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, LDL-C, decreased HDL-C), and arterial hypertension. Metabolic syndrome and type 2 diabetes, as one of its manifestations, are the leading causes of death in developed countries in Europe and North America.
One of the features of type 2 diabetes is a long, low-symptom course. In the early stages of the disease, a chronic increase in glucose levels contributes to the gradual development of insulin secretion disorders, and later leads to depletion and a decrease in the mass of pancreatic beta cells. 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 higher) increase in glycemia leads to low patient referrals to medical institutions, creates the 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), impaired kidney function (mycomacroproteinuria), vascular damage to the heart, brain, and lower extremities. Atherosclerotic lesions of the heart and brain vessels are the leading cause of death and high disability in patients with type 2 diabetes.
Today, the treatment of type 2 diabetes consists in eliminating the symptoms of decompensation of carbohydrate metabolism, gradual normalization of glycemia, lipid spectrum and blood pressure. All of the above actions are the basis for eliminating the threat of hyperosmolar syndrome and are aimed at preventing the development of vascular lesions, nervous tissue, bone and joint apparatus, etc.epidemiological and interventional measures for the development of complications of diabetes have now been Completed, and have revealed ways to prevent/reduce the development of complications of diabetes (table 1). Several clinical studies have proved the importance of normalizing glycemia in relation to the prognosis of microcirculation disorders in type 2 diabetes. the situation is Somewhat different with respect to vascular lesions of the musculoskeletal type. The contribution of hyperglycemia to the development of atherosclerosis is unquestionable, but other components of the metabolic syndrome (obesity, lipid disorders, hypertension) are also powerful factors in the development and progression of macroangiopathy.
In the UKPDS (United Kingdom Prospective Diabetes Study), which has become a classic study on the treatment of type 2 diabetes, improvement in carbohydrate metabolism against the background of monotherapy with insulin or sulfonylureas (PSM) had a slight effect on reducing overall mortality or mortality from diabetes (7% and 20%, respectively), and the incidence of myocardial infarction (MI) (21%). Metformin had a significantly more pronounced positive prognostic effect, reducing overall mortality, mortality from DM or MI by 36, 42, and 39%, respectively (1, 2). It is interesting to note that the glycemic indices on Metformin, PSM, and insulin were similar.
Table 1. Influence on risk factors for vascular diseases in type 2 diabetes
Factor Reduction of relative risk, % Frequency of manifestations after 2 years, %
No effect No effect 11.0
Cholesterol (reduced by 0.6 mol / l) 25 8,3
Blood PRESSURE (decrease by 5/2 mm Hg) 27 6.0
HbA1c (down 0.9%) 13 5.2
Aspirin 9 4.7
Pathogenetic prerequisites for the use of Metformin
This effect of Metformin on the development of diabetes complications and mortality can be explained by its pathogenetic effect and, above all, by a decrease in the underlying insulin resistance – the cause of carbohydrate metabolism disorders, dyslipidemia, hypertension, and vascular complications of the disease. In relation to this drug, there are indisputable laboratory and clinical results on proven cardioprotective and vasculoprotective effects. So, conducted since the 60s of the XX century. studies aimed at studying the effects of Metformin in relation to experimental atherosclerosis revealed that the administration of Metformin to laboratory animals prevented vascular damage typical of developing DM. There was also a reduction in the risk of developing and progressing microangiopathies when the drug was added to mice with insulin resistance or impaired carbohydrate tolerance.
Studies on modulating acute ischemia in animals without and with carbohydrate metabolism disorders have also revealed anti-ischemic effects of Metformin (3, 4). In addition to the above effects, Metformin has been shown to enhance vascular relaxation in laboratory animals by potentiating the effects of substances acting through NO. It was found that by affecting insulin resistance and reducing the levels of atherogenic lipids, Metformin weakens the inclusion of lipids in the vascular wall and the proliferation of smooth muscle cells. Metformin administration improves fibrinolysis by reducing the volume of visceral fat, insulin resistance, reducing the activity and production of IAP-1. It is also noted that Metformin inhibits the activity of clotting factor XIII, weakening the formation of blood clots (6, 9).
Wiernsperger (7) studies revealed the ability of Metformin to improve the state of the microcirculatory bed, normalize adhesive processes, and vascular wall permeability (figure 1) (10, 11, 12, 13).
The clinical significance of the use of Metformin
As noted above, hyperglycemia and underlying type 2 diabetes insulin resistance are powerful and independent factors that lead to the development of macro – and microvascular pathology, violation of neurological regulation. All this leads to a decrease in life expectancy and working capacity in people with diabetes. Most patients with type 2 diabetes die from cardiovascular disease.
For many decades, treatment of diabetes has focused on normalization of glycemia. Achieving effective glycemic control, reducing glycated hemoglobin (HbA1c), and indicators of fasting or post-meal glycemia is certainly important in the prevention or development of complications of diabetes. At the same time, there is enough data showing the need for aggressive influence on arterial hypertension, blood lipids in DM or initial disorders of carbohydrate metabolism. This is due to the fact that type 2 diabetes, as a component of the metabolic syndrome, requires not only the normalization of glycemia, but also the elimination of factors that affect the formation or progress of atherosclerosis.
In the UKPDS study, Metformin had a significantly better effect on reducing mortality or vascular complications compared to insulin or sulfonylurea derivatives (PSM) at similar HbA1c values. The cardioprotective effect of Metformin today can be explained by a mass of additional effects aimed at improving the state of the endothelium, blood rheology, capillary blood flow, etc. (see figure 1). The effectiveness of Metformin in reducing mortality, the frequency of vascular accidents, and revascularization measures is similar or superior to the effectiveness of classes of drugs used in the treatment of hypertension, CHD, MS, and DM in various combinations (table 2). All these data made it possible to recommend Metformin as the first line both in the treatment of hyperglycemia and in improving the prognosis of patients with diabetes for vascular complications.