Monitoring safety in the treatment of metformin includes the definition. Metformin and cardiovascular complications of diabetes mellitus: “Reflections at the front door

A. Bogdanov, FRCA

Many patients are already taking medications (often several) by the time of admission to the hospital, the effect of which affects the outcome of surgical treatment and anesthesia. In turn, these drugs under the influence of perioperative conditions change their pharmacological properties, which affects the patient's condition. A natural question arises - what to do and how to modify the already ongoing drug therapy to optimize the outcome of treatment? Information on this subject is scattered and scarce in various sources, so doctors tend to rely more on their personal experience and the practice adopted in the hospital.

Recently, a study was published (Kennedy J.M. et al "Polypharmacy in a general surgical unit and concequences of drug withdrawal" BR. J. of Clinical Pharmacology, 2000, 49, 353-362), the results of which are thought provoking. It was found that the results of surgical treatment were worse when patients did not receive their usual drug therapy, such patients also had a higher rate of postoperative complications. In other words, a relationship was found between the cessation of perioperative drug therapy and the outcome of treatment.

Below is a translation of review articles on this topic with changes and additions. The overview is somewhat sketchy and brief on each topic; in the future (hopefully) more detailed articles will be published on diabetes and some other endocrinological problems.

Both the general issues of perioperative drug therapy and the current state of the issue for various specific groups of drugs will be discussed here.

General provisions

Preoperative fasting: during anesthesia, the risk of aspiration of gastric contents is increased and in the case of elective surgery, a fasting regimen is usually applied from midnight before the operation. While there is generally no controversy regarding food intake, recent evidence suggests that there is no need to limit fluid intake to 2 hours before surgery. It was shown that in patients after taking liquids (water, tea, juice without pulp) 2 hours before surgery, the volume of gastric contents did not exceed that of patients who did not take anything for 9 hours. Therefore, it is considered reasonable to allow at least small amounts of water up to 2 hours before surgery.

Interactions of drugs with drugs used during anesthesia: there are a significant number of potentially serious interactions between the above groups of drugs. However, only a relatively small number of them should be discontinued. A complete list of such interactions is published in the European Journal of Anaesthesiology, 1998,15,172 - 189. In the context of this work, only the most important ones need to be mentioned: enflurane can cause convulsions in patients taking tricyclic antidepressants, pethidine and other opiates can lead to fatal reactions in patients taking MAO ; anticholinesterase drugs (neostigmine in myasthenia gravis) prolong the effect of depolarizing muscle relaxants (succinylcholine, ditilin); serotonergic drugs (pethidine) can cause serotonin syndrome in patients taking selective serotonin reuptake inhibitors (modern antidepressants of the Prozac group). To reduce the likelihood of such interactions, attention should be paid to a detailed pharmacological history.

Stress response to surgery: Operational stress is accompanied by the release of catabolic hormones (cortisol), catecholamines and cytokines. The degree of this response depends on the degree of surgical trauma. It is recommended to pay special attention to patients with adrenal insufficiency and diabetes mellitus.

Bleeding and thromboembolic disorders: An increased risk of bleeding occurs in patients taking anticoagulants and drugs that inhibit platelet function (aspirin and other anti-inflammatory drugs). A more serious risk is venothrombosis, which develops as a result of forced bed rest, increased blood clotting after surgery; the development of such complications is most likely in patients taking oral contraceptives and hormone replacement therapy (menopause).

Continue medication or stop it?

Due to the aforementioned interactions between perioperative drug therapy, anesthetics and the operation itself, a decision must be made as to which drugs can be taken in the perioperative period and which should be discontinued. During the preoperative examination, it may be necessary to change the routine medication regimen long before the operation. Making such decisions is especially difficult in the case of emergency surgery, so it is important to anticipate the consequences, such as stopping the usual medications.

It is desirable to continue taking some drugs before and after surgery to prevent the condition for which they were used to aggravate or to avoid the development of a withdrawal syndrome. Continued use may mean administering the drug in a variety of ways or switching to another drug with similar properties. The choice of alternative drugs should be made with caution, since even small changes can be accompanied by serious impairments in the bioavailability of the drug,

Table 1. Drugs to be continued.

Drug group	Alternative Therapy	Remarks
Antiepileptic	The use of intravenous or rectal drugs. Fluids can be given through a nasogastric tube	The bioavailability of drugs varies, when switching to another drug, check the doses. It is desirable to control the level in the blood. When using intravenous phenytoin, cardiac monitoring is necessary.
Drugs for the treatment of hypertension, angina pectoris and arrhythmias	Use intravenous administration in the absence of oral administration. Switching to another drug is possible	BP monitoring. Intravenous drugs have different bioavailability - check dosages
Drugs for the treatment of Parkinson's disease	Oral drugs before surgery, then switching to liquid forms or dissolvable tablets, possibly via a nasogastric tube	There is a small risk of arrhythmias and hypotension in patients taking levodopa/dopamine carboxylase inhibitors. Some antiemetics may increase levodopa levels or worsen disease
Antipsychotics and anxiolytics	Some drugs are available as injections, syrups, or suppositories.	There is no need to replace when using depot drugs. Antipsychotics may reduce anesthetic requirements and potentiate arrhythmias
Corticosteroids	Need a replacement regimen (usually IV hydrocortisone) to avoid adrenal insufficiency
Asthma medications	Conventional drugs are given before surgery, then therapy is continued in the form of inhalations	It is necessary to achieve the best possible condition of the patient before the operation
Immunosuppressants	For patients with transplanted organs, coritecosteroids, azathioprine, cyclosporins are available as injections.	Seek advice from an organ transplant specialist. Azathioprine injections are rarely used - it irritates the vein wall when injected. Cyclosporins are not used in patients allergic to castor oil.
Selective serotonin reuptake inhibitors	Some preparations are available in the form of a syrup	Be aware of the possibility of serotonin syndrome and avoid serotonergic drugs - pethidine and pentazocine

Drugs to stop taking: There are a small number of drugs that should ideally be discontinued in the perioperative period:

Diuretics: Potassium-sparing diuretics (spironolactone) should be discontinued, as a decrease in renal perfusion in the postoperative period can lead to the development of hyperkalemia. Thiazide and other diuretics are not included in this group and their use can be continued (preoperative correction of possible hypokalemia is necessary).

Anticoagulants: Warfarin is usually stopped a few days before surgery for obvious reasons. Heparin is used as a substitute in the preoperative and early postoperative period until oral warfarin is resumed.

Aspirin and other non-steroidal anti-inflammatory drugs: Aspirin can increase blood loss as a result of impaired platelet function, so it is recommended to stop taking it 7 days before elective surgery to normalize platelet function. The above applies to patients with unstable angina. Other non-steroidal anti-inflammatory drugs should be stopped 1 day before surgery for short-acting drugs, and 3 days before surgery for long-acting drugs.

Oral contraceptives and female hormone replacement therapy: These are usually discontinued a few weeks before surgery to reduce the risk of postoperative venothrombosis.
Lithium: It is recommended to stop taking lithium 24 hours before surgery. Under the condition of a normal water and electrolyte balance, lithium intake can and should be resumed in the immediate postoperative period.

MAO inhibitors: they are stopped two weeks before surgery. If necessary, this group of drugs can be replaced by reversible MAO inhibitors (moclobemide). If this is not possible, then the intake of MAO inhibitors is continued, but then drugs with which undesirable interactions occur - pethidine, pentazocine are not used.

Use of steroids in the perioperative period

Influence of surgery: surgical trauma causes an increase in plasma concentrations of adrenocorticotropic hormone and cortisol. After minor surgery (hernia repair), the increase in cortisol secretion is minimal. In the case of major surgery (eg, hemicolectomy), cortiol secretion may increase from 30 mg/day to 75 to 150 mg/day. However, in patients who regularly take steroids for one reason or another, the hypothalamic-pituitary-adrenal axis (HPA) can seriously change its activity under the influence of exogenous steroids, and the natural response to injury will change accordingly. This means that such patients are at risk of a hypoadrenal crisis accompanied by cardiovascular collapse and shock. The normal stress response is similarly disturbed in patients taking steroids due to adrenal insufficiency (Addison's disease).

When should steroids be prescribed?

It is generally accepted that in patients with an increased risk of adrenal depression, as well as in patients with already known adrenal hypofunction, additional amounts of steroids should be prescribed in the pre- and postoperative period. However, not all patients receiving steroids have suppression of adrenal function; it depends on the dose of steroids and duration of administration. No evidence of adrenal suppression was found with 5 mg or less of prednisone per day. In practice, it is believed that the additional prescription of steroids in the perioperative period is necessary only when the dose of prednisolone taken before surgery exceeds 10 mg per day (recently this dose has been reduced to 7.5 mg). It should not be forgotten that suppression of adrenal function can occur with the use of high doses of steroids in the form of inhalers, for example, beclomethasone 1.5 mg per day.

Adrenal depression can develop as soon as a week after starting steroids. Based on earlier studies, experts believe that a patient who has stopped taking steroids less than 3 months before surgery may still have some degree of adrenocortical insufficiency. Such patients require replacement therapy depending on the severity of the operational stress.

Replacement Therapy Regimes

At one time, a wide variety of replacement therapy regimens were proposed. The earliest (1950s) consisted of administering approximately 4 times the usual dose. However, there are concerns that such high doses are not needed and may even lead to undesirable complications, delaying wound healing, increasing the duration of treatment, and increasing the number of postoperative complications.

A more modern regimen of steroid replacement therapy takes into account the dose and duration of steroid therapy, the nature of the surgical intervention - respectively, the amount of operational stress. Currently there are 2 such modes:

1. Patients undergoing large or medium-sized surgery receive the usual oral dose of prednisone the morning before surgery. They then receive 25 mg hydrocortisone intravenously under induction anesthesia followed by an infusion of 100 mg hydrocortisone over 24 hours. The infusion is stopped after 24 hours in the case of moderately traumatic surgery (eg, abdominal hysterectomy) or continued up to 72 hours (cardiac surgery). After that, they switch to the usual regimen of steroid therapy for the patient. In the case of a minor traumatic operation (hernia repair), the patient takes the usual dose of steroids orally or receives 25 mg of hydrocorticone during induction anesthesia in the morning before the operation.

2. This mode uses a bolus of steroids as opposed to a continuous infusion. In traumatic interventions, patients taking high (up to 40 mg per day) doses of prednisolone before surgery receive 40 mg of prednisolone orally, and then 50 mg of hydrocortisone is administered intravenously every 8 hours after surgery for 24 to 72 hours.

In cases of traumatic surgery in a patient taking up to 5 mg of prednisolone per day, 5 mg of prednisolone is administered orally as premedication, and then 25 mg of hydrocortisone is administered intravenously during the operation and with an 8-hour interval in the postoperative period for up to 48 hours after it.

There are currently no studies on the comparative evaluation of both methods. Purely theoretically, the infusion technique seems to be more preferable, since it avoids the sharp fluctuations in the level of steroids in plasma, which is observed with bolus administration.

diabetes and surgery

Potential Problems in Diabetic Patients

The stress response to surgery causes the release of hormones that increase blood sugar levels. In patients with type 1 diabetes (insulin-dependent), this can lead to severe hyperglycemia, ketoacidosis, increased protein catabolism, and water and electrolyte disturbances. In patients with type 2 diabetes (non-insulin dependent), these changes are less pronounced, but nevertheless, in the absence of adequate therapy, these patients may experience significant hyperglycemia and protein catabolism.

With constantly elevated sugar levels, the healing of the surgical wound is disrupted and the risk of wound infection increases. On the other hand, hypoglycemia due to fasting or improper insulin dosing also poses a real danger during surgery. Since anesthesia masks the signs of hypoglycemia, it is recommended to regularly determine the level of glycemia during surgery and in the immediate postoperative period.

Preoperative examination

Attention should be paid to the regimen of drug therapy, the degree of glycemic control, complications of diabetes and concomitant diseases (CHD, hypertension, nephropathy, neuropathy), as well as to clarify the question of the course of previous operations.

It is important to achieve adequate control of diabetes in the preoperative period, based on the measurement of glycosylated hemoglobin in the blood. Usually there is no need for early hospitalization of the patient for elective surgery, provided that diabetes is well controlled and there are no fluid and electrolyte disturbances. It is also not recommended to cancel surgery on the basis of a single finding of high blood sugar if previous control of diabetes has been satisfactory. In cases of emergency surgery, there is often no time to fully optimize the patient's condition, however, control of glucose levels can be quickly achieved with the infusion of a glucose-insulin mixture (see below). If possible, surgery for diabetic patients, especially type 1, should be performed first. This allows you to reduce the time of preoperative fasting, and if problems arise in the postoperative period, there is time to solve them with the presence of the most experienced staff in the clinic.

Preoperative drug therapy for type 1 diabetes

If the patient receives short- and medium-acting insulin 2 times a day, then this regimen is continued until the morning of the operation. If the patient receives the same types of insulin, but 3 times a day with the introduction of insulin of medium duration in the evening, some authors suggest that this evening dose should not be administered. On the other hand, there is a widespread belief that it increases the risk of hyperglycemia and ketoacidosis. In any case, long-acting insulin preparations before surgery are replaced with medium- and short-acting ones.

type 2 diabetes

If this type of diabetes is controlled only by diet, then no specific preparations for surgery are required. Patients taking long-acting sulfonylurea drugs (glibenclamide) should switch to shorter-acting drugs of the same group (glipizide, glikazide, tolbutamide) 3 days before surgery to avoid postoperative hypoglycemia. Metformin, which can cause lactic acidosis in renal dysfunction, is most commonly stopped 48 to 72 hours before surgery. If the patient is undergoing a minor operation that is unlikely to affect kidney function, continued use of metformin is likely safe, but is usually discontinued. For all oral hypoglycemic agents, the morning dose before surgery is waived. If the preoperative examination reveals that the control of diabetes in such patients with the help of oral drugs is insufficient, then they switch to subcutaneous administration and the management of such patients is based on the regimen for patients with insulin-dependent diabetes.

Use of insulin during surgery

Type 1 Diabetes: It is preferable to administer insulin intravenously rather than subcutaneously during surgery. Two alternative approaches are used. In the first mode, separate intravenous transfusion of insulin, glucose and potassium chloride is performed. Another technique involves mixing all three components. Each method has its own advantages and disadvantages. Separate infusion allows greater flexibility in glucose control. However, if one of the infusion lines is blocked, then the continued infusion of the other two components is a real threat of hypo- or hyperglycemia. In addition, when transporting a patient from the operating room to the postoperative unit, the risk of an error in setting the infusion rate for 3 parameters is higher than for one.

The method of intravenous insulin infusion according to the so-called sliding scale is widespread. Its essence lies in the fact that the infusion device (as a rule, these are special infusor syringes for insulin with a capacity of 5 ml) are used for variable insulin infusion depending on the level of glycemia. In parallel, an intravenous infusion of 5% glucose is performed. The technique is quite simple and convenient. There are several variants of this sliding scale, the most common one is given below:

Sliding Insulin Infusion Scale

Another option in the absence of special equipment is the so-called Alberti regimen, the essence of which is the use of insulin infusion and 5% glucose solution at a rate of 100 ml / hour. The solution for infusion in the classic version consists of 1 liter of 5% glucose, 16 units of insulin and 10 mmol / l of potassium chloride. The infusion rate is maintained constant, the amount of insulin varies depending on glycemia. This regime in its more modern modification will be discussed below.

The Alberti regimen is more flexible, with its use the risk of complications is less. However, to change the dosage, it is necessary to change the entire solution.

Although there are few studies on this topic, a small study in terms of the number of patients

conducted in New Zealand showed that the use of separate infusion gives more stable glycemic control in the perioperative period.

Type 2 diabetes: Patients with this form of diabetes should be switched to intravenous insulin for medium or large operations, even if oral medications provide good glycemic control. inadequate. Such patients with fasting glucose levels less than 11 mmol/l usually do not need any special measures other than regular glucose monitoring.

Requirements for insulin, glucose and potassium chloride

In type 1 and type 2 diabetics, optimal metabolic control includes sufficient insulin to prevent hyperglycemia, lipolysis, and proteolysis, and sufficient glucose to avoid hypoglycemia. Glucose is usually used as a 5% solution at an infusion rate of 100 mg per hour. When using 5% glucose, insulin is administered at a dose of 1.5-2.0 units per hour (0.3-0.4 units per gram of glucose). However, in patients with obesity, infectious processes, impaired liver function, or long-term use of steroids, insulin resistance may develop and the need for it may be higher (0.4 - 0.8 units per gram of glucose administered). The need for insulin may be even higher with cardiosurgery using AIC (up to l.2 units)

In order to avoid hypokalemia, 10–20 mmol of potassium chloride is added to each liter of the poured solution. With an increase in the rate of insulin infusion above 0.4 units / kg / hour, an additional dose of potassium is required. Plasma potassium is usually measured every 4 to 6 hours.

Perioperative glucose monitoring

There is currently no clear agreement on how often glucose should be measured, although there is a general rule that the worse glycemic control is, the more often measurements should be taken. The usual recommended level is 5-10 mmol/l. At the same time, there is an opinion that very tight glycemic control should not be achieved, a level below 10 mmol is considered quite acceptable. A normal-weight patient with well-controlled type 1 diabetes requires hourly glycemic testing prior to elective surgery. At the same time, in such a patient during the hypothermic phase of AIC, the determination of the glucose level is carried out every 30 minutes.

Transition to the usual regimen of maintenance therapy

For patients with type 1 and type 2 diabetes who received insulin, the transition to the usual regimen of therapy should be carried out with caution. The first light breakfast after surgery is usually taken while infusing glucose with insulin to test food tolerance. Patients who usually receive subcutaneous insulin receive their usual dose 30 minutes before dinner. Infusion of insulin with glucose continues for another hour (or until the end of the meal). Patients receiving insulin 2 times a day, the usual dose is administered before dinner. If, after switching to the usual regimen of insulin administration, glycemic control is not restored, the patient is again transferred to the intravenous regimen with the obligatory consultation of an endocrinologist.

Patients with type 2 diabetes treated with oral medications but switched to intravenous insulin during surgery may need additional subcutaneous insulin before glycemic control is achieved with the usual regimen. After minor surgeries, oral medications are started with meals.

Hormonal contraceptives and female hormone replacement therapy

Women taking hormonal contraceptives or hormone replacement therapy have an increased risk of venothrombosis with subsequent thromboembolism. The operation itself is a risk factor for TE, the frequency of which varies depending on the type of operation. Surgical intervention leads to damage to the vascular wall, the patient remains in a forced position after surgery for quite a long time, blood clotting will increase as a result of injury - these are the risk factors for the development of phlebothrombosis. Additionally, factors such as advanced age, obesity, pregnancy, varicose veins, tumors, and the introduction of exogenous estrogens are called.

Postoperative venothrombosis is most likely in the case of major operations. In the absence of thromboprophylaxis, the frequency of venothrombosis in general surgical interventions is 25–33%, reaching 45–70% in hip arthroplasty. The frequency of pulmonary embolism is 0.1-0.8% for elective general surgery, 1-3% for elective hip arthroplasty, 4-7% for emergency prosthetics.

Hormonal contraception and surgery

Oral contraceptives: The incidence of spontaneous phlebothrombosis in healthy, non-pregnant women not taking oral contraceptives is 5 per 100,000 per year. The risk is increased in those taking combined oral contraceptives, especially third-generation drugs containing the progestogens desogestrel and gestodine. The currently available data allow us to estimate the frequency of venothrombosis for drugs of the 2nd generation (containing levonorgestrol) 15 per 100,000 per year, for the 3rd generation - 25 per 100,000.

The risk of venothrombosis is especially increased in women with a hereditary mutation of factor Y Leiden (the most common form of thrombophilia). In this case, the risk is increased to 285 per 100,000.

Change in clotting factors

The mechanisms by which oral contraceptives increase the risk of venothrombosis are not entirely clear. In women taking such drugs, there is an increase in the activity of procoagulants: fators 7,10 and fibrinogen, which is combined with a decrease in antithrombin activity. The activity of these factors returns to normal 8 weeks after discontinuation.

Studies show that the operation itself is an additional risk factor for the development of venothrombosis. According to some reports, the frequency of this complication was 2 times higher in women taking oral contraceptives compared with the control group in abdominal operations. Data available to date suggest that progesterone-only contraceptives (ethinodiol acetate, norethisterone, levonorgestrel, hydroxyprogesterone acetate, norgestrel) do not increase the risk of venothrombosis.

Perioperative management

Published recommendations to date for stopping or continuing oral contraceptives before surgery are conflicting. The general recommendation from the manufacturers of these drugs is to stop taking them at least 4 to 6 weeks before surgery or before long-term immobilization is anticipated. In addition, it is recommended to start taking these drugs only 2 weeks after the restoration of normal motor activity after surgery. These recommendations do not apply to minor surgeries (eg laparoscopic sterilization).

On the other hand, a group of specialists who studied the issue concluded that in women with an increased risk of venothrombosis, thromboprophylaxis should be applied at the individual level. In other words, the risk of venothrombosis and continued drug use must be weighed against the risk of unwanted pregnancy. So what are the general recommendations in this case? Women taking progestogen-based drugs may not stop taking them and continue it in the postoperative period. In the case of combined oral contraceptives, the risk of venothrombosis in the event of continued use, the risk of unwanted pregnancy and the wishes of the woman herself should be assessed.

The general recommendation in the case of a major elective operation is that combined contraceptives should be stopped and thromboprophylaxis should be started (low molecular weight heparin, elastic stockings, and so on). Alternatively, it is recommended to switch to progestogen-only preparations 4 weeks before surgery. Whatever approach is chosen, it should be discussed with the patient.

Hormone replacement therapy

When taking replacement therapy (menopause, hysteroophorectomy), the risk of venothrombosis increases by 2-4 times.

The situation here is similar to that described above. The manufacturers of the drug recommend stopping its use 4 weeks before elective surgery (especially orthopedic or intra-abdominal), despite the fact that menopausal symptoms may return.

The review team believes that routine discontinuation of hormone replacement therapy does not have a sufficient basis. In their opinion, women taking this therapy due to their age already have a number of factors that increase the risk of venothrombosis, which necessitates the use of thromboprophylaxis. Based on these 2 points of view, current recommendations - in the case of a major operation, it is recommended to continue taking replacement therapy, combining it with thromboprophylaxis. In the case of minor operations, the need for thromboprophylaxis is eliminated.

Drugs affecting the cardiovascular system

For patients taking drugs of this group, a detailed preoperative examination is very important. In addition to a detailed pharmacological history, information is needed on the functional state of the cardiovascular system, details of previous operations, including information on abnormal bleeding, organ disorders. The preoperative examination program includes cardiovascular risk factors (diabetes, high cholesterol, obesity, and so on). The information obtained makes it possible to quantify the degree of risk for such patients.

Patients with pacemakers usually do not have serious problems, but some types of pacemakers are sensitive to electromagnetic interference that occurs when diathermy is used.

With lesions of the valvular apparatus, a thorough preoperative examination is necessary; if necessary, antibiotic prophylaxis of endocarditis should be used.

In the preoperative period, it is necessary to make a decision about which drugs should be continued and which should be discontinued. Ideally, the state of the cardiovascular system should be as optimized as possible before surgery. However, the only reason for canceling the operation is the fact that active treatment of concomitant (in this case, cardiac) disease will improve the prognosis of surgical treatment.

Warfarin: Patients taking warfarin may have an increased risk of thromboembolism if warfarin is stopped abruptly. On the other hand, with continued use, the risk of postoperative bleeding is increased. There is little evidence that warfarin can be safely continued in case of upcoming minor surgery (skin, tooth extractions, some ophthalmic surgeries). The British Standards Committee in Hematology recommends performing the above minor surgeries, provided that the INR (Prothrombin Index Equivalent) does not exceed 2.5. However, in most cases, warfarin is stopped about 4 days before surgery to bring the INR down to 1.5 or below. For warfarin replacement, intravenous heparin infusion is routinely used up to 6 hours before surgery; the speed is maintained based on the data of APPT (activated partial prothrombin time) in the range of 1.5 - 2.5. If complete anticoagulation is required after surgery, then heparin infusion is started 12 hours after its (operation) completion with APP check every 4-6 hours. Warfarin is started when the patient can take oral medications. An alternative to intravenous heparin is the subcutaneous injection of low molecular weight heparin. However, it should be borne in mind that the duration of action of such heparin is higher than usual.

Venothrombosis: After the first episode of venothrombosis or pulmonary embolism, warfarin is usually given for 3 to 6 months. Discontinuation of the drug may cause rethrombosis. Therefore, where possible, it is advisable to delay surgery in order to complete the course of warfarin. At least the duration of admission should be at least a month. If the operation cannot be postponed, the above regimen with heparin is used, depending on the timing of the proposed operation. If the operation is to be performed within a month after venothrombosis, then it is desirable to use intravenous heparin both before and after the operation. During surgery on the 2nd or 3rd month, heparin can only be administered in the postoperative period.

Patients who have been on warfarin for at least 3 months usually do not need preoperative heparin but should receive it postoperatively until warfarin begins to take effect.

Arterial thrombosis: it is recommended to avoid elective surgery in the first month after thrombosis; if this is not possible, heparin should be used as described above. Postoperative heparin is used only if the risk of bleeding is low.

In patients with atrial fibrillation who have not had a recent episode of embolism, the risk of thromboembolism is considered not high enough to use intravenous heparin both before and after surgery. It is recommended to use subcutaneous injection of low molecular weight heparin in the postoperative period.

Mechanical prosthetic heart valves: these patients usually take regular anticoagulants, without which the incidence of TE is 9 out of 100 cases during the year. Recommendations in this case vary, but generally come down to the advice to stop warfarin 4 days before surgery and start the introduction of low molecular weight heparin. In the postoperative period, heparin is used only in patients with mitral valve replacement (high risk of TE).

Emergency surgery: when there is no time to wait for the effect of warfarin to stop, it is recommended to include a hematologist in the operating team. Fresh frozen plasma transfusion (10 - 15 ml/kg) and intravenous vitamin K (1 - 2 mg) are used to reduce the INR to 1.5. However, after the introduction of vitamin K, there may be subsequent problems with achieving an anticoagulant effect.

Aspirin: Low-dose aspirin (75-150 mg/day) is currently widely used as the primary means of prevention in patients with atherosclerotic vascular disease. There are no data on whether to stop or continue taking aspirin. If a decision is made to stop taking it, then this should be done 7 to 9 days before the operation - the time required for the restoration of platelet function.

Based on the data available to date, it is recommended that aspirin should be discontinued in patients undergoing prostate resection.

In patients with CABG, continued aspirin increases the risk of bleeding but improves shunt patency.

Before minor surgical interventions (on the skin, in ophthalmology), there is no need to stop taking aspirin. The general recommendation is that aspirin should be stopped in cases where the consequences of bleeding are very serious (retinal surgery, neurosurgery). These considerations must be weighed against the possible complications of discontinuation, especially in patients with unstable coronary artery disease.

Other cardiovascular drugs: as a general rule, drugs for the treatment of hypertension, coronary artery disease, arrhythmias should be continued in the perioperative period. This helps prevent the development of perioperative cardiovascular complications and avoid the development of withdrawal syndrome.

Beta-blockers: In hypertensive patients, anesthesia and surgery can cause tachycardia and increased blood pressure. Beta-blockers help to at least mitigate these effects. A number of studies have shown that perioperative administration, for example, atenolol, significantly reduced mortality in the postoperative period.

Diuretics: Discontinuation of potassium-sparing diuretics is recommended on the grounds that operative stress reduces renal perfusion with subsequent postoperative hyperkalemia. Thiazide diuretics and furosemide drugs can be continued, bearing in mind that they can cause hypokalemia, which should be diagnosed and corrected before surgery.

Angiotensin-converting enzyme inhibitors: there is no clear evidence in one direction or another. It is possible that patients taking these drugs may develop more hypotension than usual during induction of anesthesia. Some cardiac anesthesiologists believe that ACE inhibitors increase the risk of hypotension in the immediate postoperative period, but this opinion is actively disputed. Therefore, it is recommended to continue taking these drugs, but with caution.

Antiarrhythmic drugs: it is recommended to continue taking drugs of this group in the perioperative period. Some of the drugs (desoptramid, procainamide, quinidine) can prolong the effect of non-depolarizing muscle relaxants, although a slight reduction in the dose of the latter usually solves the problem. When using amiodarone, complications such as perioperative bradycardia, deep vasodilation, a sharp decrease in cardiac output, sometimes with a fatal outcome, have been described. However, it is not recommended to stop taking it, since it must be stopped several months before the operation, and this significantly increases the risk of arrhythmia returning.

It is recommended to continue taking digoxin in the perioperative period, if necessary, switching to its intravenous administration. In such patients, it is desirable to determine the level of digoxin in the blood, as well as to monitor the level of potassium during the entire stay in the hospital.

Regional anesthesia: Regional blocks (including epidural and spinal) in patients taking warfarin or aspirin increase the risk of epidural hematoma. The risk is highest during insertion and removal of the catheter.

Literature

1. Drug and Therapeutics Bulletin, vol 37, no. 8, 1999, p 62
2. Dug and Therapeutic Bulletin, vol 37, N9, 1999, p 68
3. Org and Therapeutic Bulletin, vol 37, NIO, 1999, p 78
4. Dug and Therapeutic Bulletin, vol 37, N12, 1999, p 89

Summary

Metformin belongs to the group of biguanides. It increases tissue sensitivity to insulin and lowers blood sugar levels. There are concerns that metformin may lead to the development of lactic acidosis in patients undergoing diagnostic procedures requiring the administration of iodine-containing contrast agents, and in patients with renal or heart failure. Numerous studies have reviewed the data on which these concerns are based and concluded that metformin is rarely the cause of lactic acidosis. The generally accepted view that all patients need to stop taking metformin 48 hours before and within 48 hours after performing interventions with the introduction of contrast agents seems illogical, devoid of any evidence base and does not correspond to the principles of good clinical practice. In patients with heart failure, this disease may predispose to the development of lactic acidosis, while the appointment of metformin leads to an improvement in observed outcomes rather than an increase in possible risks.

Keywords

Metformin, lactic acidosis, risk.

Metformin, a drug from the group of biguanides, increases the sensitivity of tissues to insulin, inhibits the course of gluconeogenesis in the liver and, as a result, lowers blood sugar levels. It can be given in combination with any other oral antidiabetic agent and with insulin. It is characterized by a short half-life - about 6 hours; 90% of the drug is excreted by the kidneys within 24 hours. With the use of metformin, there are the same concerns as with the use of its biguanide precursor, phenformin: the latter was found to have a strong relationship with the development of lactic acidosis, in connection with which in 1978 he was banned for clinical use.

Among doctors, the opinion has formed that metformin causes lactic acidosis in patients with diabetes or renal dysfunction. Therefore, the possibility of its use in patients with heart disease during intravenous or intra-arterial administration of contrast agents, as well as in patients with heart failure, is controversial. Many cardiac catheterization protocols stipulate that metformin must be discontinued 48 hours before and within 48 hours after any planned diagnostic or therapeutic intervention. In patients who have not stopped taking metformin, intervention is often delayed, which worsens the expected results from it.

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

Risks associated with discontinuing metformin

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

Risks Associated with Continued Metformin

Lactic acidosis in patients without diabetes mellitus develops in the presence of infections, cancer, liver and kidney failure, and in the absence of correction of these diseases always leads to death. Risk factors for lactic acidosis are largely similar and independent of diabetic status. Risk factors predisposing to the development of lactic acidosis:

— age> 80 years;

- tissue hypoxia;

- decrease in cardiac output;

- respiratory failure;

- liver failure;

- renal failure;

- sepsis;

- surgical intervention;

- ethanol intoxication;

- diabetic ketoacidosis;

- starvation / reduced nutrition;

- syndrome of a shortened small intestine (jejuno-ileal anastomosis, resection of the small intestine);

— antiretroviral therapy;

- high doses (intentional overdose) of metformin> 2 g / day.

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

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

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

Metformin and heart failure

Diabetes is a common comorbidity in patients with heart failure and is associated with a poorer prognosis. Metformin is "contraindicated" in heart failure due to the theoretical risk of developing lactic acidosis, despite the fact that appropriate long-term studies have not been performed. On the other hand, the literature on heart failure has accumulated a significant amount of data confirming the safety of metformin. The results of large retrospective registry analyzes suggest that, paradoxically, metformin is the only antidiabetic agent that reduces morbidity (reduction in the rate of readmissions for heart failure) and mortality in patients with heart failure, including elderly patients. Moreover, no cases of lactic acidosis were noted in these studies.

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

A pilot study was recently undertaken to evaluate the feasibility of a large randomized controlled trial with endpoints to evaluate the safety of metformin in heart failure. The randomization plan included either metformin 1500 mg/day or a comparable placebo for 6 months. As a result, no patients could be recruited into the study as all 58 screening patients were excluded from the study. The main reasons for exclusion from the study were reduced to the use of insulin, the presence of glycosylated hemoglobin levels< 7 % и приему высоких доз метформина. Пилотное исследование было прервано, а шансы на проведение крупного исследования стали почти безнадежными.

Many questions also arise regarding the validity of "contraindications" to the appointment of metformin in patients with diabetic cardiomyopathy, based on outdated and unsupported concerns about the ability of this drug to cause lactic acidosis.

Security Data

To reduce the tension around the safety of metformin, the pharmaceutical company Bristol-Myers Squibb (New York, USA) initiated a large 1-year COSMIC study (the Comparative Outcomes Study of Metformin Intervention versus Conventional approach - A comparative study of the safety of metformin and other antidiabetic drugs) which compared treatment with metformin and "usual therapy" with other antidiabetic agents. As a result, no difference in safety was found between 7227 patients taking metformin and 1505 patients taking "usual therapy". None of the groups developed lactic acidosis.

Two large, pharmaceutical-independent clinical trials have produced very impressive evidence for the safety and efficacy of metformin. First, in the large UKPDS (UK Prospective Diabetes Study) study, a subpopulation of 753 overweight patients was randomized to either conventional diet-only treatment (n = 342) or intensive glycemic control. control with metformin (n = 411). Metformin was superior in reducing the incidence of diabetes-related endpoints, including macrovascular complications, without compromising safety in either this randomized cohort or the entire UKPDS study population (n = 4075) over a median follow-up time of 10.7 of the year . It should be noted that metformin also leads to weight loss, which has a positive effect on cardiovascular risks in patients with diabetes and obesity. The safety and efficacy of metformin was confirmed by the Diabetes Prevention Program (n = 2155), which showed that this drug reduces the risk of developing diabetes by 31% compared with placebo.

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

Despite the results of controlled trials, registries, and meta-analyses, the risk of metformin-mediated lactic acidosis has been firmly established in our lives through anecdotal published reports and typical guidance in guidelines issued by major professional associations (Table 1).

One recently completed review of such individual reports found that the vast majority of metformin-associated cases of lactic acidosis (especially fatal ones) were more likely to be due to the presence of comorbidities or to the fact that diabetic patients are prone to developing serious medical complications that can lead to the development of lactic acidosis, rather than taking metformin itself. Another review analyzing all cases of lactic acidosis that developed after intravenous contrast administration indicated that patients had poor kidney function or other contraindications for the use of metformin. The absence in these patients of a correlation between the content of lactate and metformin in the blood plasma also indicated the "innocence" of metformin. In such patients, the need for contrast injection should be carefully re-evaluated and, if positive, an aggressive hydration regimen should be used to minimize the risk of developing contrast-induced nephropathy.

conclusions

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

Financial support: Biomedical Research Council (BRC).

Conflict of interest: not declared.

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

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

Bibliography

1. Dembo A.J., Marliss E.B., Halperin M.L. Insulin therapy in phenformin-associated lactic acidosis; a case report, biochemical considerations and review of the literature // Diabetes. - 1975. - 24. - 28e35.

2. Willfort-Ehringer A., ​​Ahmadi R., Gessl A. et al. Neointimal proliferation within carotid stents is more pronounced in diabetic patients with initial poor glycaemic state // Diabetologia. - 2004. - 47. - 400e6.

3. Timmer J.R., Ottervanger J.P., de Boer M.J. et al. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction // J. Am. Coll. cardiol. - 2005. - 45. - 999e1002.

4. Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program // Diabetes Care. - 2003. - 26. - 977e80.

5. Knowler W.C, Barrett-Connor E., Fowler S.E. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin // N. Engl. J. Med. - 2002. - 346. - 393e403.

6. Misbin R.I., Green L., Stadel B.V. et al. Lactic acidosis in patients with diabetes treated with metformin // N. Engl. J. Med. - 1998. - 338. - 265e6.

7. Brown J.B., Pedula K., Barzilay J. et al. Lactic acidosis rates in type 2 diabetes // Diabetes Care. - 1998. - 21. - 1659e63.

8. Salpeter S., Greyber E., Pasternak G. et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus // Cochrane Database Syst. Rev. - 2006. - 1. - CD002967.

9. Kreisberg R.A., Wood B.C. Drug and chemical-induced metabolic acidosis // Clin. Endocrinol. Metab. - 1983. - 12. - 391e411.

10. Calabrese A.T., Coley K.C., DaPos S.V. et al. Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy // Arch. Intern. Med. - 2002. - 162. - 434e7.

11. Emslie-Smith A.M., Boyle D.I., Evans J.M. et al. Contraindications to metformin therapy in patients with type 2 diabetes — apopulation-based study of adherence to prescribing guidelines // Diabet. Med. - 2001. - 18. - 483e8.

12. Tang W.H. Glycemic control and treatment patterns in patients with heart failure // Curr. cardiol. Rep. - 2007. - 9. - 242e7.

13. Eurich D.T., McAlister F.A., Blackburn D.F. et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review // BMJ. - 2007. - 33. - 497.

14. Masoudi F.A., Inzucchi S.E., Wang Y. et al. Thiazolidine-diones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study // Circulation. - 2005. - 111. - 583e90.

15. Gundewar S., Calvert J.W., Jha S. et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure // Circ. Res. - 2009. - 104. - 403e11.

16. Eurich D.T., Tsuyuki R.T., Majumdar S.R. et al. Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality // Trials. - 2009. - 10. - 12.

17. Tahrani A.A., Varughese G.I., Scarpello J.H. et al. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? // BMJ. - 2007. - 335. - 508e12.

18. McCormack J., Johns K., Tildesley H. Metformin’s contraindications should be contraindicated // CMAJ. - 2005. - 173. - 502e4.

19. Cryer D.R., Nicholas S.P., Henry D.H. et al. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study // Diabetes Care. - 2005. - 28. - 539e43.

20. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) // Lancet. - 1998. - 352. - 854e65.

21. Golay A. Metformin and body weight // Int. J. Obes. (Lond.). - 2008. - 32. - 61e72.

22. Stades A.M., Heikens J.T., Erkelens D.W. et al. Metformin and lactic acidosis: cause or coincidence? A review of case reports // J. Intern. Med. - 2004. - 255. - 179e87.

23. McCartney M.M., Gilbert F.J., Murchison L.E. et al. Metformin and contrast media: a dangerous combination? // clinic. Radiol. - 1999. - 54. - 29e33.

24. Lalau J.D., Race J.M. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations // Drug Saf. - 1999. - 20. - 377e84.

25. National Institute for Health and Clinical Excellence. Quick reference guided the management of type 2 diabetes, 2008. Available at http://www.nice.org.uk/Guidance/CG66/ (accessed 23 July 2009).

26Smith S.C. Jr, Feldman T.E., Hirshfeld J.W. Jr et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention) // Circulation . - 2006. - 113. - e166e286.

27. American Diabetes Association. Standards of medical care in diabetes - 2009 // Diabetes Care. - 2009. - 32(Suppl. 1). — S13e61.

28. Thomsen H.S., Morcos S.K. Contrast media and metformin: guidelines to diminish the risk of lactic acidosis in non-insulin-dependent diabetics after administration of contrast media. ESUR Contrast Media Safety Committee // Eur. Radiol. - 1999. - 9. - 738e40.

This material discusses mechanism of action of metformin- a popular oral antidiabetic drug, which is prescribed for the treatment of type 2 diabetes, as well as for people who are overweight and obese. prevents the development of cardiovascular diseases and complications of diabetes, helps the body increase sensitivity to insulin.

Despite the popularity the effect of metformin on the human body is not fully understood. also called "the bestseller, not read to the end." To this day, various studies are being actively conducted and scientists are discovering new facets of this drug, revealing its additional beneficial properties and side effects.

It is known that the World Health Organization has recognized one of the most effective and safe medicines used in the healthcare system.

On the other hand, although metformin was discovered back in 1922, it was only in 1995 that it began to be used in the United States. And in Germany, metformin is still not a prescription drug and German doctors do not prescribe it.

The mechanism of action of metformin

Metformin activates the secretion of the liver enzyme AMP-activated protein kinase (AMPK), which is responsible for the metabolism of glucose and fat. AMPK activation is required for inhibitory effect of metformin on gluconeogenesis in the liver.

In addition to suppressing the process of gluconeogenesis in the liver metformin increases tissue sensitivity to insulin, increases peripheral glucose uptake, increases fatty acid oxidation, while reducing the absorption of glucose from the gastrointestinal tract.

In simpler terms, after a high-carbohydrate meal is ingested, pancreatic insulin begins to be secreted to keep blood sugar levels within normal limits. Carbohydrates found in foods are digested in the intestines and converted into glucose, which enters the bloodstream. With the help of insulin, it is delivered to the cells and becomes available for energy.

The liver and muscles have the ability to store excess glucose, as well as easily release it into the bloodstream if necessary (for example, during exercise). In addition, the liver can store glucose from other nutrients, such as fats and amino acids (the building blocks of proteins).

The most important effect of metformin is the inhibition (suppression) of glucose production by the liver, which is characteristic of type 2 diabetes.

Another effect of the drug is expressed inhibition of glucose absorption in the intestine, which allows you to get lower blood glucose levels after meals (postprandial blood sugar), as well as increase cell sensitivity to insulin (target cells begin to respond more quickly to insulin, which is released when glucose is absorbed).

How does metformin work in pregnant women with gestational diabetes?

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

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

In animal experiments, no adverse effect of metformin on fetal development was observed.

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

When lactating, metformin should be abandoned., because it passes into breast milk. Treatment with metformin while breastfeeding should be discontinued.

How does metformin affect the ovaries?

Metformin is most often used to treat type 2 diabetes, but it is also prescribed for polycystic ovary syndrome (PCOS) due to the relationship between these diseases, because Polycystic ovary syndrome is often associated with insulin resistance.

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

In the UK, metformin is not recommended as first-line therapy for polycystic ovary syndrome. As a recommendation, clomiphene is indicated and the need for lifestyle changes is emphasized, regardless of drug therapy.

Metformin for female infertility

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

Another study recommends unqualified metformin as the primary treatment option, as it has a positive effect not only on anovulation, but also on thyroiditis, hirsutism, and obesity, which is often seen in PCOS.

prediabetes and metformin

Metformin may be given to pre-diabetics (those at risk of developing type 2 diabetes), which reduces their chances of developing the disease, although intense exercise and a carbohydrate-restricted diet are much preferable for this purpose.

In the United States, a study was conducted according to which one group of subjects was given metformin, while the other went in for sports and dieted. As a result, in the healthy lifestyle group, the incidence of diabetes mellitus was 31% less than in prediabetics taking metformin.

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

"People with elevated blood sugar levels who do not have diabetes are at risk of developing clinical type 2 diabetes, the so-called" pre-diabetes ". prediabetes usually applicable to boundary level fasting plasma glucose (impaired fasting glucose levels) and / or to the level of glucose in the blood plasma, donated 2 hours after the oral glucose tolerance test with 75 g. sugar (impaired glucose tolerance). In the United States, even the upper borderline level of glycated hemoglobin (HbA1c) has come to be considered prediabetes.
Individuals with prediabetes have an increased risk of microvascular injury and macrovascular complications. similar to long-term complications of diabetes. Halting or reversing the progression of decreased insulin sensitivity and destruction of β-cell function is the key to achieving type 2 diabetes prevention.

Many weight loss interventions have been developed: pharmacological treatment (metformin, thiazolidinediones, acarbose, basal insulin injections and weight loss drugs) and bariatric surgery. These measures aim to reduce the risk of developing type 2 diabetes in people with prediabetes, although positive results are not always achieved.

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

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

Can Metformin be taken for weight loss? Research results

According to research, metformin may help some people lose weight. However, it is still not clear how metformin leads to weight loss.

One theory is that metformin reduces appetite, which leads to weight loss. Despite the fact that metformin helps to lose weight, this drug is not directly intended for this purpose.

According to randomized long-term study(cm.: PubMed, PMCID: PMC3308305), weight loss from metformin use tends to occur gradually over one to two years. The number of kilograms dropped also varies from person to person and is associated with many other factors - with the constitution of the body, with the number of calories consumed daily, with lifestyle. According to the results of the study, the subjects, on average, lost from 1.8 to 3.1 kg after two or more years of taking metformin. When compared with other methods of losing weight (low-carbohydrate diets, high physical activity, fasting), this is more than a modest result.

Thoughtless use of the drug without observing other aspects of a healthy lifestyle does not lead to weight loss. People who eat a healthy diet and exercise while taking metformin tend to lose more weight. This is because metformin increases the rate at which calories are burned during exercise. If you don't exercise, then you probably won't have this benefit.

Is metformin given to children?

Reception of Metformin by children and adolescents over ten years of age is acceptable - this has been verified by various clinical studies. They did not reveal any specific side effects related to the development of the child, but the treatment should be carried out under the supervision of a physician.

conclusions

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

Sources:

1. Petunina N.A., Kuzina I.A. Metformin analogues of prolonged action // The attending physician. 2012. №3.
2. Does metformin cause lactic acidosis? / Cochrane systematic review: main provisions // News of Medicine and Pharmacy. 2011. No. 11-12.
3. Long-Term Safety, Tolerability, and Weight Loss Associated With Metformin in the Diabetes Prevention Program Outcomes Study // Diabetes Care. 2012 Apr; 35(4): 731-737. PMCID: PMC3308305.

Gross formula

C 4 H 11 N 5

Pharmacological group of the substance Metformin

Nosological classification (ICD-10)

CAS code

657-24-9

Characteristics of the substance Metformin

Metformin hydrochloride is a white or colorless crystalline powder. Let's well dissolve in water and practically insoluble in acetone, ether and chloroform. Molecular weight 165.63.

Pharmacology

pharmachologic effect- hypoglycemic.

Lowers the concentration of glucose (on an empty stomach and after eating) in the blood and the level of glycosylated hemoglobin, increases glucose tolerance. Reduces intestinal absorption of glucose, its production in the liver, potentiates sensitivity to insulin in peripheral tissues (increased absorption of glucose and its metabolism). Does not alter insulin secretion by pancreatic islet beta cells (fasting insulin levels and daily insulin response may even decrease). Normalizes the lipid profile of blood plasma in patients with non-insulin dependent diabetes mellitus: reduces the content of triglycerides, cholesterol and LDL (determined on an empty stomach) and does not change the levels of lipoproteins of other densities. Stabilizes or reduces body weight.

Experimental studies in animals at doses 3 times the MRDC in terms of body surface area did not reveal mutagenic, carcinogenic, teratogenic properties and effects on fertility.

Rapidly absorbed from the gastrointestinal tract. Absolute bioavailability (on an empty stomach) is 50-60%. C max in plasma is achieved after 2 hours. Food intake lowers C max by 40% and slows down its achievement by 35 minutes. The equilibrium concentration of metformin in the blood is reached within 24-48 hours and does not exceed 1 μg / ml. The volume of distribution (for a single dose of 850 mg) is (654 ± 358) liters. Slightly binds to plasma proteins, can accumulate in the salivary glands, liver and kidneys. It is excreted by the kidneys (mainly by tubular secretion) unchanged (90% per day). Renal Cl - 350-550 ml / min. T 1/2 is 6.2 h (plasma) and 17.6 h (blood) (the difference is due to the ability to accumulate in red blood cells). In the elderly, T 1/2 is prolonged and C max increases. In case of impaired renal function, T 1/2 is prolonged and renal clearance decreases.

The use of the substance Metformin

Type 2 diabetes mellitus (especially in cases accompanied by obesity) with ineffective correction of hyperglycemia by diet therapy, incl. in combination with sulfonylurea drugs.

Contraindications

Hypersensitivity, kidney disease or renal insufficiency (creatinine level is more than 0.132 mmol / l in men and 0.123 mmol / l in women), severe liver dysfunction; conditions accompanied by hypoxia (including heart and respiratory failure, acute phase of myocardial infarction, acute cerebrovascular insufficiency, anemia); dehydration, infectious diseases, major surgery and trauma, chronic alcoholism, acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma, history of lactic acidosis, adherence to a low-calorie diet (less than 1000 kcal / day), research using radioactive iodine isotopes , pregnancy, breastfeeding.

Application restrictions

Children's age (efficacy and safety of use in children have not been determined), elderly (over 65 years old) age (due to slow metabolism, it is necessary to evaluate the benefit / risk ratio). It should not be given to people doing heavy physical work (increased risk of developing lactic acidosis).

Use during pregnancy and lactation

During pregnancy, it is possible if the expected effect of therapy outweighs the potential risk to the fetus (adequate and strictly controlled studies on the use during pregnancy have not been conducted).

At the time of treatment should stop breastfeeding.

Side effects of Metformin

From the digestive tract: at the beginning of the course of treatment - anorexia, diarrhea, nausea, vomiting, flatulence, abdominal pain (reduce when taken with food); metallic taste in the mouth (3%).

From the side of the cardiovascular system and blood (hematopoiesis, hemostasis): in isolated cases - megaloblastic anemia (the result of malabsorption of vitamin B 12 and folic acid).

From the side of metabolism: hypoglycemia; in rare cases, lactic acidosis (weakness, drowsiness, hypotension, resistant bradyarrhythmia, respiratory disorders, abdominal pain, myalgia, hypothermia).

From the side of the skin: rash, dermatitis.

Interaction

The effect of metformin is weakened by thiazide and other diuretics, corticosteroids, phenothiazines, glucagon, thyroid hormones, estrogens, incl. as part of oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium antagonists, isoniazid. In a single dose in healthy volunteers, nifedipine increased absorption, C max (by 20%), AUC (by 9%) of metformin, T max and T 1/2 did not change. The hypoglycemic effect is enhanced by insulin, sulfonylurea derivatives, acarbose, NSAIDs, MAO inhibitors, oxytetracycline, ACE inhibitors, clofibrate derivatives, cyclophosphamide, beta-blockers.

A single dose interaction study in healthy volunteers showed that furosemide increased Cmax (by 22%) and AUC (by 15%) of metformin (without significant changes in renal clearance of metformin); metformin reduces C max (by 31%), AUC (by 12%) and T 1/2 (by 32%) of furosemide (without significant changes in the renal clearance of furosemide). There are no data on the interaction of metformin and furosemide with long-term use. Drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, and vancomycin) secreted in the tubules compete for tubular transport systems and, with long-term therapy, can increase Cmax of metformin by 60%. Cimetidine slows down the elimination of metformin, resulting in an increased risk of developing lactic acidosis. Incompatible with alcohol (increased risk of lactic acidosis).

Overdose

Symptoms: lactic acidosis.

Treatment: hemodialysis, symptomatic therapy.

Routes of administration

inside.

Metformin Substance Precautions

It is necessary to constantly monitor kidney function, glomerular filtration, blood glucose levels. Especially careful monitoring of blood glucose levels is necessary when using metformin in combination with sulfonylurea drugs or insulin (risk of hypoglycemia). Combined treatment with metformin and insulin should be carried out in a hospital until an adequate dose of each drug is established. In patients on continuous metformin therapy, it is necessary to determine the content of vitamin B 12 once a year due to a possible decrease in its absorption. It is necessary to determine the level of lactate in plasma at least 2 times a year, as well as with the appearance of myalgia. With an increase in the content of lactate, the drug is canceled. Do not apply before surgical operations and within 2 days after they are carried out, as well as within 2 days before and after performing diagnostic studies (in / in urography, angiography, etc.).

Interactions with other active substances

Trade names

Name	The value of the Wyshkovsky Index ®
	0.0414
	0.0359
	0.0238
	0.0176
	0.0168
	0.0109
	0.007
	0.0048
	0.0041
	0.0025
	0.0023
	0.0019
	0.0012
	0.001
	0.0008
	0.0007
	0.0007
	0.0006
	0.0006
	0.0005
	0.0005