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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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

How can metformin be useful in bodybuilding?

It’s no secret (and for some it’s a secret) that bodybuilders’ main weapon for fat loss is a low-carb diet. During a low-carbohydrate diet, the body receives few carbohydrates (which are the main and preferred “fuel” for the body), and therefore the body is forced to switch to fat nutrition (burns accumulated fat reserves).

Thus, we can say that a low-carbohydrate diet and taking metformin create essentially similar conditions in the body. Both lead to fat burning by limiting the amount of carbohydrates entering the body and lowering blood sugar levels.

Therefore, metformin can be used in bodybuilding in two ways: to “replace” a low-carbohydrate diet (that is, in cases where the athlete wants to burn fat without dietary restrictions, or without resorting to too strict restrictions), or to complement a low-carbohydrate diet, in order to obtain more pronounced results.

How else can metformin be useful?

Although there are rumors (more precisely, not even rumors, but the results of scientific research) according to which metformin can increase life expectancy. The studies have so far been conducted on animals, which does not allow us to say 100% that this will have the same effect on humans. However, this possibility cannot be ruled out.

This information is difficult to verify in practice (in relation to humans), since the human life expectancy is already quite long, and conducting such an experiment on humans seems problematic (to wait too long for the results to make sure whether this is really the case).

Metformin in bodybuilding: how to take it

And of course, finally, let’s figure out how to properly take metformin in bodybuilding.

The generally accepted norm is to take 500-850 mg of metformin 2-3 times a day (but not more than 3000 mg per day). As you can see, the spread in dosages with such a recommendation can be quite large (1000-3000 mg). This spread is explained by the following factors:

• Body weight (big people need more, small people need less)
• Adaptation (you can start with smaller dosages, then move on to larger ones)
• Personal tolerance (for some, small dosages are enough, for others, large dosages are not enough)

In general, you can give advice to start with small dosages and increase them, listening to how you feel. When calculating dosages, do not forget to pay attention to the weight of the tablets (500 mg, 850 mg, 1000 mg), and measure the dosage, first of all, not in the number of tablets, but in milligrams.

You may also be interested in the article on how to take glutamic acid for bodybuilding.