Metformin in type 2 and type 1 diabetes mellitus

One of the most frequently prescribed drugs is metformin for diabetes. This is a drug that can be taken both independently and as part of a complex treatment. The drug is aimed primarily at normalizing metabolic processes, stabilizing and harmonizing hormonal levels. Due to the increasing frequency of prescriptions for this drug, more and more questions arise regarding the specifics of its use, mechanism of action, indications and contraindications. Let us consider in more detail the main questions regarding this drug.

Metformin was first synthesized in the 1920s and was found to lower blood glucose levels, however, it was not used for long. Metformin was reintroduced in 1957 when clinical trial results were published confirming its effect on diabetes. Metformin is now widely prescribed as an antidiabetic drug; however, there have been significant concerns about its side effects, particularly ketoacidosis.[ 1 ]

Can you take metformin if you don't have diabetes?

Traditionally, it is believed that metformin is prescribed for the treatment of diabetes. However, if you read the instructions, you can notice a fairly extensive mechanism of action of the drug. In this regard, a fairly natural question arises: "Can I take metformin if I do not have diabetes?" So, in order to answer this question, we need to consider the specifics of its pharmacological effect on the body. First of all, the ability of the drug to suppress gluconeogenesis processes attracts attention. When taking this drug, there is a delay in the absorption of glucose in the gastrointestinal tract.

The drug promotes stabilization or moderate weight loss by normalizing metabolism, including carbohydrate metabolism. A decrease in the level of triglycerides, LDL, and VLDL is noted. The ability to improve the fibrinolytic properties of blood is also noteworthy, which can be achieved by suppressing the plasminogen activator inhibitor.

According to a 2012 randomized, double-blind clinical tolerability study, analyzing side effects and the effect of Metformin adherence on weight and waist circumference changes compared to placebo, Metformin used for diabetes prevention was found to be safe and well tolerated. [ 2 ]

Thus, all of the above allows us to conclude that the drug not only normalizes glucose levels, controls gluconeogenesis processes, but also performs a number of other important functions. In particular, the ability to control body weight and normalize carbohydrate metabolism allows this drug to be used to treat excess body weight, obesity against the background of metabolic disorders, to stabilize hormonal levels and biochemical parameters. The drug is also an excellent means of preventing atherosclerosis, [ 3 ], [ 4 ] coronary heart disease, thromboembolic disease, varicose veins, and other vascular diseases.

It is also used in women with polycystic ovary syndrome. Metformin can make menstrual cycles more regular and increase fertility. [ 5 ] The US National Institutes of Health has recommended that metformin be prescribed to women with polycystic ovary syndrome and a body mass index greater than 25 to treat anovulation and infertility when other treatments have failed to produce acceptable results. [ 6 ]

It has a neuroprotective effect compared to placebo, reducing the risk of developing dementia in patients with diabetes. [ 7 ]

In one study, metformin use reduced the risk of pancreatic cancer by 62% compared to a placebo group that did not use metformin. Participants taking sulfonylurea or insulin had a 2.5- and 5-fold increased risk of pancreatic cancer, respectively, compared to the placebo group. [ 8 ] Metformin has shown strong antiproliferative effects on colon, pancreatic, breast, ovarian, prostate, and lung cancer cells. [ 9 ] It has antioxidant activity. [ 10 ]

Metformin - a cure for old age

It is often said that metformin is a cure for old age. However, in reality, this is far from true. On the contrary, the drug is not recommended for patients over 60 years of age, since it is poorly absorbed by the body and can cause serious kidney dysfunction. Otherwise, the drug helps to normalize carbohydrate and fat metabolism, stabilizes weight, improves well-being, normalizes the condition of the heart and blood vessels, and is a preventive measure for many cardiovascular diseases and metabolic disorders. However, it should be taken into account that the drug can cause side effects, so taking it without adequate indications is highly discouraged. It should also be understood that no drug, including metformin, will be a panacea for all diseases and old age. At least because metformin affects tissue metabolism processes, and aging occurs at the cellular level.

Metformin appears to reduce cancer incidence and improve survival in patients with diabetes. In vitro data and animal studies support these findings from human epidemiological studies. Metformin has several potential mechanisms by which it inhibits cancer development and growth. For example, metformin inhibits hepatic gluconeogenesis, thereby reducing circulating glucose levels, and increases insulin sensitivity, thereby reducing circulating insulin levels. Intracellularly, metformin activates AMPK, which reduces protein synthesis and cell proliferation. Metaformin also reduces aromatase activity in mammary stromal cells. Finally, metformin reduces the risk of recurrence and tumor aggressiveness by reducing stem cell populations and inhibiting epithelial-to-mesenchymal transition. [ 11 ] However, the scientific evidence for its potential beneficial effects on cancer needs to be critically reviewed before further lengthy and expensive trials are initiated. [ 12 ]

Indications Metformin

The main indications for the use of metformin are type 2 diabetes mellitus. This is an insulin-independent form of the disease. The drug is prescribed to correct metabolic processes, to normalize the metabolism of carbohydrates and fats. It is effective in obesity, excess weight, for the prevention of atherosclerosis, conditions associated with metabolic disorders in the body.

Metformin treatment in individuals at increased risk of developing diabetes reduces weight, insulin resistance, improves lipid profiles, and reduces the incidence of diabetes by 40%.[ 13 ] Decades of clinical use of metformin have shown that it is generally well tolerated and safe for therapeutic use in the prevention of prediabetes.[ 14 ]

The use of some antiretroviral drugs in HIV infection has been associated with glucose tolerance, insulin resistance, hyperinsulinemia, and type 2 diabetes mellitus. These patients have low HDL-C, hypertriglyceridemia, and a high risk of cardiovascular disease. These metabolic changes are often associated with loss of subcutaneous fat and increase in visceral fat. [ 15 ], [ 16 ]

Antiretroviral therapy with protease inhibitors inhibits glucose transport mediated by glucose transporter (GLUT)-4.[ 17 ] They are likely partly responsible for insulin resistance and body composition changes in HIV-infected patients. Metformin has been shown to reduce visceral adiposity and insulin resistance after 8 weeks of drug therapy at a dose of 850 mg 3 times daily.[ 18 ]

Recent studies have shown that metformin may have therapeutic or renoprotective effects against nephrotoxic agents. [ 19 ] It has also been shown to have good efficacy in diabetic nephropathy. [ 20 ], [ 21 ] In addition, it significantly reduces albuminuria in diabetic patients. However, the exact mechanism behind these effects is still unknown. Recent studies have shown that the therapeutic effect of metformin is mediated by its action on adenosine monophosphate (AMP)-activated kinase in tissues. [ 22 ], [ 23 ] Various studies have shown that metformin is able to reduce the amount of intracellular reactive oxygen species (ROS). [ 24 ] It protects tubular damage by regulating oxidative stress and restoring renal tubular biochemical changes. Metformin may also protect podocytes in diabetic nephropathy. [ 25 ]

Metformin for type 2 diabetes

Metformin is prescribed mainly for type 2 diabetes. But this is not the main indication. This type of disease is characterized as an insulin-independent form. The condition can be corrected with the help of rational physical activity, proper dietary nutrition, which will allow you to control glucose. Metformin is also an additional remedy. It allows you to control carbohydrate metabolism, normalizes hormonal levels. Gluconeogenesis processes are normalized. This drug does not have a significant effect on insulin levels, which is why it is ideal for treating insulin-independent forms of the disease.

According to a study by Bannister CA, Holden SE, et al. in 2014, patients with type 2 diabetes who started treatment with metformin monotherapy had a longer survival rate than non-diabetic controls (by 15%). Patients who received sulfonylurea had a significantly shorter survival rate (38%) compared to both the control group and those who received metformin monotherapy. [ 26 ]

Metformin for type 1 diabetes

Metformin in type 1 diabetes significantly changes insulin levels, reducing the need for an insulin dose. [ 27 ] This is due to the fact that the drug sharply reduces the ratio of bound and free insulin. The ratio between insulin and proinsulin also increases. It also has a positive effect on the patient's ability to control blood glucose levels, due to the effect not only on the main links of glucose synthesis in the body, but also on the processes of its absorption through the walls of the intestinal tract. Positive effects can be achieved by normalizing the entire carbohydrate metabolism, as well as by normalizing other links in metabolism, in particular, by controlling the level of fatty acids, glucose carriers.

Release form

The main form of metformin is tablets. They are covered with a film coating on top. The tablets are packed in cells of 10 pieces. Then the cells are packed in cardboard packs, 3, 5, 6, 10, 12 cells per pack. One tablet contains 1000 mg of the active substance - metformin hydrochloride.

For diabetes, metformin tablets are prescribed. They are intended for oral administration. They have a hypoglycemic effect on the body, normalize the main indicators of carbohydrate metabolism, fatty acid synthesis. Accordingly, not only the general metabolism is normalized, but also the hormonal background, which has a positive effect on the well-being and objective indicators of the patient's health.

Pharmacodynamics

Analyzing the pharmacodynamics of the drug, it is worth noting that the active substance is metformin hydrochloride. Metformin reduces fasting plasma glucose and HbA1c levels, usually dose-dependent. [ 28 ] Metformin increases peripheral blood glucose utilization, which occurs mainly due to increased nonoxidative glucose utilization in skeletal muscles, and does not cause hypoglycemia. [ 29 ] It affects carbohydrate and fat metabolism, affects peripheral insulin receptors, redistributes insulin in the body, and stimulates liver function. Of note is the ability to change the fibrinolytic properties of blood. The drug primarily affects tissue metabolism.

Activates the enzyme adenosine monophosphate kinase (AMPK), which leads to the inhibition of key enzymes involved in gluconeogenesis and glycogen synthesis in the liver, stimulating insulin signaling and glucose transport in muscles. AMPK regulates cellular and organ metabolism. [ 30 ], [ 31 ]

Metformin reduces endogenous glucose production in patients with type 2 diabetes by 33% by reducing gluconeogenesis.[ 32 ]

Pharmacokinetics

When analyzing the pharmacokinetics, it is worth noting that this drug slowly penetrates the blood by gradual absorption through the walls of the gastrointestinal tract. The maximum concentration of the drug in the blood is detected after 2.5 hours. The bioavailability of the drug is 50-60%. Simultaneous intake of food and metformin delays the rate of its absorption. The distribution of the drug in tissues occurs quite quickly. Binding to plasma proteins is practically not observed. Accumulation of the drug in the salivary glands, liver and kidneys is noted. The drug is excreted by the kidneys unchanged. The half-life is 2-6 hours. If a person has impaired renal function, metformin may be gradually eliminated from the body.

Dosing and administration

As a rule, the method of administration and dosage of the drug are prescribed by a doctor, based on the results of laboratory tests. In particular, it is necessary to know the level of glucose in the blood. Also, in many ways, the method of administration and dosage depend on whether the drug is prescribed as monotherapy or as part of complex therapy.

The drug is prescribed orally. It can be taken both during and after meals. If monotherapy is carried out, the initial single dose is 500 mg, 1-3 times a day. If necessary, an initial dose of 850 mg is prescribed. If necessary, the dose can be gradually increased, up to 2-3 grams per day. The dose is increased gradually - at intervals of a week. For children, the initial dose is no different from the adult dose (500 or 850 mg). The daily dose can be increased to a maximum of 2 grams per day. In this case, the daily dose should be divided into 2-3 doses. It should be borne in mind that children are children aged 10 years and older. Metformin is not prescribed to children under 10 years of age.

In combination therapy, 500 or 850 mg is prescribed as an initial dose, with a frequency of administration of 2-3 times a day. Every 10-15 days, the dose should be adjusted, based on the results of laboratory tests, blood glucose levels.

How to take metformin correctly for diabetes?

A person who is treated with metformin must know how to take metformin correctly for diabetes. So, first of all, you need to understand that the dosage of the drug depends on the level of glucose in the blood. Therefore, it would be correct to first take a blood test for glucose content. After that, you should contact a doctor who will prescribe the appropriate treatment and select the dosage. The dosage depends on age, treatment regimen. Usually, with the most standard treatment regimen, the drug is prescribed in an initial dose of 500-850 mg per dose. The drug is taken 2-3 times a day.

The second thing the patient should remember is that the dosage can be increased if necessary. It should be increased gradually, at weekly intervals. The maximum allowed dose is 2.5 grams of the drug per day.

The third important condition for proper treatment with metformin is to take a repeat blood glucose test every 10-15 days. Depending on the results obtained, the dosage and treatment regimen are adjusted.

How long can you take metformin?

One of the main questions that bother patients taking metformin is: "How long can I take metformin?" The instructions for the drug do not indicate a specific duration of treatment. Accordingly, the drug is intended for long-term use. Thus, it is aimed at normalizing metabolic processes, which in principle cannot be a short-term event. Metformin can be taken from several months to a year or more. It is important to monitor glucose levels. You should not stop taking the drug if the blood glucose level and other biochemical indicators have returned to normal. Cancellation can cause a return of pathological changes and can cause a deterioration in the condition. It is important to achieve stable stabilization of blood glucose levels. To do this, the monitored indicators must be within the reference values for at least 2-3 months.

Application for children

Sometimes there is a need to use metformin for children. It is usually prescribed for type 2 diabetes. Less often, the drug can be prescribed for the treatment of type 1 diabetes. It can also be prescribed to children to correct carbohydrate and fat metabolism, to normalize blood glucose levels, to stabilize weight, to reduce the risk of developing blood clots with a tendency to thrombosis. The drug is not recommended for children under 10 years of age. Before starting treatment, you should consult a doctor. The dose is selected depending on the blood glucose level and other biochemical parameters, so before prescribing the drug to a child, it is necessary to conduct laboratory tests. Metformin has been proven to be safe and effective for the treatment of type 2 diabetes in children. It significantly improves glycemic control. [ 38 ]

How to take metformin for weight loss?

Metformin can be prescribed for weight loss, since it is a drug that normalizes carbohydrate and fat metabolism, stabilizes hormonal levels. It allows you not only to reduce body weight, but also ensures its stabilization at the achieved level. How to take metformin for weight loss can be suggested by a doctor, since the scheme is selected individually, depending on the main biochemical parameters of the body. In the most general form, the treatment scheme can be presented as follows: 500 mg per day, daily. After 10-15 days, a blood test is taken for glucose levels, after which the dose is adjusted.

Use Metformin during pregnancy

Currently, there is no reliable data and adequate studies that would allow us to draw a conclusion about the specific effects of the drug on the body of a pregnant woman and the fetus. The use of metformin during pregnancy is allowed if there is an urgent need for it. If the risk of refusing this drug is fraught with serious adverse effects, it is recommended to take it. It is known that the drug has the ability to penetrate the placental barrier. There is no sharply negative effect on the fetus. The teratogenic effect occurs only in cases where the dosage of the drug is 2-3 times higher than the therapeutic dose. However, the usual therapeutic doses used in clinical practice do not cause any reaction from the fetus. There is also no mutagenic effect.

Children exposed to metformin in utero had larger subcutaneous fat masses, but total body fat was similar to children whose mothers were treated with insulin alone. Further follow-up is needed to determine whether these changes persist in later life and whether metformin-exposed children have less visceral fat and are more sensitive to insulin.[ 33 ]

Contraindications

Metformin has contraindications for use. Thus, it is not recommended to prescribe it for acute and chronic kidney pathologies. This is due to the fact that the drug is metabolized in the kidneys, excreted through the kidneys, due to which the load on the kidneys increases sharply. This can lead to an exacerbation. The drug is strictly contraindicated in renal failure, diabetic coma and pre-comatose state. You should not take the drug in ketoacidosis, severe dehydration, against the background of any acute inflammatory and infectious diseases. This drug is especially dangerous with an increased risk of hypoxia, including such conditions as cardiac and respiratory failure, myocardial infarction. The drug is not prescribed in preparation for diagnostic studies that require the use of iodine-containing contrast agents. For example, it cannot be used if urography, cholangiography, angiography are planned. Sometimes there are cases of individual intolerance to the drug, which are accompanied by allergic reactions, increased sensitivity and reactivity of the body. Contraindications include intoxication of the body, including acute alcohol intoxication or chronic alcoholism.

Side effects Metformin

Metformin showed a lower risk than insulin for cardiovascular disease and all-cause mortality, and a slightly lower risk for all-cause mortality compared with other oral hypoglycemic agents in 51,675 patients followed for 4 years.[ 34 ]

In some cases, side effects may occur during treatment with metformin, such as dyspeptic disorders such as nausea, vomiting, diarrhea, and abdominal discomfort. Such effects usually occur in the early stages of treatment. In rare cases, liver disorders, such as hepatitis, are observed. As a rule, these manifestations are short-term and disappear fairly quickly after discontinuation of the drug. Also, in some cases, signs of lactic acidosis and impaired absorption of B vitamins may be observed.

Metformin has long been thought to cause lactic acidosis (LA), but evidence from multiple sources has led researchers to question a direct cause-and-effect relationship. Diabetes, not metformin, is the major risk factor for LA.[ 35 ]

Gastrointestinal intolerance is one of the most common side effects. [ 36 ] The incidence of myocardial infarction (MI) is also an important side effect, but is less common with metformin than with sulfonylurea. [ 37 ]

Overdose

There are no known cases of metformin overdose, as the drug is metabolized by the liver and kidneys. Its excess is freely excreted in the urine almost unchanged. The exception is cases of renal dysfunction, in which the drug accumulates in the kidneys. This can cause signs of intoxication.

Interactions with other drugs

When taking metformin, it is necessary to take into account the peculiarities of interaction with other drugs. Thus, the drug enhances its effect if taken together with insulin, salicylates, oxytetracycline, sulfonylurea derivatives. Also, the effect of the drug is enhanced when taken together with MAO inhibitors, ACE, clofibrate, cyclophosphamide.

If the drug is taken during treatment with some hormonal agents, or when taking hormonal contraceptives, a decrease in the hypoglycemic effect is possible. Also, the hypoglycemic effect is reduced when combined with diuretics, derivatives of nicotinic acid.

The drug is not compatible with contrast agents used for diagnostic studies, as it may cause renal dysfunction, up to and including failure. Lactic acidosis may also develop. The drug should not be combined with beta-adrenergic agonists, or the blood glucose concentration should be strictly controlled. When combined with cimetidine, loop diuretics, lactate acidosis develops. Nifediline and cationic drugs help increase the absorption capacity of the drug and increase the rate of absorption of the substance into the blood.

Metformin and alcohol

Patients treated with metformin should remember that metformin and alcohol are incompatible. The combined use of this drug with ethanol can lead to the development of lactic acidosis, as well as cause severe impairment of the functional state of the kidneys. In the most severe cases, renal failure develops.

Storage conditions

As a rule, storage conditions for drugs are indicated on the packaging. In most cases, meformin is stored in a dry place, protected from direct sunlight, away from heating sources. The drug should be stored in a place protected from moisture, at a fairly normal room temperature. The place should be inaccessible to children and animals.

Shelf life

Usually the expiration date is indicated on the packaging. For metformin, it is usually 2-3 years from the date of manufacture. If the expiration date of the drug has expired, you cannot take it. Taking an expired drug can lead to poisoning, other adverse effects. Or the drug may simply be ineffective.

Analogues

There are no direct analogues of metformin. However, as indirect means, which in one way or another can be considered as analogues of this drug, we can name such drugs as digoxin, quinine, quinidine, since they compete for transport systems, when taken together they increase the absorption and assimilation of metformin. Also, as an analogue we can consider vitamin complexes 3-6-9 Omega, compounds that include rationally selected proteins, fats, carbohydrates, various means and food additives aimed at normalizing tissue and carbohydrate metabolism.

What can replace metformin for diabetes?

If you do not know what to replace metformin with for diabetes, of course, you need to consult with your doctor. In no case should you cancel the drug or replace it on your own, as this can cause the development of serious complications and further metabolic disorders. Many experts recommend replacing metformin with medicinal herbs, homeopathic remedies. Let's consider the main herbs that can replace metformin.

In diabetes, instead of metformin, herbs such as stevia, [ 39 ] goat's rue, [ 40 ] amaranth, [ 41 ] wormwood are often prescribed. [ 42 ]

Herbs are used as part of monotherapy, or medicinal infusions are prepared from them. Many herbs are used in the form of herbal decoctions, infusions, balms. Some are used as tea or as food supplements.

Most often, herbs that reduce blood glucose levels are prescribed for diabetes. The herbs that are considered below are herbs that are aimed at reducing glucose levels.

• yarrow; [ 43 ]
• common barberry; [ 44 ]
• Viburnum vulgare; [ 45 ]
• marshmallow root; [ 46 ]
• sage; [ 47 ]
• peppermint. [ 48 ]

Doctors' reviews

We have analyzed the reviews of doctors who prescribe metformin to their patients. Thus, most doctors consider type 2 diabetes to be the main indication for prescribing this drug. However, there is experience of its successful use for the treatment of type 1 diabetes, for the treatment and prevention of hormonal disorders, obesity. The advantage of the drug is that it not only normalizes metabolism, reduces weight, but also maintains it at a relatively stable level.

Positive reviews prevail. Doctors note that with the correct selection of the treatment regimen, with the selection of an adequate dosage, the drug is quite well tolerated by patients. It can be taken for a long period of time, it is well absorbed and tolerated by the body, and practically does not cause side effects. It is also quite difficult to cause an overdose, since the drug is simply excreted with the kidneys if it is overdosed. With long-term use, they allow you to maintain a stable blood sugar level, prevent hyper- and hypoglycemic attacks.

Negative reviews are extremely rare. Of the negative reviews that we managed to find, almost all of them are related to the fact that the person was given an incorrect dose of the drug (underestimated). As a result, the drug was ineffective. This once again confirms the importance and significance of choosing the correct regimen for taking the drug, as well as calculating the correct treatment regimen and tactics. Many doctors note that metformin for diabetes should be taken with constant monitoring of blood glucose levels.