Metformin – the first line pathogenetic drug in the treatment of type 2 diabetes

Type 2 diabetes mellitus is a chronic disease characterized by a violation of the sensitivity of tissues to insulin, and a violation of its secretion. Among all the causes of hyperglycemia, type 2 diabetes occupies a leading position, the incidence of diabetes mellitus type 2 catastrophically growing in all countries of the world without exception, every 15-20 years it doubles the total number of people with diabetes.

It should be noted that type 2 diabetes (primarily insulin resistance) is an integral part of the so-called metabolic syndrome, which is visceral obesity, dyslipidemia (increased TG, xc-LDL, decreased xc-HDL), arterial hypertension. Metabolic syndrome and type 2 diabetes , as one of its manifestations, are the leading causes of death in the developed countries of Europe and North America.

One of the features of type 2 diabetes is a prolonged low symptom course. In the early stages of the disease, a chronic increase in the level of glucose contributes to the gradual development of insulin secretion disorders, and further leads to the depletion and decrease in the mass of β-cells of the pancreas. Hyperglycemia is also a powerful factor in the progression of atherosclerosis and damage to the nervous system.

The absence of clinical symptoms of a moderate (up to 7–10 mmol / l and above) increase in glycemia leads to a low accessibility of patients to medical institutions, creating an illusion of well-being. All this leads to the fact that at the time of detection of type 2 diabetes (usually accidental) patients already have complications of the disease in the form of visual impairment (retinopathy), kidney (myco-macroproteinuria), vascular lesions of the heart, brain, lower extremities. Atherosclerotic vascular disease of the heart and brain is the leading cause of death and high disability in patients with type 2 diabetes .

Today, the treatment of type 2 diabetes consists of the elimination of symptoms of carbohydrate metabolism decompensation, the gradual normalization of glycemia, lipid profile and blood pressure. All of the above actions underlie the elimination of the threat of the development of both hyperosmolar syndrome, and so are aimed at preventing the development of damage to blood vessels, nervous tissue, bone and joint apparatus, etc.

The epidemiological and interventional activities that have completed to date for the development of complications of type 2 diabetes mellitus have revealed ways to prevent / reduce the development of complications of type 2 diabetes .

To date, several clinical studies have been conducted that have proved the importance of normalizing glycemia in relation to the prediction of microcirculation disorders in type 2 diabetes . The situation is somewhat different with respect to lesion of the vessels of the muscular-elastic type. The contribution of hyperglycemia to the development of atherosclerosis is undoubted, however, other components of the metabolic syndrome (obesity, lipid disorders, hypertension) are also powerful factors in the development and progression of macroangiopathy.

In the now classic study for the treatment of type 2 diabetes – UKPDS (United Kingdom Prospective Diabetes Study), the improvement of carbohydrate metabolism indicators on the background of insulin monotherapy or sulfonylurea drugs (PSM) alone had a slight effect on reducing overall mortality or mortality from type 2 diabetes (7 and 20%, respectively), the incidence of myocardial infarction (MI) (21%). Metformin had a much more pronounced positive prognostic effect, reducing overall mortality, mortality from type 2 diabetes or MI at 36, 42 and 39%, respectively.Interesting is the fact that the glycemia indicators at the reception of metformin, PSM and insulin were similar.

Pathogenetic background of using metformin as a first line of pharmacotherapy. Type 2 diabetes mellitus 2 types

This effect of metformin on the development of complications of type 2 diabetes mellitus and mortality can be attributed to its pathogenetic effect and, above all, a decrease in the development of type 2 diabetes mellitus insulin resistance, causes of disorders of carbohydrate metabolism, dyslipidemia, hypertension and vascular complications of the disease. There are indisputable laboratory and clinical results for proven cardioprotective and vasculoprotective effects of this drug.

So, held since the 60s. The twentieth century of work aimed at studying the effects of metformin on experimental atherosclerosis revealed that administration of metformin to laboratory animals prevented vascular damage typical for developing type 2 diabetes . Also, there was a decrease in the risk of development and progression of microangiopathy when the drug was added to mice with insulin resistance or impaired carbohydrate tolerance.

Studies on the modulation of acute ischemia in animals without and with impaired carbohydrate metabolism have also revealed the anti-ischemic effects of metformin. In addition to the above effects, it has been shown that metformin in laboratory animals enhances vascular relaxation, potentiating the effects of substances acting through NO. By affecting insulin resistance and reducing atherogenic lipid levels, it was found that metformin weakens the incorporation of lipids into the vascular wall and the proliferation of smooth muscle cells.

Metformin administration improves fibrinolysis by reducing the volume of visceral fat and insulin resistance, reducing the activity and production of PAI-1. It was also revealed that metformin inhibits the coagulation factor XIII activity, weakening the formation of blood clots. In studies N. Wiernsperger revealed the ability of metformin to improve the state of the microvasculature, normalize the adhesive processes, the permeability of the vascular wall .

The clinical relevance of using metformin

As noted above, hyperglycemia and the underlying development of type 2 diabetes Insulin resistance are the most powerful and independent factors leading to the development of macro-and microvascular pathology, impaired neurological regulation.

All this leads to a decrease in life expectancy and the period of working capacity in people with diabetes. Most patients with type 2 diabetes perish from cardiovascular pathology. For many decades, the treatment of type 2 diabetes focused on the normalization of glycemia.

Achieving effective glycemic control — reducing glycated hemoglobin (HbA1c), fasting or after-meal glycemia indicators is certainly important in preventing or developing complications. Type 2 diabetes mellitus . At the same time, enough data has been accumulated showing the need for an aggressive effect on arterial hypertension, blood lipids in type 2 diabetes mellitus or initial disorders of carbohydrate metabolism. This is due to the fact that diabetes mellitus type 2 , as a component of the metabolic syndrome, requires not only the normalization of glycemia, but also the elimination of factors that influence the formation or progress of atherosclerosis. In the UKPDS study, metformin was significantly better in reducing mortality or the incidence of vascular complications compared with insulin or sulfonylurea derivatives (PSM) with similar HbA1c values.

The cardioprotective effect of metformin today can be explained by the mass of additional effects aimed at improving the state of the endothelium, blood rheology, capillary blood flow, etc. The effectiveness of metformin in reducing mortality, frequency of vascular catastrophes, revascularization measures is similar or exceeds the effectiveness of classes of drugs used in the treatment of hypertension , ischemia and type 2 diabetes in various combinations (Table 2). All these data allowed to recommend Metformin as the first line in the treatment of hyperglycemia, as well as improving the prognosis in patients with type 2 diabetes in relation to vascular complications.

Currently in key clinical guidelines (IDF 2005, recommendations of the National Institutes of Health of the United Kingdom (NICE), consensus treatment of type 2 diabetes mellitus ADA / EASD, 2006 and 2008 etc.) Metformin is the first step in pharmacotherapy. Type 2 diabetes in persons with overweight and obesity.

Thus, in the supplemented and revised clinical guidelines of IDF 2005 in all sections without exception (highly professional, standard and minimal medical care for type 2 diabetes ), in particular in Recommendations 2, 3, 4 of the section tablets it is indicated that “pharmacotherapy Diabetes 2 types should begin with metformin, dose titration (usually an increase of 500-850 mg) to reduce gastrointestinal disorders is carried out weekly, the main parameter of safety control is GFR (with caution in CC 2). “

With the ineffectiveness of monotherapy with metformin, the most acceptable combinations are considered “metformin with PSM or metformin with glitazones”. Similar recommendations on the advisability of using metformin are given in the sections on insulin therapy, regardless of the types of insulin preparations prescribed.
In July 2006, experts from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) adopted the onsensus for pharmacotherapy type 2 diabetes .

These recommendations are based on the results of numerous clinical studies with diabetes mellitus and set the goal of achieving and maintaining glycemia close to physiological values. The choice of each class of drugs is based both on their glucose-lowering activity and on the potential impact on the complications of diabetes. This algorithm involves the gradual enhancement of pharmacotherapy to maintain satisfactory glycemic parameters (HbA1c, 7.0%).
The first stage (initiation of therapy) is a change in lifestyle and diet with the normalization of body weight. For effective maintenance of normoglycemia and taking into account the positive effect on weight loss, metformin is the first line of pharmacotherapy. Type 2 diabetes mellitus . The advantage of metformin is the absence of risk of hypoglycemia and its affordable cost.

The second stage (additional therapy) – with the ineffectiveness of therapy with metformin, it is advisable to add “basal” insulin to the treatment (inexpensive, improves the parameters of the lipid spectrum, but requires self-control and causes hypoglycemia), PSM (cheap, but contribute to weight gain and cause hypoglycemia) or glitazones (roads, but there is no risk of hypoglycemia). If the target parameters of glycemia are not achieved, it is advisable to strengthen pharmacotherapy to maintain normal parameters of carbohydrate metabolism.

Since October 2008, the consensus has changed somewhat . This modification is associated both with the entry into clinical practice of new classes of drugs (i-DPP-IV, GLP-1 analogues), and the end of several large-scale studies (ACCORD, ADVANCE, VADT, etc.) that influenced the concept of therapy.

The main objective of the treatment of type 2 diabetes is the normalization of blood glucose to “normal” or “subnormal” level, as well as more stringent control over blood pressure, lipids, body weight, procoagulologicheskim status, reduction of insulin resistance.

Because unlike Saharna th Type 1 diabetes, where blood glucose improvement leads to a direct reduction in the risk of development and progression of diabetic complications in diabetes mellitus type 2 normalization of glucose reduces the risk of microangiopathy.

The above clinical studies aimed at achieving optimal glycemia values in type 2 diabetes mellitus showed no significant effect on the macrovascular complications of the disease, in some of them the “aggressive” hypoglycemic therapy even increased the overall mortality. In this regard, the main recommended drugs for the treatment of type 2 diabetes are either highly active and inexpensive substances (insulin, PSM), or drugs that have a positive effect on body weight (GLP-1 analogues) that safely reduce insulin resistance (pioglitazone).

And it is important to note that regardless of the presence or absence of any other drug, at all stages of treatment, type 2 diabetes mellitus metformin is present.

The recommendations especially emphasize the following features of the drug:

  • good glycemic reduction (-1.5% HbA1c);
    • well tolerated;
    • lack of hypoglycemia in monotherapy;
    • despite the effect on the absorption of vitamin B12, long-term therapy with metformin practically does not lead to anemia;
    • neutrality with respect to weight gain or its “soft” decrease;
    • Excellent UKPDS data for reducing cardiovascular disorders in type 2 diabetes ;
    • high safety in the risk of lactic acidosis (less than 1 case per 100 thousand patients);
    • safety in case of initial impaired renal function (GFR> 30 ml / min).


Based on the characteristics of pharmacodynamics, the effect on reducing glycemia (on average by 1.5% HA1c), no risk of hypoglycemia in monotherapy, additional effects on reducing vascular catastrophes and mortality in people with type 2 diabetes , metformin is recommended for use as a first-line drug worldwide. The starting dose of the drug should begin with 500-850 mg during or after meals (preferably in the evening) with a gradual titration of 500-850 mg weekly.

The average therapeutic dose may be 2000-2500 mg, increasing the dose of more than 3000 mg / day is impractical. The first “control” point of the effectiveness of therapy is the normalization of fasting blood glucose, which allows to reduce the elevations of postprandial glycemia.

At the same time, metformin can have a good effect throughout the day, since besides reducing the glucose production by the liver at night, the drug improves the insulin sensitivity of the tissues throughout the day.

Metformin is generally well tolerated, does not have serious side effects, and the risk of lactic acidosis is less than 1 case per 100 thousand patients.

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