Mildronate - Location of P-FOX-inhibitors of free fatty acids in the combination therapy of cardiovascular complications to Patients with type 2 diabetes

The growing number of patients with type 2 diabetes (DM) is indisputable in recent decades, in spite of the efforts made for the development of prevention and the development of new drugs to treat this debilitating disease. A fairly large number of studies showing the formation of a high risk of complications and cardiovascular events in diabetes. Changes in cardiovascular system caused by diabetes, observed in 90-100% of patients. Such frequent and aggressive development of cardiac pathology in patients with diabetes is mediated not only and not so much by hyperglycemia, which occurs in these patients, as it cascades mediated metabolic disorders that worsen as the condition of the coronary arteries and the myocardium, promote the development of specific micro and SD macro-angiopathy, insulin resistance at the level of the myocardium and diabetic cardiac autonomic neuropathy. The resulting heart failure in diabetes is ambiguous. There are the following forms of cardiac disease: diabetic cardiomyopathy (DC), the main pathogenic factor which is considered the metabolic abnormalities in the heart muscle (in patients with type 2 diabetes, even the initial stages of glycemic profile disturbances may affect the myocardial metabolism and predispose to the occurrence of diabetic cardiomyopathy), and ischemic heart disease (IHD), the main cause of which is atherosclerosis of the coronary vessels. Unfortunately, the prevailing group of patients with diabetes there is a combination of these two forms of cardiac disease. In our opinion, this is due to a single mechanism of formation of a recreation center, and coronary artery disease in diabetic patients. What factors as aggressive form changes at the level of the vessels, the heart, the nervous system? Of course, this is due to the fact that in diabetes there are both general (age, Meno and andropause, smoking, hypertension, obesity, dyslipidemia, physical inactivity, alcoholism), and specific factors - hyperglycemia, hyperinsulinemia insulin resistance, contributing to the development of cardiovascular complications. A large clinical study UKPDS (UK Prospective Diabetes Study) has allowed to identify the most important risk factors for coronary heart disease and its complications in patients with type 2 diabetes. These include (in order of importance) increase in low density lipoprotein cholesterol (LDL), high blood pressure, smoking, low levels of high density lipoprotein cholesterol (HDL-C), increase the level of glycosylated hemoglobin. Of course, an additional contribution to the development of ischemic changes in diabetic patients make endothelial dysfunction, oxidative stress, impaired blood rheology and hemostasis. How do these factors influence the development of cardiovascular complications in diabetes?

Effect of increase in blood glucose levels on the risk of coronary heart disease found in many long-term prospective studies. It has been observed that individuals with high levels of fasting glucose and post-exercise had significantly higher mortality from cardiovascular disease. Convincing epidemiological data indicate the existence of significant correlation between the level of glycosylated hemoglobin Alc (this figure reflects the average blood glucose level over the past 3 months.) And the risk of cardiovascular morbidity and mortality. By increasing the level of glycosylated hemoglobin by 1% the risk of cardiovascular disease increases by 10% [18]. Unfortunately, even the tight control of glycemia - the very specific risk factors (many multi-center studies have shown that the mortality rate of patients with diabetes directly correlates with the level of postprandial glycemia - postprandial hyperglycemia more than 8-9 mg / dL increases the risk of cardiovascular death more than doubled) does not guarantee the absence of late complications of diabetes - micro- and macrovascular. Moreover, in 2007 ACCORD study was stopped prematurely (Action to Control Cardiovascular Risk in Diabetes), in which it was noted an increased risk of cardiovascular mortality in the intensive glycemic control to achieve the level of glycosylated hemoglobin is less than 6.5%.

Hyperinsulinemia induces proliferation and migration of smooth muscle cells, lipid synthesis in smooth muscle cells, fibroblast proliferation, activation of coagulation, increased low density lipid concentration. Insulin is a healthy person indirectly through the synthesis of NO, antiatherogenic causes vasodilation and inhibits the proliferation of smooth muscle cells. When this process is blocked diabetes that promotes atherogenesis. There is also shown role of hyperinsulinemia to the formation of diabetic cardiomyopathy.

Insulin resistance combined with atherogenic lipid profile, fibrinolysis disorder, abdominal obesity. In one conventional unit of insulin resistance have to thickening of the carotid artery 30 microns. Atherosclerotic plaques in CD peculiar. Also lipid core plaques contain high numbers of T-lymphocytes, foam cells and are very unstable fibrous sheath as collagen and elastin, reaching on its construction, have the qualities that are in people without diabetes. Such plaques quickly deform, disintegrate, "explode", which leads to thrombosis, sudden death of patients. Moreover, even in the absence of atherosclerotic changes in insulin resistance mediates the development of specific "insulin resistance" cardiomyopathy in patients with diabetes.

The changes of lipid metabolism, diabetes patients have persisting even after the blood glucose level correction, so characteristic that became known as "diabetic dyslipidemia." According to the third National Health and Nutrition in the US, 69% of patients with diabetes have lipid metabolism. For diabetes type 2 is characterized by both quantitative (increased levels of triglycerides (TG), decreased HDL-C) and qualitative changes lipidogram (characteristic small dense LDL particles with high atherogenic, which is much easier than with lipoproteins larger undergo oxidation processes. Oxidized lipoproteins play an important pathogenic role in direct damage to the endothelial cells, the conversion of circulating monocytes into foam cells, stimulate the formation of the vasoconstrictor factor - endothelin-1, inhibit local formation of endothelium-derived nitric oxide, a potent natural vascular relaxing factor.

A special role in the development of cardiovascular events in patients with diabetes plays its inherent hypertriglyceridemia, a negative role which has been demonstrated in respect of the formation of ischemic heart disease, in the event of diastolic dysfunction of the heart, the defeat of the nerve fibers in patients with diabetes development of cardiac autonomic neuropathy.

Severity of diabetic dyslipidemia, particularly hypertriglyceridemia in patients with type 2 diabetes was significantly associated with the level available to them hyperinsulinemia and insulin resistance [24]. On the other hand, hyperinsulinemia and insulin resistance, regardless of the lipid metabolism disorders are independent risk factors for coronary heart disease.

A high level of triglycerides is associated with an increase in free fatty acids (FFA) in plasma and myocardium in patients with diabetes and a violation of their metabolism.

The negative role of fatty acids in the formation of heart disease in diabetic patients is multifaceted. Lack of insulin and insulin resistance, characteristic of diabetes type 2, affect the function of the heart by reducing the transport of glucose and carbohydrate oxidation, increasing the use of free fatty acids. Oppression biogenetic action insulin promotes the content of free fatty acids in the blood plasma and their entry into cardiomyocytes. Excess FFA level cardiomyocytes mitochondrial processes leads to the predominance of b-oxidation of FFA accumulation of pyruvate and lactate in the cytoplasm, causing inhibition of oxidative phosphorylation and glucose lowering amount of ATP produced in the glycolysis process [38, 39]. Also important is the accumulation in the myocardium intermediates b-oxidation of FFA: acyl-CoA acylcarnitine, free radicals, arachidonate and prostaglandin E2. Calling the oppression of the calcium pump of sarcoplasmic reticulum and increasing the formation of cyclic adenosine monophosphate, they contribute to an overload of cardiomyocytes Ca2 +. As a consequence, a reduction in the contractile activity of the heart muscle, the development of diastolic dysfunction, diabetic cardiomyopathy inherent in [40], there is the risk of arrhythmia [41]. Acylcarnitine and acyl-CoA not only block the Ca2 + -ATPase of the sarcoplasmic reticulum and therefore calcium pump, and Na + -, K + -ATPase sarcolemma (sodium and potassium pumps), and ATP adenine nucleotide translocase pump.

Excess FFA progression of insulin resistance mediates many tissues - muscular, including myocardial, hepatic, adipose, and endothelial cells, contributes to the progression of myocardial ischemic changes, including changes associated with impaired beta oxidation of fatty acids in the myocardium.

Intracardiac accumulation of triglycerides, free fatty acids and their metabolites are characterized by the formation in the broad sense of the word "cardiac lipotoxicity", which manifests hypertrophy of cardiomyocytes, myocardial fibrosis with increased content of extracellular matrix in the interstices of ventricular wall, interstitial sclerosis, advent adipose tissue in the interstitium and disorders of the microvasculature, the formation of zones of interstitial sclerosis with disparate cardiomyocytes (CMC) with a reduced diameter and degenerative changes. The separated CMC found signs of "hibernation", dedifferentiation and apoptotic degeneration, apoptosis also exposed nerve conductors. Thus, a violation of the metabolic processes that occur in diabetes mellitus type 2, in many respects resemble those in the ischemic myocardium: activated oxygen-expensive mechanisms of energy production is suppressed glycolysis, marked accumulation of triglycerides in the cytosol of cells, accumulate products exchange FFA, which leads to drastic reduction of myocardial viability. Understanding the role of the energy of the heart metabolism in the pathogenesis of myocardial ischemia leading to the development of a new metabolic direction in the treatment of patients with coronary artery disease. It has been shown that chronic conditions use of glucose by the myocardium can be improved at FFA metabolism modulation with drugs that inhibit their oxidation.

A special role in the pathogenesis of cardiovascular complications of diabetes plays oxidative stress, with the growing disequilibrium between free radicals and the activity of antioxidant enzymes, reduced in diabetes.

Chronic hyperglycemia promotes lesion myocardium per se, on the one hand, on the other - negative enhances the impact of other risk factors for cardiovascular disease, especially oxidative stress [59, 60]. The sharp increase in the number of oxygen radicals in the mitochondria is a violation of transcription factors, gene expression, metabolite utilization infarction. Simultaneously excess radicals inhibiting nitric oxide, stimulates inflammatory reaction inhibits polyadenosine lipoprotein polymerase. The latter leads to endothelial dysfunction. In the studies of Sukmanova and Yakhontova is shown that the degree of impairment of diastolic properties of the myocardium directly depends on the formation of peroxides and endothelial dysfunction. Glycosylation is constantly present in diabetes contributes to the generation of superoxide and hydroxyl radicals that trigger oxidation of low-density lipoprotein, which greatly increases their atherogenic potential. One of the causes of the most severe course and poor prognosis of cardiac events in patients with diabetes is the presence of autonomic cardiac autonomic neuropathy (DCA), the prevalence of which, according to various epidemiological studies, up to 90%. Such frequent occurrence of this pathological condition mediated by the fact that based on the same pathognomonic for diabetes metabolic disorders and vascular factors are the basis of the nervous system listed above: inadequate glycemic control, high triglycerides, being overweight, smoking and hypertension, the formation of oxidative stress, the development of dyslipidemia, disorders of coagulation, endothelial dysfunction. Autonomic neuropathy is largely due to a decrease in coronary vasodilator reserve and increase the risk of developing life-threatening arrhythmias and sudden cardiac death. It is shown that the risk of death in patients with diabetes for 5 years is five times higher in the presence of APC.

Neutralize the "potential negative effect" of these cumulative factors for heart disease in patients with diabetes is extremely difficult. Held CHD patients basic therapy designed to optimize the ratio between the requirements of the heart muscle of oxygen, on the one hand, and its delivery to the myocardium - other. The main mechanism of action of the majority of modern drugs used for this purpose (angiotensin converting enzyme inhibitors, nitrates, beta-blockers, calcium channel blockers, inhibitors If-channels), a hemodynamic unloading of the myocardium by reducing the heart rate, as well as pre- and afterload. Accordingly, these antianginal agents have only an indirect effect on myocardial oxygen supply. Thus, the treatment of cardiac disease in patients with diabetes may not be limited to the use of basic tools neurohormonal blockade, hemodynamic support, but must necessarily include drugs metabolic correction of intracardiac metabolism (myocardial cytoprotectors), which in this case can be considered not only as a means of auxiliary activities, as as a pathogenetically grounded drugs, taking into account the above features of the metabolic formation of diabetic heart. Beta-blockers, ACE inhibitors, calcium channel blockers, inhibitors If-channels, nitrates, reducing pre- and afterload, heart rate, have only an indirect effect on the oxygen supply of myocardium they quite successfully affect hemodynamic parameters, however, can not influence on the efficiency of myocardial oxygen. In addition, they do not have a positive corrective effect on the course of metabolic processes in the myocardium, so necessary for patients with diabetes, and sometimes their use is limited due to the possible negative effects on carbohydrate and lipid metabolism in diabetic patients.

In recent years, our understanding of the role of the energy changes that occur in cardiomyocytes due to ischemia and reperfusion, hyperinsulinemia and insulin resistance, increased significantly from the standpoint of understanding the possible effects on non-functioning but viable (hibernating) myocardium. This has contributed to the creation of a new direction in the treatment of coronary artery disease using a new class of drugs - myocardial cytoprotection, effectively acting on the energy metabolism of cardiomyocytes and that improve oxygen utilization efficiency of myocardial ischemia.

As cardiac cytoprotective therapy in diabetic patients, of course, primarily shown agents blocking the partial oxidation of free fatty acids - p-FOX-inhibitors (partial fatty and oxidation inhibitors), which include ranolazine, Mildronate and trimetazidine.

Ranolazine is reversible inhibitor of NADH dehydrogenase in mitochondria leading to improved metabolic efficiency. In experiments on isolated myocytes ventricular dogs and mice, it is showed antiarrhythmic and antianginal effect, the possibility of effects on post-ischemic myocardial dysfunction in mice the size of necrosis, to improve the mechanical properties of the isolated rat heart in the post-ischemic period, including those associated with the activation of oxidative stress. The positive impact of Ranolazine on the course of experimental left ventricular chronic heart failure (HF) in dogs: an increase in strength and size of cardiac output, mechanical efficiency of the heart muscle.

In clinical practice, demonstrated the efficacy of this drug primarily in the treatment of stable angina, which was manifested in increasing exercise tolerance and decrease the frequency of stenocardial attacks. In MARISA study (Monotherapy Assessment of Ranolazine in Stable Angina) as a single agent and in the study CARISA (Combination Assessment of Ranolazine in Stable Angina) and ERICA (Efficiency of Ranolazine in Chronic Angina) in combination with Atenolol, Amlodipine, Diltiazem or only with amlodipine demonstrated the possibility of Ranolazine to reduce the need for nitrates, reduce the frequency of stenocardial attacks. Until now, research continues to assess the impact of Ranolazine in acute coronary syndrome without ST elevation ST. Noted in the experiment antiarrhythmic effect has been confirmed in a number of clinical studies that have demonstrated the possibility of Ranolazine to reduce the incidence of supraventricular and ventricular Tachycardias, but the effect of Ranolazine is mediated, according to some authors, a different mechanism of action than the effect on beta-oxidation namely inhibition of late sodium flows.

In diabetes the effectiveness of Ranolazine is practically not been studied and observed in only one study in patients with a combination of diabetes and stable angina. It is shown that at a dose of Ranolazine 750 and 1000 mg Stenocardial attacks is reduced the incidence of seizures and nitroglycerine consumption and contributed to a significant decrease in glycated hemoglobin 0.48 ± 0.18 ± 0.70% and 0.18%, respectively.

The most studied by means of this group are trimetazidine (direct inhibitor of beta-oxidation of free fatty acids) and Mildronat (inhibitor of carnitine-operation palmitic complex providing entry into the mitochondria of fatty acids). Trimetazidine inhibits mitochondrial beta-oxidation of long-chain and short-chain fatty acids, blocking the latter reaction 4-step process of oxidation of fatty acids (3-ketoacyl-CoA thiolase), which is accompanied by a relative increase in the role of glycolysis in the myocardium with a corresponding increase in efficiency energy production process and a simultaneous decrease in the formation of free radicals on the background blockade fatty acid beta-oxidation. Substitution consumed in the energy metabolism of the initial substrate leads to more efficient use of oxygen and, consequently, a more adequate energy supply for operating the myocardium. However, it should be noted that not trimetazidine prevents accumulation of activated fatty acids into the mitochondria, thus there is an inevitable accumulation of oxidized fatty acids in mitochondria. Activated fatty acid acyl-CoA and acylcarnitine accumulate in mitochondria, ATP transport block and simultaneously act as surfactants, traumatic cell membranes causing their destruction and, possibly, may be a limiting factor in the choice of trimetazidine in diabetic patients.

The efficacy of this drug in the treatment of stable angina. The use of trimetazidine against other antianginal and anti-ischemic drugs leads to a reduction of previously used doses of these drugs and increase the effectiveness of anti-anginal and anti-ischemic treatment.

Data on the antioxidant effect of trimetazidine mixed. A strong antioxidant effect of trimetazidine is installed on the model of the aorta endothelial cell cultures pigs with the addition of glucose oxidase. By adding the drug in a therapeutic concentration showed a significant decrease in lysis of endothelial cells, electron microscopy confirmed the data. In the IG Gordeev et al. the use of trimetazidine prior myocardial revascularization helped to reduce the activity of free radical processes by activating protective antioxidant enzymes. On the other hand, the study EMIP-FR (European Myocardial Infarction Project - Free Radicals) showed that trimetazidine used as an antioxidant, for example, for the treatment of myocardial infarction in a 48-hour infusion (briefly, in the acute phase), by efficiency comparable to placebo. The executed J.M. Vedrinne et al. randomized double-blind study, it was found that patients treated with trimetazidine (40 mg bolus before surgery, then intravenously at 2.5 mg / hr in the cardioplegic solution) and placebo, malondialdehyde concentration 20 min after cardiac resuscitation significantly It did not differ [128]. In a comparative study, ME Khlebodarova and VP Mihina demonstrated that the combined use of enalapril and trimetazidine were observed its effect on lipid peroxidation, endothelial dysfunction in patients with hypertension. A recent review was devoted to assessing the impact of trimetazidine on the course of heart failure. It was stressed that in the case of both ischemic heart failure, and non-ischemic nature trimetazidine improved function of the left ventricle performance indicators, without causing significant hemodynamic effects. Studies evaluating the effectiveness of trimetazidine in patients with diabetes are devoted primarily assess its anti-ischemic action. The findings TRIMPOL-I led to conclusions on the safety and high efficiency of trimetazidine in treating angina patients with diabetes. It shows a further possibility of a positive effect on glucose metabolism. The study G. Fragasso et al. to assess the impact of trimetazidine in patients with diabetes and ischemic cardiomyopathy was an increase in ejection fraction, reduced fasting glucose and endothelin-1 as in the short-term (30-day), and in long-term (6 months) use of the drug. Similar results on the effect of trimetazidine on left ventricular functional parameters of patients with DM marked in I.S. Thrainsdottir et al., G.M. Rasano et al., As well as in patients with diabetes in the post-MI [134-136]. In more recent clinical trials evaluating the efficacy of trimetazidine in patients with diabetes has proven its ability to reduce the number of drug seizures stenocardial, reduce the need for nitrates, increase exercise tolerance. All these effects of the drug are explained in terms of its influence on the processes of fatty acid beta-oxidation.

Thus, despite the prospects of using FFA p-FOX-inhibitors in patients with diabetes, to date, no data on other properties of organo Trimetazidine, which are also needed for this category of patients (renal protection, the ability to influence the course of retinopathy, neuropathy, etc. ).

Meldonium is 3- (2,2,2-trimethylhydrazinium) propionate (Mildronate, "Grindeks") reduces the intensity of the beta oxidation of free fatty acids by preventing their entry into the mitochondria: limiting transport across mitochondrial membranes only long-chain fatty acids, while short chain may freely enter the mitochondria and oxidized there, thus there is no accumulation of incompletely oxidized fatty acids within mitochondria. This means that virtually no Mildronate can exert toxic effects on mitochondrial respiration, as not all blocks oxidation of fatty acids. This occurs because the intake of Mildronate inhibits cell carnitine, which is provided with the transfer of long-chain fatty acids through the membrane. As one of the most powerful gamma-butyrobetaine hydroxylase reversible inhibitors, which catalyzes the conversion of gamma-butyrobetaine in carnitine Meldonium thereby reduces carnitine-dependent transport of fatty acids into the mitochondria of muscle tissue. Decreasing the amount of L-carnitine in tissues is not accompanied by the development of cardiac and liver toxicity.

Like all p-FOX-inhibitors antiischemic Meldonium is characterized by a high efficiency, as demonstrated in a number of studies in recent years, with angina, myocardial infarction, coronary artery bypass surgery. The positive effect of it on exercise tolerance, reduction of clinical manifestations of angina, nitrates consumption reduction. Of particular interest are the results of a recently completed international, multicenter, randomized, double-blind, placebo-controlled clinical trial MILSS II (Evaluation of the efficacy and safety of Mildronate in the treatment of chronic coronary heart disease (stable angina)), in which it was demonstrated that the standard therapy in combination with Mildronate increases tolerance of patients to physical activity, increases the time to occurrence of angina attack, increases the time before the rise of ST segment depression, improves the quality of life of patients.

Going normal metabolism to anaerobic pathway in ischemia, as well as the accumulation of excessive amounts of free fatty acids in the reduction of coronary blood flow and promotes a number pathobiochemical pathophysiological changes leading to changes in the bioelectric activity of cardiomyocytes, and the development of dangerous cardiac arrhythmias. Correction capability of the above pathologic changes was demonstrated in a study IG Gordeev et al., which confirms the previously noted anti-arrhythmogenic effect and the ability to influence Mildronate the excitability of the myocardium.

In the experiment, and clinical practice shows that Meldonium is able to have a positive effect on endothelial dysfunction, which can be quite clinically important for patients with diabetes because of stimulation of nitric oxide production by Meldonium influence to accumulation of gamma-butyrobetaine that leads to normalization of the functional state endothelium and consequently to the normalization of vascular tone. And consider a mechanism for increasing the bioavailability of nitric oxide in the background of Meldonium - reducing the intensity of its free radical inactivation. Besides Meldonium exhibits and other vascular effects: it reduces peripheral vascular resistance, eliminates vasospasm caused by adrenaline and angiotensin. The above properties of the preparation (in conjunction with the improvement of energy metabolism in the myocardium) allowed to use it successfully in the treatment of CHF with improved systolic function, including diabetic patients . In patients with heart failure and diabetes, further taking of Mildronate with a daily dose of 1000 mg in the treatment of primary cardiovascular disease, was an increase in exercise tolerance, quality of life improvement is mainly due to a decrease of CHF symptoms and limitations in everyday life, although the use of the drug has not been accompanied changes in hemodynamic parameters (blood pressure, heart rate). The same study noted a downward trend influenced of Mildronate to glycated hemoglobin in the blood, its positive impact on the lipid profile, which was reflected in a significant decrease in triglycerides and very low density lipoproteins.

Pharmacological effectiveness of Meldonium is not limited to its effect on the processes of beta-oxidation of FFA. Mildronate has an antioxidant effect, Meldonium inhibits platelet aggregation, it can be used in the treatment of a large number of diseases. Interesting data obtained during the study MI & CI, the possibility of Mildronate using with peripheral artery disease. There was a significant increase in the absolute indicator of the distance of intermittent claudication, the increase in the initial distance of intermittent claudication, regardless of age. These effects persisted 1 month after discontinuation of the drug. The data obtained during this study allow us to consider Mildronate as a very promising drug in patients with type 2 diabetes, in which the lower limbs atherosclerosis occurs 3-4 times more frequently than in the general population .

It has been suggested that by inhibiting the transport of fatty acids and consequently their oxidation, influencing the NO vasodilation and endothelium can be adapted (preconditioning) for oxygen deficiency not only cardiac muscle cells, and brain. The experimental data is allowed to be used as a neuroprotective drug Mildronate. Neuroprotective effect of Mildronate covers acute ischemic brain damage (cerebral infarction) and discirculatory encephalopathy and is primarily due to its antioxidant effect, which is based on the stimulation of the natural enzyme reactions and the ability to penetrate the blood-brain barrier. Meldonium reduces the intensity of lipid peroxidation and increases the activity of endogenous antioxidants in patients with chronic cerebrovascular disease, including patients with diabetes mellitus. The study showed improvement in cognitive function in patients with diabetes and optimize the electrophysiological functions.

A significant positive impact of Mildronate for diabetic peripheral (sensory-motor) neuropathy is proved that exhibit improved by electrophysiological properties of the nerve fiber, optimizing tissue oxygen balance. The same study demonstrated a beneficial effect of Meldonium on carbohydrate and lipid metabolism, improving the quality of life of patients with diabetic peripheral neuropathy.

An important pharmacological properties of Meldonium to patients with diabetes is marked by the ME Statsenko et al. the effect of it on the course of diabetic cardiac autonomic neuropathy. There is the possibility of correcting on the variability of cardiac arrhythmias with a decrease in the sympathetic influence on the cardiovascular system in the treatment of Mildronate. Given the fact that the presence of clinically manifest DCA indicates a high risk of acute coronary syndrome and fatal arrhythmias, reducing the imbalance of sympathetic-parasympathetic influences on the heart is a positive factor for the secondary prevention of fatal complications in patients with diabetes. The same study confirmed the ability of Mildronate increase global myocardial contractility and reduce the severity of left ventricular diastolic dysfunction (pathognomonic sign of diabetic cardiomyopathy).

As mentioned earlier, an important role in organ damage in diabetes plays a violation of intracellular energy metabolism and activation of free radical processes leading to the development of endothelial dysfunction, micro- and macro-angiopathy. Given that cytoprotectors able to positively influence the development of these key pathological mechanisms of target organ damage, the use in the treatment of microvascular cytoprotectors seems urgent.

Conducted to date studies to assess the effectiveness of Meldonium for treatment of microvascular complications of diabetes have shown it should be included in a comprehensive treatment of diabetic retinopathy, a positive effect on the course of diabetic nephropathy. Turning Mildronate in complex treatment of chronic heart failure in patients with diabetes was accompanied by a statistically significant reduction in the severity of albuminuria, increased creatinine clearance, a positive influence on the state intraglomerular hemodynamics - a decrease in the number of patients with renal functional reserve depleted. Held in the correlation analysis revealed a relationship to improve kidney function by improving cardiac hemodynamics.

It is impossible not to note the possibility of implementing the additional positive clinical effect in patients with diabetes through Meldonium impact on glucose metabolism. The experiment shows that Mildronate stimulates production of insulin in response to glucose and glucose utilization rate during the glucose tolerance test and insulin-stimulated 2-deoxyglucose uptake cardiomyocytes. In experimental diabetes type 2 Mildronate reduces the concentration of L-carnitine in the plasma of experimental animals, fasting and postprandial hyperglycemia, inhibited the cumulation fructosamine and neglected disorders of pain sensitivity. At the level of the aortic improved contractile function during administration of phenylephrine . Reported experimental results have been confirmed in clinical trials, which demonstrated a significant impact on Mildronate glycated hemoglobin levels in patients with type 2 diabetes with chronic heart failure.

n the experiment, and in the clinical studies noted a positive effect on lipid metabolism meldonium. It is noted that long-term administration of Mildronate reduces the size of atherosclerotic plaques in the aorta and the content of L-carnitine in aortic tissues was significantly positive effect on the lipid profile parameters in an experiment, and when used in the combined treatment of diabetic patients. In these works once again demonstrated the ability to influence of Meldonium on the severity of lipid peroxidation and activity of antioxidant enzymes - superoxide dismutase and catalase.

Of course, that revealed the ability of Meldonium significantly reduce the severity of insulin resistance also find good use in the clinical practice of the treatment of cardiovascular complications of patients with diabetes. In a study evaluating the effectiveness of Meldonium in chronic heart failure of ischemic etiology of combination therapy in patients with metabolic syndrome have shown that the drug can reduce blood insulin levels, which is accompanied by a significant decrease in HOMA index.

Thus, presented an overview of the literature data suggest that p-FOX-inhibitors will occupy a worthy place in the treatment of vascular, cardiovascular complications in patients with type 2 diabetes not only in connection with their cardio be protective, but also to identify additional organo properties .