorrow it fights inflammation, the day after tomorrow it helps you lose weight, and next week it completely prolongs life. Readers might have the impression that this medicine overcomes any disease. Unfortunately, this is not entirely true and almost every piece of good news comes with a “yes, but.” So we decided to write about metformin again - this time a long text that will explain to those who missed everything where this drug came from, what it treats and how successful it is.
Story
It all started with grass. Goat's rue, aka goat's rue, aka Italian ferret, aka, scientifically, Galega officinalis
- a perennial herbaceous plant. In medieval Europe, it was used to treat frequent urination - one of the symptoms of diabetes - and some other diseases. It is difficult to say how long goat's rue has been used in folk medicine, but it is known that the famous English aesculapian Nicholas Culpeper mentioned it back in 1652 in the book “The English Physician”.
At the end of the 19th century, scientists took a closer look at goat's rue and found that it contains large amounts of guanidine (this colorless crystalline substance was first synthesized in 1861). In 1918, during experiments on rabbits, scientists showed that guanidine lowers blood glucose levels. But the compound turned out to be too toxic to treat people, so scientists began experimenting with guanidine derivatives. In 1922, Emil Alphonse Werner and James Bell synthesized N, N-dimethylguanidine to obtain dimethylbiguanidine, known to us as metformin, and seven years later the German scientist Karl Slotta tested it on animals . There were other drugs based on guanidine - galegin (isoamylene-diguanidine), biguanides Syntalin A and B. Synthalins were even used in clinical practice for some time, but after the industrial production of insulin began (in 1923 by Eli Lilly and Company
started selling it under the name “Iletin”), they forgot about guanidine derivatives.
Galega officinalis
or goat's rue is the grandfather of the most popular antidiabetic drug.
In 1949, metformin came into the hands of Philippine infectious disease specialist Eusebio Garcia. He called the substance “flumamine” and used it to treat influenza and malaria. A year later, in the article Fluamine, a new synthetic analgesic and antiflu drug, Garcia said that a single injection of the drug relieved the headaches of thirty patients and completely cured them in 24 hours. The doctor did not know the exact mechanism of action, and suggested that flumamine lowers the concentration of sugar in the blood, but did not provide any evidence.
These speculations were enough to interest another physician, the Frenchman Jean Stern, a specialist in diabetology. He conducted experiments on dogs, rats and rabbits and found that six months of treatment had no effect on their development or liver function. Even during the autopsy, no anomalies were found. Stern conducted clinical trials on humans, called the drug a “glucophage” (“sugar eater,” similar to a bacteriophage) and began treating diabetics with it.
French doctor Jean Stern and the hospital where he studied the properties of metformin.
Metformin almost immediately had competitors - the more powerful phenoformin and buformin. But these drugs caused lactic acidosis - a dangerous condition that is accompanied by depression of the central nervous system, impaired breathing, cardiovascular function and urination. Therefore, by the end of the 70s they were no longer used in most countries. And that’s when metformin became the main alternative to insulin. It was sold in France and the UK in the late 50s, in Canada in the 70s, and only entered the American market after approval by the Food and Drug Administration (FDA) in 1994 year. There he quickly became a “bestseller”
What do we know about metformin
Metformin is now considered a “first-line drug” for the treatment of type 2 diabetes. Its main advantage is that it practically does not cause hypoglycemia, which distinguishes it from insulin and another class of glucose-lowering drugs - sulfonylurea derivatives. Metformin reduces blood glucose concentrations by inhibiting its production in the liver, while sulfonylureas increase the release of insulin from beta cells in the pancreas. In addition, it does not promote weight gain. Of course, it also has side effects, unpleasant, but not fatal: the most common are gastrointestinal disorders, in particular nausea, vomiting, flatulence and diarrhea. And reducing appetite is even beneficial.
Much of what we know about the health effects of metformin comes from clinical studies. This drug was originally developed to lower blood sugar, and was studied, of course, primarily in the context of diabetes. In order to talk about the advantages and disadvantages of metformin, you need to talk at least a little about how doctors obtained this information - otherwise the story will turn into “scientists have proven it.” Here are some of the most significant clinical trials on type 2 diabetes:
- The University Group Diabetes Program, UGDP (University Group Diabetes Program)
- United Kingdom Prospective Diabetes Study, UKPDS (British Prospective Diabetes Study)
- Diabetes Prevention Program, DPP (Diabetes Prevention Program)
The UGDP was the first randomized clinical trial focused on diabetes. It involved 1,027 people, the study lasted 21 years, from 1960 to 1981, and the first results were published in 1970. Scientists wanted to find out which medicine is most effective in preventing the development of cardiovascular complications. The clinical trial was subject to fierce criticism, including due to errors in randomization. However, the FDA found no reason to disbelieve its findings. Participants were not taking metformin, but the UGDP declared another drug in the same class, phenformin, ineffective, and as a result, the “similar” drug was not approved for use in the United States. It was thanks to the UGDP that the drug's entry into the market in this country was delayed for many years. UKPDS was the largest clinical study at that time - it included 5102 patients with type 2 diabetes. The test lasted 20 years, from 1977 to 1997. UKPDS was meant to answer the question: can intensive blood glucose control prevent complications, and what is the best medicine to do this? Participants were taking first-generation sulfonylureas, insulin, or following a diet. After the publication of the results, doctors began to recommend metformin more often.
3,234 people participated in the DPP The goal of the study was to find the most effective way to prevent type 2 diabetes in people with prediabetes. To do this, one group was given diet, exercise and lifestyle changes, another was given metformin, and the third was given a placebo. After the clinical trial, they conducted another one - the Diabetes Prevention Program Outcomes Study, DPPOS, or, in Russian, “Diabetes Prevention Program: Study of the Outcomes.” Doctors studied the health status of DPP participants after 15 years.
During the UKPDS, only overweight patients received metformin. The results showed that the drug reduced the risk of death from diabetes complications by 42% and all-cause mortality by 36%. A good result, but not so impressive considering that the drug was compared to a regular diet. The risk of cardiovascular complications in patients on metformin, insulin and sulfonylureas was practically no different. When paired with urea derivatives, the drug even increased mortality. But, unlike other drugs, metformin did not promote weight gain and was less likely to cause hypoglycemia. Therefore, scientists have proposed no less than metformin as a first-line drug in the treatment of obese patients. This marked the beginning of his popularity.
DPP/DPPOS showed that taking metformin could reduce the risk of developing diabetes in people with prediabetes by 31%. But it’s better to change your lifestyle - in this case, the incidence is reduced by 58%. Good old exercise and diet turned out to be almost 2 times more effective. But the drug had another advantage - metformin helped to lose weight. People with prediabetes who took the drug lost an average of two kilograms. The effect lasted as long as the study participants took the pills, and the medicine was well tolerated.
Of course, there have been other studies of metformin and even meta-analyses of these studies. However, we still do not know everything about the advantages and disadvantages of this drug. For example, scientists are still trying to figure out how metformin affects the development of cardiovascular diseases and mortality - data on this matter is contradictory. A 2011 review of 30 papers found that a diabetes drug did neither significant harm nor significant benefit to the heart, and only performed well when compared to a placebo or no treatment at all. A 2021 paper that analyzed 300 studies found that there was no difference at all between nine classes of glucose-lowering drugs in terms of mortality and cardiovascular disease. However, the authors of the analysis acknowledge that the selected articles had a high risk of bias - more than half of the publications presented information selectively, and sponsors participated in the work on them. On the other hand, a recent study based on 17 publications shows that in patients with chronic kidney disease, congestive heart failure and chronic liver failure, metformin does reduce mortality.
New application
In Russia and the USA, metformin is approved only for the treatment of type 2 diabetes, but they are also trying to treat other diseases. And the more that becomes known about the mechanisms of action and the effect of the drug on the body, the more actively they are looking for new uses for it.
It has long been known that taking metformin is accompanied by weight loss. DDP and DDPOS did not open doctors' eyes, but only confirmed previous observations. Therefore, doctors tried to treat healthy obese people with metformin. One of the first such studies was published in 1970 in the Lancet
. Scientists compared the effectiveness of metformin and fenfluramine on the example of 34 women aged 22-59 years. After 8 weeks of therapy, they concluded that fenfluramine worked better and had fewer side effects.
Work from 1998 and 2001 rehabilitated the glucose-lowering drug and showed that it reduced weight in non-diabetics, but a later meta-analysis came out that called these results into question. The scientists selected 57 studies and excluded 48 of them because they did not meet clinical trial standards. There were only 9 left - and after analysis it became clear that there was not enough data on the effectiveness of metformin. Three years later, another review came out and confirmed the results of the previous one. Metformin seemed to reduce weight by 3-9 kilograms, but the sample of such studies was small, the duration was short, and the design was “weak.” In addition, in addition to taking the medicine, the participants did physical exercise - try to figure out what exactly helped them lose weight. Several longer trials without these shortcomings showed only minor weight loss.
Four years ago, the results of perhaps the largest clinical study devoted to the treatment of obesity in non-diabetics were published. If in previous works we were talking about three to four dozen people, now there were 200 volunteers. 20% were unable to lose weight at all, and 9 people gained it. The remaining study participants lost an average of 5% of their body weight, and the drug helped people with impaired insulin sensitivity the most. But there was also a methodological pitfall in this study: there was no randomization of the control group.
Overweight children and adolescents are also treated with metformin, but not particularly successfully. In 2021, Cochrane, an international NGO that studies the effectiveness of health technologies, presented a systematic review and showed that not only metformin, but also other drugs are ineffective in this population. And the quality of the available data leaves much to be desired. In general, doctors admit that it is too early to recommend a diabetic drug for the treatment of obesity for both children and adults. The problem is still solved mainly by diet and exercise.
Another use of metformin is in the treatment of polycystic ovary syndrome (PCOS). PCOS is a condition in which women's levels of male hormones (androgens) increase, the functioning of the ovaries is disrupted and the menstrual cycle is disrupted. As a result, ovulation does not occur, and it becomes difficult (although not always impossible) to get pregnant. Many patients experience excess hair growth on the face and body, acne appears, and about half gain excess weight. It was not possible to fully understand the causes of PCOS, and it is not possible to cure it once and for all. But it is already known that the disease is associated with tissue insensitivity to insulin, and women with this syndrome have an increased risk of developing type 2 diabetes. Metformin, which fights insulin resistance, comes in handy here.
But it's not that simple. In 1994, the drug worked well - then Venezuelan scientists conducted a study with the participation of 29 women, 7 of whom restored their menstrual cycle, and three spontaneously became pregnant. “Many, if not all, of the metabolic disorders of PCOS can be reversed with metformin,” the authors wrote. True, they immediately stipulated that they did not perform randomization and did not use a placebo for comparison. However, larger and more sophisticated clinical trials in 2006-2007 did not confirm the optimistic assumptions. Metformin did not stimulate ovulation particularly effectively and was inferior to clomiphene (trade name Clostilbegit).
According to the clinical guidelines of the International Endocrine Society, the diabetic drug helps with metabolic disorders and irregular periods, but has limited or no effectiveness in treating infertility, acne and excess hair growth. Participants in a seminar organized by the American Society for Reproductive Medicine came to a similar conclusion. They recommended metformin only for women with impaired glucose tolerance. But a 2014 Cochrane review says the drug is more effective than placebo and increases the chance of getting pregnant. True, the quality of the evidence base of the studies was considered low, and the likelihood of error was considered high.
And metformin, theoretically, can help fight cancer. But to what extent these hopes are justified is still unknown. They began to take a serious look at the medicine from this side only 12 years ago - an insignificant period if you remember how long it lasted, for example, UKPDS. In 2005, Josie Evans and her colleagues from the University of Dundee reported that taking metformin reduced the incidence of cancer among diabetics by 23%. They came to these conclusions after analyzing data from the DARTS electronic medical database.
The publication inspired other doctors, and they began to double-check their colleagues’ findings using other medical registries. Gradually, more and more studies confirmed the benefits of metformin. Reviews of scientific papers appeared that showed a decrease in incidence at the level of 31-34%. Then - experiments on cell cultures and mice. It turned out that in rodents, under the influence of a diabetic drug, the growth of tumors slows down by as much as 50% - however, the drug was fed to them in doses exceeding human doses.
Why can’t we please readers and say that we have finally found a new effective cure for cancer? For two reasons. Firstly, there is no abstract “cancer” - it is a collection of different oncological diseases. How effectively metformin combats each of these needs to be tested in clinical trials, a process that is far from complete. Second, the reliability of the data that generated early enthusiasm has been called into question. In two dozen papers, errors were found that could distort the results. And where they didn’t find it, they didn’t find a connection between metformin and cancer incidence. In general, more time is needed, more research is needed.
Metformin and aging
If metformin is mentioned in the media, the article is probably talking about life extension. Gerontologists look to the old drug with hope, and they have good reason for this. Firstly, in recent years, scientists have begun to actively study the molecular and genetic mechanisms of aging. Research shows that calorie restriction increases the lifespan of mice and rats by about 30 to 40%. According to an article published this year, such “therapeutic fasting” also prolongs the life of primates. “What does metformin have to do with it?” you ask. According to some scientists, metformin causes approximately the same changes in the body as calorie restriction: it increases sensitivity to insulin, lowers cholesterol, and improves physical condition. And gene expression in rodents fed metformin resembles that in animals on a low-calorie diet.
So scientists set out to test the drug’s effect on model organisms. Caenorhabditis elegans worms treated with metformin lived 18-36% (depending on the dose) longer than their relatives from the control group. Mice - by 5%. By the way, similar experiments were carried out here in Russia, at the Oncology Research Institute named after. N. N. Petrova. Scientists fed metformin not to ordinary rats, but to a breed created specifically for studying hypertension and cardiovascular diseases. In such animals, the average life expectancy increased by 37.8%. Gerontologists even got to crickets: in the species Acheta domesticus, after treatment with an antidiabetic drug, the maximum life expectancy was 138% compared to the control group.
The next logical step would be to conduct human trials. The results of one such study have already been published. Scientists analyzed data from 180,000 people: 78,000 had diabetes and took metformin, 12,000 took sulfonylureas, and 90,500 were healthy. This information was obtained not from a double-blind, placebo-controlled trial, but from the Clinical Practice Research Datalink. The results showed that diabetics on metformin live 15% longer than healthy people. The media wrote about a drug that can prolong life, but some scientists' work entitled “Can people with type 2 diabetes live longer than healthy people?” I wasn't impressed at all. Here's what Kevin McConway, a professor of applied statistics at the British Open University, said about it:
“The title of the article is misleading because someone who reads it may misunderstand it - in fact, this study cannot answer the question asked for reasons I will give below, and it seems as if doctors have reason to recommend metformin for healthy people. But this is not what the study is about.
In the press release, Craig Curry says, “Once a person develops diabetes, their life expectancy is shortened by an average of 8 years,” and goes on to explain why. If diabetics live so much shorter than healthy people, how can they “live longer than those who don't have diabetes,” as the article and press release headlines say?
That's because the study focused on a period of time when diabetic patients were receiving metformin as first-line therapy (this group was also compared with those who received sulfonylureas as first-line therapy). At some point, many patients will be transferred to second-line therapy because their diabetes or its symptoms have worsened. But at this point the research simply ends.
So the quote about reducing life expectancy in patients with type 2 diabetes by 8 years is talking about the patient's entire life after diagnosis, including the period when they are on more aggressive second-line therapy. But the study only takes into account the period of time before a change in treatment regimen. This won’t fit into a succinct headline, but it’s important to note that it’s not all that simple.
But if the survival rate of diabetics taking metformin is significantly higher than that of healthy people, albeit for a limited period of time, doesn't that mean that people who don't have diabetes should take metformin to live longer? No, it doesn't mean that. This apparent difference may be due to something other than metformin. […]
The difference in survival between diabetics on metformin and controls was statistically significant, but essentially quite small and likely within the range that can be explained by residual confounding (the influence of other variables not taken into account in the analysis).”
In addition, it would be remiss not to mention that the study was funded by pharmaceutical companies AstraZeneca
and
Bristol-Myers Squibb
.
Employees of these firms had access to the study data, although the article says they had no influence on the analysis, peer review or publication process. And the scientists themselves are quite familiar with the pharmaceutical industry. Five worked for Pharmatelligence
, a research consulting company that receives grants from drug manufacturers.
Another was an employee of Bristol-Myers Squibb
. This in itself does not make the results unreliable, but, you see, it is somewhat alarming. Especially considering the fact that both sponsoring companies produce metformin.
So, without full-fledged clinical trials, this issue cannot be understood. One of the first studies on the connection between metformin and aging was to be the Metformin in Longevity Study. But since its launch in 2014, no information has appeared about it. Preliminary results were supposed to be obtained two years ago, but since then not a single publication has been published.
Another clinical trial is approaching - Targeting age with Metformin (TAME). This double-blind, randomized, placebo-controlled study is the gold standard, just the way we like it. It will be attended by 3,000 people aged 65 to 79 years. TAME is quite unusual for several reasons. Firstly, it is aimed at studying something that does not seem to exist. Aging, from a medical point of view, is not a disease. There is also no generally accepted biomarker by which one could understand whether this process is slowing down or not. Therefore, the goal of the study is to determine whether metformin can slow down the development of age-related diseases: cardiovascular, neurological, oncological, and so on.
Scientists hope they can set a precedent so that in the future the FDA will recognize aging as an “indication,” a condition that can be treated. "I think the FDA would be more likely to accept something called 'comorbidities' than something called 'aging,'" said Nir Barzilai, the team's chief scientific officer. - Even in our... in my opinion, old age is not a disease. It's human nature, you know! We are born, we die, and in between we grow old... I mean, “I don’t care what you call it, as long as I can delay it.”
Another unusual detail is that the study is not sponsored by pharmaceutical companies or the government. Funds are raised by the American Federation for Aging Research, and anyone can donate. According to Barzilai, conducting clinical trials will cost "$50 million, give or take 20 million." The results will not come soon: it will take some time to raise money, the research itself will last 3-4.5 years, plus time for processing and publishing the data. But when it comes to prolonging life, you can wait.
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Metformin may be helpful for autism.
Indications and contraindications
Metformin, the instructions emphasize this, is prescribed for the treatment of type 2 diabetes mellitus (non-insulin dependent). It is indicated in cases where diet therapy and planned effective exercise have proven ineffective in the fight against obesity. For adults, the drug can be used as monotherapy, as well as in combination with insulin or other drugs with a hypoglycemic effect. For children, a combination is possible only with insulin or as a stand-alone drug.
The main contraindication for taking the drug is hypersensitivity to the active substance and other auxiliary components in the composition. The medicine is not prescribed for people under 10 years of age or during pregnancy, since pathologies in the development of intrauterine pathologies in the unborn child cannot be ruled out. Also prohibited from using the product are various kidney pathologies, as well as diseases that lead to disruption of their functions.
Other contraindications:
- Liver disorders.
- Heart and respiratory failure.
- Myocardial infarction.
- Postoperative conditions and injuries.
- Diabetic ketoacidosis.
- Lactic acidosis.
Treatment with the drug should be avoided in case of chronic alcoholism, as well as in a state of acute alcohol poisoning. This increases the risk of developing lactic acidosis. There are other contraindications that the doctor will definitely take into account when prescribing treatment for type 2 diabetes with metformin.
Prescribe medication to older people with caution. Dangers arise after 60 years for those who work physically hard. The doctor makes an informed decision about taking the drug in the presence of renal failure. When breastfeeding, there is a risk of side effects in the baby, since the active substance passes into the mother's milk. When prescribing the drug, the doctor must take into account the compatibility of metformin with other medications.
Metformin, 60 pcs., 500 mg, film-coated tablets
Lactic acidosis
Lactic acidosis is a rare but serious (high mortality unless promptly treated) complication that may occur due to accumulation of metformin. Cases of lactic acidosis when taking metformin occurred mainly in patients with diabetes mellitus with severe renal failure.
Other associated risk factors should be taken into account, such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure and any condition associated with severe hypoxia. This may help reduce the incidence of lactic acidosis.
The risk of developing lactic acidosis should be taken into account when nonspecific signs appear, such as muscle cramps accompanied by dyspeptic symptoms, abdominal pain and severe asthenia. Lactic acidosis is characterized by acidotic shortness of breath, abdominal pain and hypothermia followed by coma.
Diagnostic laboratory parameters are a decrease in blood pH (less than 7.25), lactate content in the blood plasma over 5 mmol/l, increased anion gap and lactate/pyruvate ratio.
If metabolic acidosis is suspected, stop taking the drug and consult a doctor immediately.
Surgical operations
The use of metformin should be discontinued 48 hours before elective surgery and can be continued no earlier than 48 hours after, provided that renal function was found to be normal during the examination.
Metformin should be replaced with another hypoglycemic drug (for example, insulin) 48 hours before an x-ray examination with intravenous contrast agents and continued for another 48 hours after this examination.
Kidney function
Since metformin is excreted by the kidneys, before starting treatment and regularly thereafter, it is necessary to determine CC: at least once a year in patients with normal renal function, and 2-4 times a year in elderly patients, as well as in patients with CC at the lower limit norms.
Particular caution should be exercised in case of possible impairment of renal function in elderly patients, with simultaneous use of antihypertensive drugs, diuretics or non-steroidal anti-inflammatory drugs.
Use in children and adolescents
The diagnosis of type 2 diabetes mellitus must be confirmed before starting treatment with metformin.
In clinical studies lasting 1 year, metformin was shown to have no effect on growth and puberty. However, due to the lack of long-term data, careful monitoring of the subsequent effects of metformin on these parameters in children, especially during puberty, is recommended. The most careful monitoring is necessary in children aged 10–12 years.
Other Precautions
Patients are advised to continue to follow a diet with even carbohydrate intake throughout the day. Overweight patients are recommended to continue to follow a hypocaloric diet (but not less than 1000 kcal/day).
It is recommended that routine laboratory tests be performed regularly to monitor diabetes mellitus.
It is not recommended to prescribe the drug if there is a risk of dehydration.
Metformin does not cause hypoglycemia when used alone, but caution is recommended when used in combination with insulin or other hypoglycemic agents (for example, sulfonylureas, repaglinide). When combined treatment requires careful monitoring of blood glucose concentrations.
Impact on the ability to drive vehicles and machinery
Monotherapy with the drug does not cause hypoglycemia and therefore does not affect the ability to drive vehicles and machines. Patients should be warned about the risk of developing hypoglycemia when using metformin in combination with other hypoglycemic drugs (sulfonylurea derivatives, insulin, repaglinide, etc.), which impair the ability to drive vehicles and engage in other potentially hazardous activities that require increased alertness and quick response. psychomotor reactions.
Possible adverse reactions
Negative reactions can occur from various systems of the human body. In particular, disruptions in the functioning of the nervous system occur, which are characterized by impaired taste perception. Side effects may include nausea, diarrhea, and vomiting. These occurrences are accompanied by loss of appetite and pain. Sometimes taking the drug is accompanied by itching and rash on the skin. Metabolism develops much less frequently, which provokes the development of lactic acidosis. Irregularities in the liver and problems with the biliary tract were also recorded, but after stopping metformin, such manifestations disappear.
In case of overdose, an increase in blood glucose levels is not observed. But if the maximum daily dose is exceeded, the risks of an increase in lactic acid levels in the blood increase, which leads to the development of lactic acidosis. In this case, the use of the medication is stopped and the patient is hospitalized. Treatment is symptomatic. If necessary, a decision is made about hemodialysis.
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
Dosage and use of the product
For the treatment of type 2 diabetes mellitus in adults, it is recommended to start taking the drug with a minimum dosage. This is 500 mg 2-3 times a day. Dose adjustments are made 10-15 days after measuring glucose levels. By increasing the dose at a slow pace, it is possible to minimize the risks of disruptions in the gastrointestinal tract. A maintenance dose of metformin is considered to be 2000 mg/day, divided into 2-3 doses. It is possible to increase it to 3000 mg/day.
To improve control of blood glucose levels in patients suffering from type 2 diabetes mellitus, complex therapy with insulin is used. In this case, the initial dose is also 500 mg or 850 mg 2-3 times a day, but the dosage of insulin is selected depending on the concentration of glucose in the blood. During long-term treatment with the drug, it is necessary to perform regular glycemic control. The drug can be taken without interruption every day. If you refuse the drug, you must inform your doctor.
Taking the medication does not affect the ability to drive. This is explained by the fact that hypoglycemia does not occur when treated with it. The shelf life of the drug is 2 years. To do this, you need to choose a dark, dry place that is inaccessible to children.
Metformin
Use during pregnancy and breastfeeding
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, and the concentration of metformin in breast milk may be 1/3 of the concentration in maternal plasma. 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 in 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.
Use for liver dysfunction
Contraindicated in cases of severe liver dysfunction.
Use for renal impairment
Contraindicated in cases of severe renal impairment.
special instructions
Use is not recommended for acute infections, exacerbation of chronic infectious and inflammatory diseases, injuries, acute surgical diseases, or danger of dehydration.
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. Elderly patients often experience asymptomatic renal dysfunction. Particular caution is required if renal dysfunction is caused by taking antihypertensive drugs or diuretics, as well as 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.
Preclinical studies have shown that metformin does not have carcinogenic potential.
