The main purpose of metformin is the treatment of type 2 diabetes, especially for people who are overweight. In this group of more than 10 years of treatment, metformin reduced the risk of diabetes complications and overall mortality by about 30% compared with insulin and sulfonylurea drugs (glibenclamide and chlorpropamide) and about 40% compared with the group that received only dietary recommendations. These differences persist in patients who were observed for 5-10 years after the study. Since intensive blood glucose control with metformin reduces the risk of diabetes-related endpoints in diabetic patients with overweight and is associated with less weight gain and fewer hypoglycemic seizures than in the group that received insulin and sulfonylureas, metformin may be drug of choice in such patients.
Metformin has a lower risk of hypoglycemia than sulfonylurea drugs, although it sometimes occurs during intense physical exertion, calorie deficiency or when used with other antidiabetic drugs. Metformin is also not associated with weight gain and moderately reduces LDL and triglyceride levels.
In addition, it can be used in complex therapy with other drugs in the treatment of obesity.
Metformin is increasingly used in the treatment of polycystic ovary syndrome (PCOS), non-alcoholic fatty liver diseases and premature puberty - in other diseases that are manifested by insulin resistance. These readings are still considered experimental. The advantage of metformin in non-alcoholic fatty liver disease has not been widely studied; Although some randomized controlled trials have found significant improvement in its use, evidence is still insufficient.
Treatment with metformin in people at risk of developing type 2 diabetes can reduce the likelihood of developing the disease, although intense exercise and correction of the diet are much better suited for this purpose. In a large US study known as the Diabetes Prevention Program, participants were divided into groups. One group received a placebo, another - metformin, and the third - recommendations on lifestyle changes; all three were observed on average for three years. The intensive lifestyle change program included 16 lessons on diet and exercise; The patients were given the goal of reducing their body weight by 7% and physical activity for at least 150 minutes a week. The incidence of diabetes was 58% lower in the group with lifestyle modification and 31% in the group treated with metformin. Among young people with a higher body mass index, lifestyle changes were no more effective than using metformin, and for older people with a low body mass index, metformin was no better than placebo in the prevention of diabetes. After ten years, the incidence of diabetes was 34% lower in the group with lifestyle modification and 18% lower in the group that received metformin. It is unclear whether metformin slowed the progression of pre-diabetes to diabetes mellitus (the true preventive effect) or whether the reduction in the risk of developing diabetes mellitus was simply due to its sugar-lowering effect (therapeutic effect).
Polycystic Ovary Syndrome
Antidiabetic therapy has been proposed since the late 1980s as a treatment for polycystic ovary syndrome (PCOS), in which insulin resistance often occurs. The use of metformin for PCOS was first reported in 1994, in a small study conducted at the University of Andes, Venezuela. In 2004, the National Institutes of Health of the United Kingdom recommended that women with PCOS and a body mass index above 25 should be prescribed metformin for the treatment of anovulation and infertility when other treatment methods did not bring positive results. However, two large clinical trials conducted in 2006–2007, received mostly negative results: the use of metformin for PCOS is not more effective than placebo and the combination of metformin and clomiphene is not more effective than monotherapy with clomiphene. Given this, in subsequent reviews it was noted that large randomized controlled trials in general did not confirm the promise of such therapy, proposed in early small trials. International guidelines on clinical practice do not recommend metformin as a first line treatment of PCOS or are not recommended at all, with the exception of women with impaired glucose tolerance. Guides suggest clomiphene as a first-line drug and highlight the importance of lifestyle changes, regardless of medication.
In another view, a systematic review of the four comparative tests of metformin and clomiphene showed their equal efficacy for the treatment of infertility. The BMJ Editorial Board noted that four studies showed positive results of using metformin in patients who had ineffective clomiphene, and suggested using metformin as a second-line drug when treatment with clomiphene is ineffective. Another review recommended metformin as a first-line drug, because it has a positive effect not only on anovulation, but also on insulin resistance, hirsutism and obesity, which are often associated with PCOS. A large review of the Cochrane Collaboration 27 randomized clinical trials found that metformin improves ovulation and pregnancy, especially in combination with clomiphene, but this is not associated with an increase in the number of live births.
The results of recent studies have shown that metformin can reduce the likelihood of premature delivery and late spontaneous abortion in patients with polycystic ovary syndrome, but the drug does not affect the risk of developing gestational diabetes.
During the tests, it was revealed that the risk of late spontaneous abortion (in the second trimester of pregnancy) and premature birth (before the 37th week) is approximately two times lower in patients who received metformin. Only 9 women (5%) out of 211 who completed clinical studies in the metformin group failed to endure pregnancy. In the control group, this figure was 10% (23 participants from 223 people). A total of 487 patients were involved in the study.
Several review and randomized controlled trials have shown that metformin is as effective and safe as insulin for treating gestational diabetes, and in small case-control studies it was considered that children of mothers who received metformin instead of insulin may be healthier in neonatal period. However, some problems have been raised regarding studies published so far, and evidence of the long-term safety of metformin for mother and child is still missing.
A large case-control study conducted at the MD Anderson Cancer Center showed that metformin can protect against pancreatic cancer. The risk of pancreatic cancer in subjects who took Metformin was 62% lower than in study participants who did not take it, and in subjects who received insulin or sulfonylurea drugs, an increase of 5 times and 2.5 times was found pancreatic cancer, respectively, compared with participants who received nothing. The study had some limitations, however, and the reason for this risk reduction is unclear. Observational studies conducted at the University of Dundee showed a decrease of 25-37% in cases of cancer in diabetics who took Metformin.
Several epidemiological and case-control studies have shown that diabetics using metformin may have a lower risk of developing cancer than those who use other antidiabetic drugs. The causes of this phenomenon remain unclear, and the results require confirmation in controlled studies.
One randomized controlled trial showed that metformin can reduce weight gain in patients taking atypical antipsychotics, especially when combined with lifestyle changes (training, diet and exercise).
In the experiment of the National Institute for the Study of Aging, the life expectancy of mice treated with metformin at a relatively low dosage increased by 5.83% compared to normal, with the onset of age-related diseases being delayed. At the same time, higher doses proved to be toxic, and the life of the mice that received them was low.
Metformin is contraindicated in people with any condition that may increase the risk of lactic acidosis, including kidney disease (creatinine levels more than 150 µmol / L (1.7 mg / dL), although this is a conditional limit), lung and liver, and alcoholism. According to manufacturers, heart failure, in particular, unstable or acute congestive heart failure increases the risk of lactic acidosis when using metformin. However, a systematic review of controlled clinical trials in 2007 showed that metformin is the only antidiabetic drug that is harmless to people with heart failure, and that it can reduce mortality compared with other antidiabetic agents.
It is recommended to temporarily cancel metformin two days before any radiographic study with the introduction of iodine contrast (for example, with CT or angiography with contrast enhancement), since the contrast agent may temporarily reduce kidney function, indirectly leading to lactic acidosis and causing a delay in metformin in the body. It is recommended to resume taking metformin only after two days, when kidney function is restored.
Also contraindications: hypersensitivity, hyperglycemic coma, ketoacidosis, acute myocardial infarction, dehydration, hypocaloric diet (less than 1,000 kcal / day), lactic acidosis (including history), pregnancy, lactation period.
With caution. Age over 60 years of age, hard physical work (increased risk of lactic acidosis).
The most common side effects of metformin are gastrointestinal disorders, including a metallic taste in the mouth, loss of appetite, diarrhea, intestinal colic, nausea, vomiting, and flatulence; Metformin is more commonly associated with gastrointestinal side effects than most other antidiabetic drugs.
In a clinical study in which 286 patients participated, 53.2% of 141 participants who received immediate-release metformin reported diarrhea, compared with 11.7% in the placebo group, and 25.5% reported nausea, vomiting, compared with 8.3% in the placebo group.
A gastrointestinal disorder can cause severe discomfort for the patient; it occurs more often with the first appointment of metformin or with increasing doses. Discomfort can often be avoided by starting with a low dose (1-1.7 g per day) and gradually increasing the dose. Gastrointestinal disorders after prolonged, continuous use are less common.
Prolonged use of metformin has been associated with increased levels of homocysteine and impaired absorption of vitamin B12. High doses and prolonged use are associated with an increased incidence of vitamin B12 deficiency, and some researchers recommend early detection and prevention of such conditions.
Lactic acidosis is the most severe side effect when using biguanides. Phenformin, another biguanide, was withdrawn from the pharmacological market due to the high risk of lactic acidosis (40–64 cases per million person-years). However, metformin is safer than phenformin. This complication with the use of metformin is very rare, and the vast majority of such cases are associated with comorbid conditions, such as abnormal liver function or kidney function.
Liver absorption of lactate decreases with metformin because lactate is a substrate for hepatic gluconeogenesis — a process that inhibits metformin. In healthy individuals, this small excess is simply removed by other mechanisms (including absorption by the kidneys when their function is not impaired), and there is a slight increase in the level of lactate in the blood. However, with impaired renal function, the removal of metformin and lactate is reduced, which leads to an increase in their blood levels and ultimately causes lactic acidosis due to the accumulation of lactic acid. Because metformin reduces liver uptake of lactate, any condition that can cause lactic acidosis is a contraindication to its use. The most common causes of increased lactic acid formation are: alcoholism (due to depletion of NAD + stores), heart failure and respiratory diseases (due to insufficient oxygenation of tissues); Kidney disease is the most common cause of impaired lactic acid excretion.
In addition, it is suggested that metformin increases the formation of lactate in the small intestine; this may potentially contribute to the development of lactic acidosis in patients with risk factors. However, the clinical significance of this phenomenon is unknown, and the risk of developing metformin-associated lactic acidosis is most often due to a decrease in hepatic absorption, and not an increase in education in the small intestine.
Other side effects
It has also been found that metformin reduces the level of thyroid-stimulating hormone in the blood of patients with hypothyroidism, while in men it reduces the level of testosterone. The clinical significance of these changes is still unknown. In case of allergy to the drug, a skin rash is possible. In isolated cases, megaloblastic anemia develops.
In cases of side effects, the dose should be reduced or canceled.
The H2-histamine receptor blocker, cimetidine, leads to an increase in plasma concentration of metformin by reducing its excretion from the body by the kidneys; Since metformin and cimetidine are excreted from the body by tubular secretion, in particular, the cationic (positively charged) form of cimetidine can compete with metformin for the same transport mechanism. A small, double-blind, randomized study showed that cephalexin also increases the concentration of metformin by the same mechanism. Theoretically, any other cationic drug (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, and vancomycin) can lead to a similar effect. Incompatible with ethanol (lactic acidosis). With caution prescribed in combination with indirect anticoagulants. Sulfonylurea derivatives, insulin, acarbose, MAO inhibitors, oxytetracycline, ACE inhibitors, clofibrate, cyclophosphamide and salicylates enhance the effect. When used simultaneously with GCS, hormonal contraceptives for oral administration, epinephrine, glucagon, thyroid hormones, phenothiazine derivatives, thiazide diuretics, nicotinic acid derivatives, the hypoglycemic action of metformin may be reduced. Nifedipine increases absorption, Cmax, slows excretion.
Metformin tablets (500 mg) sold in the UK.
Inside, during or immediately after a meal, patients who do not receive insulin - 1 g (2 tablets) 2 times a day for the first 3 days or 500 mg 3 times a day, followed by 4 to 14 days - 1 g 3 times a day; after 15 days, the dosage can be reduced taking into account the content of glucose in the blood and urine. Supporting daily dose of 1-2 g. Tablets retard (850 mg) taken 1 morning and evening. The maximum daily dose is 3 g. With simultaneous use of insulin in a dose of less than 40 U / day, the dosage regimen of metformin is the same, while the insulin dose can be gradually reduced (by 4-8 U / day every other day). When the insulin dose is more than 40 U / day, the use of metformin and the reduction of insulin dose require great care and are carried out in the hospital.
A five-year review of intentional and accidental overdose with metformin showed that there were rare cases of serious adverse events, although the risk was higher in older patients. A similar study, where reported overdose cases were analyzed at the Texas Poisons Control Center from 2000 to 2006, found that taking more than 5 g of a dose often caused serious medical outcomes in adults. In the medical literature, cases of survival after deliberate overdose of up to 63 g of metformin have been reported. Overdose deaths are rare, but do occur. In healthy children, doses of less than 1,700 mg do not cause significant toxic effects.
The most common overdose symptoms are nausea, vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and rarely hypoglycemia or hyperglycemia. The main potentially life-threatening complication of metformin overdose is lactic acidosis, which leads to the accumulation of lactate in the body. Patients with signs of lactic acidosis require immediate hospitalization. There is no specific antidote for overdose with metformin. Initially, lactic acidosis may use sodium bicarbonate solution, although large doses are not recommended, as this may increase intracellular acidosis. Acidosis, which does not respond to the introduction of sodium bicarbonate, requires the use of standard hemodialysis or continuous veno-venous hemofiltration. In addition, due to the low molecular weight of metformin and the absence of its binding to plasma proteins, these methods are very effective in removing metformin from blood plasma, preventing further accumulation of lactate.
Determining the level of metformin in plasma or serum is possible to control the treatment, to confirm the diagnosis of overdose in hospitalized patients or during a forensic examination to establish the cause of death. The concentration of metformin in the blood or plasma, as a rule, is 1–4 mg / l in persons receiving the drug for therapeutic purposes, 40–120 mg / l in persons with overdose and 80–200 mg / l in a fatal outcome. Usually used chromatographic methods.
At a dose of 85 g of metformin, hypoglycemia did not develop, even if lactic acidosis developed under the same conditions, which can also be caused by an overdose of metformin hydrochloride or concomitant risk factors. Early symptoms of lactic acidosis are fever, abdominal pain, myalgia, tachypnea, dizziness, impaired consciousness, and coma can be noted later.
When treatment is necessary to control renal function; determination of lactate in plasma should be carried out at least 2 times a year, as well as the appearance of myalgia. With the development of lactic acidosis, metformin should be immediately discontinued. Not recommended in case of danger of dehydration. Large surgical interventions and injuries, extensive burns, infectious diseases with fever may require discontinuation of oral hypoglycemic drugs and insulin administration. With combined treatment with sulfonylurea derivatives, careful monitoring of blood glucose concentration is necessary. Combined use with insulin is recommended in the hospital.