Metformin in type 2 diabetes mellitus

One of the commonly prescribed drugs is  metformin for diabetes. This is a drug that can be taken both independently and as part of a comprehensive treatment. The drug is aimed mainly at the normalization of metabolic processes, stabilization and harmonization of hormonal levels. In connection with the increase in cases of prescribing this drug, there are more and more questions regarding the specifics of its use, mechanism of action, indications and contraindications. Let us consider in more detail the main issues related to this drug.

Metformin was first synthesized in the 1920s and it was found that it lowers blood glucose levels, however, it has not been used for a long time. Metformin was resumed in 1957 when the results of clinical trials were published confirming its effect on diabetes. Metformin is currently widely prescribed as an antidiabetic drug; however, there were serious concerns about its side effects, especially ketoacidosis. [1]

Can metformin be given if there is no diabetes?

It is generally accepted that metformin is prescribed for diabetes. However, if you read the instructions, you can notice a fairly extensive mechanism of action of the drug. In this regard, a rather logical question arises: "Is it possible to take metformin if there is no diabetes?" So, in order to answer this question, you need to consider the specifics of its pharmacological effects on the body. First of all, the ability of the drug to suppress gluconeogenesis processes is noteworthy. When taking this drug, there is a delay in the absorption of glucose in the digestive tract.

The drug helps to stabilize, or moderate weight loss due to normalization of metabolism, including carbohydrate metabolism. There is a decrease in the level of triglycerides, LDL, VLDL. Also noteworthy is the ability to improve the fibrinolytic properties of the blood, which can be achieved by suppressing the plasminogen activator inhibitor.

According to a 2012 randomized, double-blind clinical trial of tolerance, analysis of side effects and the effect of Metformin's adherence to weight and waist circumference compared with placebo, Metformin, used to prevent diabetes, is 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 you to use this drug to treat excess body weight, obesity against a background of impaired metabolism, to stabilize the hormonal background and biochemical parameters. Also, the drug is an excellent means for 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 Institute of Health recommended the administration of metformin for women with polycystic ovary syndrome and a body mass index of over 25 for the treatment of anovulation and infertility, when other treatments did not give acceptable results. [6]

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

In one study, the use of metformin reduced the risk of pancreatic cancer by 62%, compared with the placebo group that did not use metformin. Participants taking sulfonylurea or insulin had a 2.5 and 5 times higher risk of developing pancreatic cancer, respectively, compared with the placebo group. [8] Metformin showed a strong antiproliferative effect on cancer cells of the colon, pancreas, breast, ovaries, prostate and lungs. [9] It has antioxidant activity. [10]

Metformin is a cure for old age

It is often said that metformin is a cure for old age. However, in reality this is far from the case. 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 renal impairment. 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 prevention of many cardiovascular diseases and metabolic disorders. However, it must be borne in mind that the drug can cause side effects, so taking it in the absence of adequate indications is highly discouraged. You also need to understand that not a single drug, including metformin, will become a panacea for all diseases and old age. At least because metformin affects the processes of tissue metabolism, and aging occurs at the cellular level.

Metformin appears to reduce cancer incidence and improve prognosis of survival in patients with diabetes. In vitro and animal studies support these findings from epidemiological studies in humans. Metformin has several potential mechanisms by which it inhibits the development and growth of cancer. For example, metaphormine inhibits hepatic gluconeogenesis, thereby lowering circulating glucose levels, and increasing insulin sensitivity, thereby lowering circulating insulin levels. Intracellularly, metformin activates AMPK, which reduces protein synthesis and cell proliferation. Metaphormine also reduces aromatase activity in stromal cells of the mammary gland. Finally, metformin reduces the risk of relapse and tumor aggressiveness by reducing the stem cell population and inhibiting the transition from epithelial to mesenchymal type. [11]However, the scientific evidence for its potential beneficial effects on cancer should be critically reviewed before further lengthy and costly trials begin. [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 for the correction of metabolic processes, to normalize the metabolism of carbohydrates, fats. Effective in obesity, overweight, 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 the lipid profile, and also 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 for the prevention of prediabetes. [14]

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

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

Recent studies have shown that metformin may have a therapeutic or renoprotective effect against nephrotoxic agents. [19] It has also been shown to be highly effective in diabetic nephropathy. [20],  [21] Furthermore, it significantly reduces albuminuria in diabetic patients. However, the exact mechanism beyond these effects is still unknown. Recent studies have shown that the therapeutic effect of metformin is mediated by its action on kinase activated by adenosine monophosphate (AMP) 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 lesions by regulating oxidative stress and restoring biochemical changes in the renal tubules. Metformin may also protect podocytes in diabetic nephropathy. [25]

Type 2 diabetes metformin

Metformin is prescribed primarily 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 diet, which will allow you to control glucose. An additional tool is metformin. It allows you to control carbohydrate metabolism, normalizes hormonal levels. There is a normalization of gluconeogenesis processes. This drug does not have a significant effect on insulin levels, which is why it is ideal for the treatment of non-insulin-dependent forms of the disease.

According to a study conducted by Bannister CA, Holden SE et al. In 2014, Patients with type 2 diabetes who started treatment with metformin monotherapy had greater survival than control groups of people without diabetes (15%). Patients treated with sulfonylurea had a significantly lower survival rate (38%) compared with both the control group and those who received metformin monotherapy. [26]

Type 1 diabetes metformin

Metformin in type 1 diabetes significantly changes insulin levels, reducing the need for a dose of insulin. [27]This is due to the fact that the drug dramatically reduces the ratio of bound and free insulin. The ratio between insulin and proinsulin also increases. Also, the ability to control the level of glucose in the blood positively affects the patient, due to the impact not only on the main links in the synthesis of glucose 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 all carbohydrate metabolism, as well as by normalizing other metabolic links, in particular, by controlling the level of fatty acids, glucose transporters.

Release form

The main form of release of metformin is tablets. From above they are covered with a film membrane. Tablets are packed in boxes of 10 pieces. Then the cells are packed in cardboard packs, 3, 5, 6, 10, 12 cells in a pack. One tablet contains 1000 mg of the active substance - metformin hydrochloride.

For diabetes, metformin tablets are prescribed. Intended for oral administration. They have a hypoglycemic effect on the body, normalize the main indicators of carbohydrate metabolism, the synthesis of fatty acids. 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 in a dose-dependent manner. [28]Metformin increases the utilization of glucose in peripheral blood, which occurs mainly due to an increase in non-oxidative utilization of glucose in skeletal muscle, does not cause hypoglycemia. [29]It has an effect on carbohydrate and fat metabolism, affects peripheral insulin receptors, redistributes insulin in the body, and stimulates liver function. The ability to change the fibrinolytic properties of blood is noteworthy. The drug mainly affects tissue metabolism. 

It 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 the transmission of insulin signals and glucose transport in muscles. AMPK regulates cellular and organ metabolism. [30], [31] 

Metformin reduces the production of endogenous glucose in patients with type 2 diabetes by 33% due to a decrease in gluconeogenesis. [32]

Pharmacokinetics

When analyzing the pharmacokinetics, it is worth noting that this drug slowly penetrates the blood through 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%. The simultaneous ingestion of food and metformin delays its absorption rate. The distribution of the drug in the tissues occurs rather quickly. Plasma protein binding is practically not observed. The accumulation of the drug in the salivary glands, liver and kidneys is noted. The drug is excreted by the kidneys unchanged. The elimination half-life makes 2-6 hours. If a person has impaired renal function, metformin may gradually be eliminated from the body.

Dosing and administration

As a rule, the method of administration and dose of the drug is prescribed by the doctor, based on the results of laboratory tests. In particular, you need to know the level of glucose in the blood. Also, in many ways, the method of application and dose depend on whether the drug is prescribed as monotherapy, or as a component of complex therapy.

The drug is administered orally. It can be taken both with meals and after. 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 there is such a need, the dose can gradually increase, up to 2-3 grams per day. The dose is increased gradually - with an interval of a week. For children, the initial dose does not differ from the dose of adults (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 mean children aged 10 years and older. Children under 10 years of age are not prescribed metformin.

With combination therapy, 500 or 850 mg are prescribed as an initial dose, with a multiplicity of administration 2-3 times a day. Every 10-15 days, the dose must be adjusted, focusing on the results of laboratory tests, the level of glucose in the blood.

How to take metformin for diabetes?

A person who is being treated with metformin must definitely know how to take metformin in diabetes mellitus. 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 will be correct to first pass a blood test for the content of glucose in it. After this, you should consult a doctor who will prescribe the appropriate treatment, select the dosage. 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 reception. The drug is taken 2-3 times a day.

The second thing that the patient should remember is that, if necessary, the dosage may increase. It needs to be raised gradually, with an interval of a week. Maximum allowed to take 2.5 grams of the drug per day.

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

How long can I take metformin?

One of the main questions that concern patients taking metformin is: “How long can I take metformin?” The instructions for the drug do not indicate the specific duration of treatment. Accordingly, the drug is intended for long-term use. So, 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 control glucose levels. Do not throw the drug if the level of glucose in the blood, and other biochemical parameters have returned to normal. Cancellation can cause a return of pathological changes, can cause deterioration. It is important to achieve stable stabilization of blood glucose levels. For this, at least within 2-3 months, the controlled indicators should be within the limits of the reference values.

Application for children

Sometimes there is a need for the use of metformin for children. It is usually prescribed for type 2 diabetes. Less commonly, the drug may be prescribed in 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 blood clots with a tendency to thrombosis. The drug is not recommended for children under the age of 10 years. Before you begin, you need to consult a doctor. The dose is selected depending on the level of glucose in the blood and other biochemical parameters, therefore, before prescribing the drug to the 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 greatly 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, fat metabolism, stabilizes hormonal levels. It allows not only to reduce body weight, but also ensures its stabilization at the achieved level. How to take metformin for weight loss can tell the doctor, because the scheme is selected individually, depending on the main biochemical parameters of the body. In its most general form, the treatment regimen can be represented 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 are no reliable data and adequate studies to conclude on the characteristics of the effects of the drug on the body of a pregnant woman and the fetus. The use of metformin during pregnancy is acceptable if there is an urgent need for it. If the risk of abandoning this drug is fraught with serious adverse consequences, it is recommended to take it. It is known that the drug has the ability to penetrate the placental barrier. There is no sharp negative effect on the fetus. The teratogenic effect occurs only in cases where the dosage of the drug is 2-3 times the therapeutic dose. However, the usual therapeutic doses used in clinical practice do not cause any reaction from the fetus. Mutagenic effects also do not occur.

The babies who were exposed to metformin in the womb had large sizes of subcutaneous fat, but the total body fat was the same as in children whose mothers were treated with insulin alone. Further observation is required to find out whether these changes remain in later life, and whether children exposed to metformin will have less visceral fat, or will be more sensitive to insulin. [33]

Contraindications

Metformin is not without contraindications. So, it is not recommended to appoint it in acute and chronic kidney pathologies. This is due to the fact that the drug is metabolized in the kidneys, excreted through the kidneys, and therefore the load on the kidneys increases sharply. This can lead to exacerbation. The drug is strictly contraindicated in case of renal failure, diabetic coma and precomatous state. You should not take the drug with 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 in conditions such as heart and respiratory failure, myocardial infarction. The drug is not prescribed in preparation for diagnostic studies that require the use of contrasting iodine-containing substances. For example, it cannot be used if it is planned to conduct urography, cholangiography, angiography. Sometimes there are cases of individual intolerance to the drug, which are accompanied by allergic reactions, increased sensitivity and reactivity of the body. Contraindication is 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 to other oral hypoglycemic agents in 51 675 patients who were observed for 4 years. [34]

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

For a long time it was believed that metformin causes lactic acidosis (LA), but data from various sources made researchers doubt the direct causal relationship. Diabetes, not metformin, is a major risk factor for developing LA. [35]

Gastrointestinal intolerance is one of the most common diseases. [36] Myocardial infarction (MI) incidence is also an important side effect, but less observed with metformin compared with sulfonylurea. [37]

Overdose

There are no known cases of overdose with metformin, since the drug is metabolized by the liver and kidneys. Its excess is freely excreted in the urine almost unchanged. The exception is cases of impaired renal function, in which there is an accumulation of the drug in the kidneys. This can cause signs of intoxication.

Interactions with other drugs

When taking metformin, you must take into account the characteristics of the interaction with other drugs. So, the drug enhances its effect if it is taken together with insulin, salicylates, oxytetracycline, urea sulfonyl derivatives. Also, the effect of the drug is enhanced when taken together with MAO inhibitors, ACE inhibitors, clofibrate, cyclophosphamide.

If the drug is taken during treatment with some hormonal drugs, 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 contrasting agents, which are used for diagnostic tests, since impaired renal function may develop, up to the development of insufficiency. The development of lactic acidosis is also possible. You can not combine the drug with beta-adrenergic agonists, or strictly control the concentration of glucose in the blood. When combined with cimetidine, loop diuretics, the development of lactic acidosis occurs. Nifedilin and cationic drugs increase the absorption capacity of the drug, and also increases the rate of absorption of the substance into the blood.

Metformin and alcohol

Patients who are treated with metformin need to 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 serious impairment of the functional state of the kidneys. In the most severe cases, renal failure develops.

Storage conditions

Typically, 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 heat sources. The drug should be stored in a place protected from moisture, it is enough normal room temperature. The place must not be accessible to children and animals.

Shelf life

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

Analogs

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

How to replace metformin with diabetes?

If you do not know what metformin will replace with diabetes, of course you need to consult your doctor. In no case can you independently cancel the drug or replace it, as this can cause the development of serious complications and further metabolic disorders. Many experts recommend replacing metformin with herbs, homeopathic remedies. Consider the main herbs that metformin can replace.

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

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

Most often with diabetes, herbs that lower blood glucose are prescribed. As herbs aimed at lowering glucose levels, the herbs discussed below are.

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

Doctors reviews

We have analyzed the reviews of doctors prescribing metformin to their patients. So, most doctors consider type 2 diabetes to be the main indication for prescribing this remedy. 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 right choice of treatment regimen, when choosing an adequate dosage, the drug is fairly well tolerated by patients. It can be taken for a long period of time, it is well absorbed and tolerated by the body, 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 you overdose it. With prolonged use, they can maintain a stable blood sugar level, and prevent hyper- and hypoglycemic attacks.

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