Benefits of extended release metformin

Benefits of extended release metformin

One of the most common diseases in modern society is type 2 diabetes mellitus (DM). The medical and social significance of diabetes is determined by the steady increase in its prevalence, the high risk of macro- and microvascular complications, as well as the impact of the disease on the quality and life expectancy of patients.

A key element in the pathogenesis of type 2 diabetes is insulin resistance (IR), which is defined as an impaired biological response of the body’s peripheral tissues to the effects of endogenous or exogenous insulin. Today there is convincing evidence of the genetic determination of IR. Thus, in patients with type 2 diabetes, point mutations were identified in the leptin receptor gene, in the insulin receptor substrate 1 (ISR-1) gene and PPAR-gamma (peroxisomeproliferator-activated receptor-gamma) [1]. One of the causes of secondary insulin resistance is glucose toxicity, i.e. a state of prolonged hyperglycemia, leading to a decrease in the biological effect of insulin. In the modern world, when energy consumption exceeds energy expenditure, IR has become the main factor contributing to the development of abdominal obesity, the accumulation of free fatty acids and, finally, the occurrence of type 2 diabetes. This leads to an increased risk of cardiovascular morbidity and premature mortality.

Insulin resistance is clinically manifested by loss of sensitivity to insulin in muscle, fat and liver tissues. At the same time, the supply of glucose from the blood and its utilization in myocytes decreases. Adipocytes develop resistance to the antilipolytic action of insulin, which leads to the accumulation of free fatty acids (FFA) and glycerol. FFAs entering the liver become the main source of the formation of atherogenic very low-density lipoproteins (VLDL). Insulin resistance of liver tissue is manifested by a decrease in glycogenesis and an increase in glycogenolysis and gluconeogenesis, resulting in the development of hyperglycemia [2].

In the treatment of type 2 diabetes, an important role is played by influencing the key pathogenetic link in the development of the disease - IR. For this purpose, biguanides have been used in medical practice for more than 50 years. The safest representative of this class from the point of view of the development of lactic acidosis is metformin. Today, according to the International Diabetes Federation, metformin is the first choice drug for newly diagnosed type 2 diabetes. In 2006, the American and European Diabetes Associations recommended metformin as a first-line drug in conjunction with non-pharmacological treatment of type 2 diabetes.

Metformin reduces IR, which occurs by restoring impaired post-receptor mechanisms of insulin action (in particular, tyrosine kinase, phosphotyrosine phosphatase). In this case, the following effects are realized: 1) the absorption of glucose by liver, muscle and fat cells increases, which is mediated by restoration of the quantity and activity of glucose transporters GLUT-1, GLUT-3 and GLUT-4; 2) the rate of glucose production by the liver decreases by reducing gluconeogenesis by inhibiting lipid oxidation; 3) the utilization of glucose by the intestinal mucosa increases and the concentration of glucose in the portal vein system decreases. Due to this, the fasting blood glucose level decreases and the need for insulin secretion decreases.

In addition to the antihyperglycemic properties of metformin, other clinical effects have been identified. The UKPDS study reported a 36% reduction in the risk of all-cause mortality, a 42% reduction in the risk of diabetes-related death, a 32% reduction in the risk of diabetes-related complications, and a 39% reduction in the risk of myocardial infarction in obese patients treated with metformin [3].

Metformin has a beneficial effect on the lipid profile. It significantly reduces the level of triglycerides and VLDL in the blood plasma. An analysis of 29 studies demonstrated a significant increase in high-density lipoprotein (HDL) levels with metformin [4]. Studies have also been able to demonstrate obvious benefits of the drug against microalbuminuria in patients with diabetes mellitus [5].

In addition, metformin increases fibrinolysis by reducing the activity of plasminogen activator inhibitor 1 (PAI-1) in adipocytes, myocytes, endothelial cells, reduces platelet aggregation and slows down the differentiation of monocytes into macrophages [6]. The beneficial effects of metformin on blood fibrinolytic activity and vascular pathology in type 2 diabetes were highlighted by analyzing data from the UKPDS prospective study. It was found that patients with type 2 diabetes who received monotherapy or combination therapy with metformin have a reduced risk of developing vascular complications compared with patients treated with sulfonylureas or insulin.

Metformin has an antiatherosclerotic effect in vitro, affecting the early stages of atherosclerosis development, disrupting the adhesion of monocytes, their transformation and the ability to take up lipids. The drug inhibits the proliferation of vascular smooth muscle cells. Normalization of the contraction/relaxation cycle of arterioles and reduction of vascular wall permeability are among the vasoprotective effects of metformin [7]. Metformin therapy increases glucose transport in the endothelium and vascular smooth muscle, as well as in the heart muscle. Recent studies have shown that metformin has a positive effect on oxidative stress. According to the latest scientific data, the drug can either directly intercept free radicals or indirectly reduce their content by inhibiting the intracellular formation of superoxide radical (O2-), the main source of which is oxidation by NADPH oxidase.

Metformin has an anorexigenic effect, the mechanism of which is not fully understood. It is believed that this effect is associated with the influence of the drug on the metabolism of glucagon-like peptide-1 (GLP-1), which regulates eating behavior [8]. In obese patients, metformin after a glucose load caused a significant increase in GLP-1 concentrations at the 30th and 60th minutes of the test with unchanged basal peptide levels. In mixed plasma and in a buffer solution containing dipeptidyl peptidase-4, metformin inhibited GLP-1 degradation. According to the results of experimental studies in animal models, the anorexigenic effect of metformin also appears to be associated with the central action of the drug at the level of hypothalamic neurons [9]. By modulating the expression of anorexigenic neuropeptide-gamma, metformin promotes weight loss.

Recently, special attention has been paid to the possibility of using metformin in non-alcoholic fatty liver disease, the development of which is also associated with IR. The Chen SQ study found a decrease in hepatomegaly, steatosis and normalization of liver enzymes while taking metformin [10].

Metformin is used as one of the main treatments for hormonal disorders in polycystic ovary syndrome (PCOS). The drug alone or in combination with clomiphene is used to induce ovulation in women with PCOS [11].

In modern literature, data have appeared on the use of metformin during pregnancy in women with PCOS. Research results indicate a reduced risk of fetal loss in the first trimester of these women when treated with metformin [12]. Several cohort studies in women with PCOS who took metformin throughout pregnancy have confirmed the relative safety of this drug in the second and third trimesters of pregnancy [13, 14]. But it should be noted that, despite the research, currently in the Russian Federation the instructions for the use of metformin contain information about contraindications for the drug during pregnancy.

In a recent in vitro study, metformin was shown to suppress inflammatory responses, aromatase activation, and endometrial stromal cell proliferation [15].

Metformin also affects the secretion of adipose tissue hormones involved in the regulation of energy homeostasis, the action of insulin and lipid metabolism. Thus, according to recent studies, metformin directly reduces leptin secretion by stimulating p44/p42 mitogen-activated protein at the adipocyte level [16]. A study conducted on patients with type 2 diabetes revealed an increase in plasma resistin concentrations during treatment with metformin [17].

Over the past ten years, numerous studies have established that metformin, compared to other glucose-lowering drugs, has powerful anticancer effects, inhibiting the proliferation of tumor cells of the breast, prostate, colon, endometrium, and ovaries [18]. Many observational studies have reported a reduction in the incidence of cancer in patients with type 2 diabetes when taking standard doses of metformin (1500 to 2250 mg/day in adults) [19, 20]. Evans and colleagues [21] reported a reduced risk of cancer in diabetic patients receiving metformin (compared to patients not receiving the drug). However, further clinical studies are needed to evaluate the effect of metformin on cancer recurrence and survival.

While most of the evidence supporting the role of metformin in the treatment of cancer has come from retrospective studies related to diabetes, some clinical trials have been conducted in individuals without diabetes. A recent study assessed the chemopreventive effect of metformin on rectal aberrant crypt lesions (ACFs), an endoscopic surrogate marker for rectal cancer. 26 people without diabetes with AOC were randomized, of which 12 patients received metformin at a dose of 250 mg/day for one month, 14 patients formed the control group. As a result, in the group of patients receiving metformin, the average number of AOCs per patient decreased significantly. In the control group there was no significant change in the average number of AOCs per patient. In addition, the average number of small and dysplastic AOCs was halved in the metformin group compared with baseline [22]. An interim analysis of ongoing studies involving metformin therapy in newly diagnosed breast cancer patients showed that metformin is safe, well tolerated, and has a positive effect on insulin metabolism and apoptosis, inhibiting tumor cell proliferation [23, 24].

Unfortunately, the tolerability of metformin is limited by side effects from the gastrointestinal tract (GIT), which, according to some data, develop in almost 25% of patients, leading to discontinuation of the drug in 5-10% of patients. To date, the mechanism of development of side effects from the gastrointestinal tract still remains unknown. Split doses and large numbers of tablets may lead to decreased compliance. It is the insufficiently good tolerability from the gastrointestinal tract and the need to take it more than once a day that leads to decreased adherence to metformin therapy in some patients.

The development of long-acting metformin solved these problems. Glucophage Long is a dosage form with delayed absorption for administration once a day, which prevents the occurrence of peaks in the concentration of metformin in the blood. The drug has already been registered in the Russian Federation, and its advantages include ease of use (once a day), better tolerability from the gastrointestinal tract.

Absorption of metformin from extended-release tablets occurs in a limited area of ​​the upper digestive tract; with an increase in the concentration of the drug in the intestinal lumen above a threshold level, “absorption saturation” occurs, and with a simple slowdown in the release of the active substance from the tablet, its absorption occurs throughout the entire intestine. The unique GelShield gel diffusion system ensures a gradual and uniform release of metformin from the Glucophage® Long tablet.

In table The results of two prospective and two retrospective studies of the tolerability of long-acting metformin in four UK centers are presented. The studies involved switching patients with type 2 diabetes who could not tolerate regular metformin to a long-acting drug. Most patients (62–100%) tolerated Glucophage Long well [25].

Later, a randomized, double-blind, parallel-group study in the UK showed that the effectiveness of regular metformin compared with Glucophage Long in reducing glycated hemoglobin levels was similar. In a retrospective case-control study, despite the absence of a difference in the incidence of side effects from the gastrointestinal tract between patients taking regular metformin (11.39%) and Glucophage Long (11.94%), there was a significant decrease in the severity of gastrointestinal tract symptoms. intestinal side effects in those patients who were transferred from taking regular metformin to Glucophage Long. Further observation showed increased adherence to metformin therapy in patients taking its extended-release dosage form (Glucophage Long) compared to those patients taking the standard form of metformin. In the group of patients among whom there was poor adherence to immediate-release metformin therapy, a significant increase in adherence to therapy was noted with the administration of Glucophage Long. Increased adherence to therapy observed with a change in metformin dosage form was associated with improved glycemic control, despite the administration of the drug at lower dosages [26].

Thus, metformin continues to be a first-line drug for pharmacological intervention in type 2 diabetes. Its effectiveness and safety have been proven by 50 years of successful use in clinical practice, and additional effects can reduce the risks of cardiovascular complications. The new extended-release form of metformin, Glucophage Long, improves the quality of life of patients by eliminating gastrointestinal disorders and significantly simplifies the treatment regimen.

Literature

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3. Genuth S. The UKPDS and its global impact // Diabet Med. 2008. 25: 2: 57–62.
4. Wulffele MG, Kooy A., de Zeeuw D., Stehouwer CD, Gansevoort RT The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review // J. Intern. Med. 2004. 256: 1–14.
5. Erdmann E. Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes // Int. J. Cardio. 2006. 107: 147–153.
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7. Mkrtumyan A. M., Biryukova E. V. Metformin is the only biguanide with a wide spectrum of action recommended by IDF as a first-line drug of choice // Russian Medical Journal. 2006. 14: 27: 1991–1996.
8. Mannucci E., Ognibene A., Cremasco F. et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects // Diabetes Care. 2001. 24 (3): 489–494.
9. Chau-Van C., Gamba M., Salvi R. et al. Metformin inhibits adenosine 5'-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons // Endocrinology. 2007. 148 (2): 507–511.
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12. Glueck C.J., Goldenberg N., Wang P., Loftspring M., Sherman A. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy // Human Reproduction. 2004. 19: 3: 510–521.
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N. A. Petunina, Doctor of Medical Sciences, Professor I. A. Kuzina

GBOU VPO First Moscow State Medical University named after. I. M. Sechenova Ministry of Health and Social Development of Russia, Moscow

Contact information for authors for correspondence

Metformin treatment results in small but long-term weight loss

New data from the Diabetes Prevention Program Outcomes Study (DPPOS) showed that metformin is associated with “modest but long-term weight loss,” 2% of body weight over 10 years, and appears to be safe and well tolerated.

The results support the findings of the original three-year, double-blind study, which showed that metformin (850 mg twice daily) promoted sustained weight loss. In both metformin and placebo groups, weight loss was a strong predictor of diabetes prevention.

According to the Diabetes Prevention Program Research Group, the effects of metformin are similar to those of exercise.

As previously reported, metformin therapy may represent a more cost-effective alternative to lifestyle interventions for diabetes prevention.

The DPP trial randomized overweight and obese participants with impaired glucose tolerance to lifestyle intervention, metformin, or placebo. Results up to 2002 showed that metformin therapy resulted in a 31% reduction in the risk of developing diabetes over an average of 2.8 years of follow-up.

During the study, participants randomized to receive metformin decreased in body weight and waist circumference compared with those in the placebo group (mean 2.06% ± 5.65% vs. 0.02% ± 5.52%, and 2.13 cm ± 7.06 cm versus 0.79 cm ± 6.54 cm, respectively).

During the unblinded follow-up period, which lasted 10 years from the start of the study, weight loss was significantly greater in the metformin group compared with placebo (2.0% vs. 0.2%) and was associated with the rate of therapeutic compliance.

Participants who were highly compliant with metformin therapy achieved a weight loss of 3.5% (3.1 kg, 6.8 lb), while those with low compliance experienced an initial weight loss, then their weight changed as in the placebo group for up to 5 years. in which the weight has increased.

The authors note that waist circumference increased after 2 years, with the exception of highly compliant participants, who experienced an increase after 5 years. Because body weight did not increase, the authors hypothesized that central obesity was due to redistribution of body fat.

“Metformin-induced weight loss was almost exclusively limited to reductions in fat mass, with few changes in lean tissue,” the scientists wrote, emphasizing that caloric restriction leads to loss of both lean and fat tissue.

The authors note that metformin has several effects on energy metabolism similar to those of exercise, such as phosphorylation of AMP-activated protein kinase, which is an important regulator of mitochondrial biogenetics, fatty acid oxidation in liver and muscle tissue, glucose transport, insulin secretion, and lipogenesis.

During the fourth year of the study, participants receiving metformin reported drug-related gastrointestinal symptoms more frequently than those in the placebo group (9.5% vs. 1.1%).

Mild hypoglycemia and anemia were relatively rare, with similar rates in the metformin and placebo groups during the nearly 18,000 patient-years of follow-up (n = 7 vs. 8 and 50 vs. 38, respectively). Serious adverse events were rare: there were only 3 reports of anemia (metformin, 2; placebo, 1), and no reports of lactic acidosis or hypoglycemia.

During DPP, mean hemoglobin and hematocrit decreased slightly during the first year among metformin-treated participants but remained constant thereafter (13.6 mg/dL vs. 13.8 mg/dL and 40.6% vs. 41.1% for both) .

Although the proportion of participants with low hemoglobin was similar between groups (11.2% vs. 7.6%), low hematocrit was more common among metformin-treated participants (12.6% vs. 8.4%).

Metformin during pregnancy: what results should you expect?

Relevance

In recent years, the prevalence of type 2 diabetes mellitus (DM) in pregnant women has increased worldwide.

Insulin therapy is the standard treatment for diabetes during pregnancy. Increasing insulin resistance during pregnancy requires increasing insulin doses, which in turn is associated with weight gain in patients, a large number of painful injections, high drug costs and low compliance.

At the moment, there is insufficient data on the characteristics of type 2 diabetes treatment with metformin in pregnant women.

Scientists from Canada studied the effects of metformin in the context of possible reduction in the risk of adverse outcomes for the mother and fetus.

Materials and methods

The MiTy randomized controlled trial was conducted.

The study results were presented at the professional conference Diabetes UK: Online Series on November 17 and recently published in The Lancet Diabetes & Endocrinology.

We studied 502 women from 29 centers in Canada and Australia who were diagnosed with type 2 diabetes before pregnancy or during pregnancy before 20 weeks' gestation.

Patients were randomized to receive metformin 1 g twice daily or placebo in addition to their usual insulin regimen from 6 to 28 weeks of pregnancy.

results

• Type 2 diabetes was diagnosed before pregnancy in 83% of women in the metformin group and in 90% of women receiving placebo.
• The average level of glycated hemoglobin (HbA1C) at randomization was 47 mmol/mol (6.5%) in both groups.
• The mean age of the mothers was approximately 35 years and the mean gestational age was 16 weeks.
• The average pre-pregnancy BMI was approximately 34 kg/m2.
• It is noteworthy that only 30% of the subjects belonged to the Caucasian race.
• There were no significant differences between groups for the composite primary outcome of miscarriage, preterm birth, birth trauma, respiratory distress syndrome, neonatal hypoglycemia, or neonatal intensive care unit admission for more than 24 hours (P = 0.86).
• Women in the metformin group had significantly less total weight gain during pregnancy than women in the placebo group, -1.8 kg (P < 0.0001).
• Pregnant women in the metformin group also had significantly lower HbA1C levels during pregnancy, 41 mmol/mol (5.9%) compared with 43.2 mmol/mol (6.1%) in those receiving placebo (P = 0.015); they required fewer insulin doses, 1.1 versus 1.5 units/kg/day (P < 0.0001), resulting in a reduction in daily dose of nearly 44 units.
• Among women receiving metformin, doctors were less likely to perform a cesarean section at birth: 53.4% ​​versus 62.7% in the placebo group (P = 0.03).
• There were no significant differences in gestational hypertension or preeclampsia in the compared groups.
• The most common adverse events occurred from the gastrointestinal tract: 27.3% in patients in the metformin group and 22.3% in those receiving placebo.
• There were no significant differences between groups in rates of miscarriage (P = 0.81), preterm birth (P = 0.16), birth injury (P = 0.37), respiratory distress syndrome (P = 0.49), and congenital anomalies (P = 0.16).
• The mean weight of infants born to mothers receiving metformin was lower, 3.2 kg, compared with 3.4 kg for those born to mothers in the placebo group (P = 0.002).
• Women receiving metformin were also less likely to have a baby with a birth weight of 4 kg or more, 12.1% versus 19.2%; relative risk 0.65 (P = 0.046), or a baby who was extremely large for gestational age, 8.6% vs. 14.8%; relative risk 0.58 (P = 0.046).
• Notably, metformin was also associated with an increased risk of small gestational age births by 12.9% compared with 6.6% in the placebo group; relative risk 1.96 (P = 0.03).

Conclusion

Metformin as a therapy for type 2 diabetes during pregnancy, in addition to controlling glycemic levels, has the following pleiotropic effects: weight loss, reduction in the required dose of insulin, and reduction in the risk of developing a fetus that is large for gestational age.

Intrauterine growth retardation, smoking, serious kidney pathology, and low body mass index (BMI) are risk factors for the development of a small-for-gestational-age fetus while taking metformin in pregnant women with type 2 diabetes.

Metformin inhibits the mTOR pathway, which is the primary sensor of nutrients in the placenta and may impair fetal growth.

The research team has launched the MiTy Kids study, which will follow children born to mothers treated with metformin to determine whether metformin during pregnancy is associated with reduced obesity and improved insulin resistance in children at 2 years of age.

If metformin was started before pregnancy due to fertility problems, its discontinuation is recommended immediately after pregnancy or during the first trimester.

medscape.com/viewarticle/941337

Buy Metformin Canon film-coated tablets 500 mg No. 60 in pharmacies

Instructions for use

Metformin tablet p.o 500 mg No. 60

Dosage forms

tablets 500 mg Synonyms Bagomet Vero-Metformin Gliminfor Gliformin Glucophage Glucophage Long Diaformin OD Metfogamma 1000

Metformin

Siofor 1000

Formetin Group Antidiabetic agents - biguanides International nonproprietary name Metformin Composition Active substance - metformin hydrochloride. Manufacturers Kanonpharma Production (Russia) Pharmacological action Hypoglycemic. Reduces the concentration of glucose 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. Does not alter insulin secretion by beta cells of the pancreatic islets. Normalizes the lipid profile of blood plasma in patients with non-insulin-dependent diabetes mellitus: it reduces the content of triglycerides, cholesterol and LDL and does not change the levels of lipoproteins of other densities. Stabilizes or reduces body weight. Rapidly absorbed from the gastrointestinal tract. The maximum concentration is reached after approximately 2 hours. Absorption from the gastrointestinal tract ends after 6 hours and the concentration in the blood begins to gradually decrease. Can accumulate in the salivary glands, liver and kidneys. It is excreted unchanged by the kidneys. The half-life is 6.2 hours (plasma) and 17.6 hours (blood), because accumulates in erythrocytes. Side effects At the beginning of the course of treatment - anorexia, diarrhea, nausea, vomiting, flatulence, abdominal pain (reduced when taken with meals); metallic taste; megaloblastic anemia; lactic acidosis (respiratory disturbances, weakness, drowsiness, hypotension, reflex bradyarrhythmia, abdominal pain, myalgia, hypothermia), hypoglycemia; rashes and dermatitis. Indications for use Diabetes mellitus type 2 with ineffective correction of hyperglycemia by diet therapy, incl. in combination with sulfonylureas; type 1 diabetes mellitus as an adjunct to insulin therapy. Contraindications Hypersensitivity, kidney disease or renal failure, severe liver disorders, cardiac and respiratory failure, acute phase of myocardial infarction, infectious diseases, major operations and injuries, chronic alcoholism, acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma, conducting research using radioactive isotopes of iodine, pregnancy, breastfeeding. Restrictions on use: Children and the elderly (over 65 years of age). Directions for use and dosage : Orally, during or immediately after meals. Monotherapy and combination therapy with other oral hypoglycemic agents. The initial dose is 500-1000 mg 1 time per day in the evening. After 7-15 days, if there are no adverse effects from the gastrointestinal tract, 500-1000 mg is prescribed 2 times a day in the morning and evening. A further gradual increase in the dose is possible depending on the concentration of glucose in the blood. Overdose Symptoms: lactic acidosis. Treatment: hemodialysis, symptomatic therapy. Interaction Phenothiazines, corticosteroids, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium antagonists, isoniazid, thiazide and other diuretics weaken the effect. Insulin, sulfonylurea derivatives, acarbose, NSAIDs, MAO inhibitors, oxytetracycline, ACE inhibitors, clofibrate derivatives, cyclophosphamide, beta-blockers enhance the effect. Furosemide increases the maximum concentration. Nifedipine increases absorption, maximum concentration, and prolongs elimination. Amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene and vancomycin during long-term therapy can increase the maximum concentration by 60%. Incompatible with alcohol. Special instructions It is necessary to constantly monitor renal function, glomerular filtration, and blood glucose levels. Vitamin B12 levels should be determined once a year. When transferring a patient to metformin, it is prescribed immediately after discontinuation of the previous drug, with the exception of replacing chlorpropamide. It should not be used before surgical operations and within 2 days after them, as well as within 2 days before and after diagnostic studies. Should not be prescribed to people performing heavy physical work. Storage conditions List B. In a dry place, protected from light.