[Efficacy and safety of the use of metformin in patients with chronic heart failure and type 2 diabetes mellitus. results of the study "rational effective mulicomponent therapy in the battle against diabetes mellitus in patients with chronic heart failure"].

Aim of the investigation was to study safety of therapy with metformin and its effect on clinical, hemodynamic, functional and neurohumoral status in patients with chronic heart failure and type 2 diabetes mellitus DM). Eighty one patients with light and moderate NYHA functional class (FC) II-III CHF, left ventricular ejection fraction < 45%, and DM were examined. As a result of randomization 2 groups were formed: with active (n=41) and usual (n=40) treatment. In active group with achievement of target levels of glycemia 24 (59%) patients were on oral hypoglicemic drags, 17 (41) patients received. All patients were on basal therapy of CHF. Initially efficacy and safety of metformin was investigated in a cohort of active treatment (jn metformin n=29, control n=12), including patients who were prescribed metformin not for the whole period. In addition in active group analysis was carried out among patients, who continually were treated with metformin for 12 months (n=30) in comparison with patients never treated with metformin (n=8). Total duration of the period of treatment and supervision was 12 months. Control examination was conducted before randomization, after 6 months of treatment, at the end of the study and included assessment of clunico-functional status of patients, renal function (GFR), neurohumoral profile (MNUP, NA, AII). The state of carbohydrate metabolism was assessed with the help of determination of HBA1C level and test with nutritional load given as of common breakfast -- 2-3 in the course of which fasting and postprandial level (in 2 hours after breakfast) of glucose (GLC), and fasting insulin and C-peptide. Overall safety of metformin was confirmed -- throughout whole period of follow up with different variants of comparative analysis no cases of lactic acidosis were revealed. Practical lack of positive influence of metformin on glycemia at its initially not high level was accompanied with improvement of FC CHF, parameters of central hemodynamics, augmentation of functional capacities of patients, improvement of quality of life, lowering of number of decompensations of CHF and diminishment of degree of activation of SAS. It can be suggested that this dynamics is conditioned by the presence of cardioprotective properties in metformin what allows to recommend its application in patients with CHF and type 2 DM.

Oxidative stress in patients with chronic heart failure and type 2 diabetes mellitus.

Parameters of oxidative stress were studied in patients with chronic heart failure and/or type 2 diabetes mellitus. Chronic heart failure was accompanied by severe oxidative stress, while in patients with type 2 diabetes mellitus the signs of oxidative stress were less pronounced. The intensity of free radical oxidation in patients with chronic heart failure and type 2 diabetes mellitus was not higher compared to patients with chronic heart failure.

[Effect of metformin on the magnitude of oxidative stress in patients with type 2 diabetes mellitus].

The final glycated products forming in diabetes contribute to the higher atherogenic oxidative modification of low-density lipoproteins (LDL). The impact of glycemic control on the parameters of free radical oxidation was comparatively studied in patients with type 2 diabetes who received metformin (Glucophage, Nycomed) (Group 1, n = 40) and sulfanylurea preparations (Group 2, n - 30, out of them 15 patients took maninil and 15 had diabeton) good glycemic control caused the magnitude of oxidative stress to reduce, which appeared as the decreased levels of primary (lipid hydroperoxides) and secondary (malonic dialdehyde) products of free radical oxidation in LDL and as the enhanced activity of antioxidative defense enzymes. However, with the identical degree of glycemic control, which was determined by the level concentrations of HbA1c and lipids in both groups, the plasma levels of lipid peroxides decreased by more than 5 times in Group 1 patients receiving metformin than in Group 2 patients and the rate of LDL oxidability reduced by 4.5 times. Such a marked effect of metformin on the attenuated manifestations of oxidative stress is indicative of its antioxidative effect independent of the hypoglycemic effect of the drug.

Oxidative stress in atherosclerosis and diabetes.

We measured the content of lipid peroxides in plasma LDL from patients with chronic CHD not accompanied by hypercholesterolemia; CHD and hypercholesterolemia; type 2 diabetes mellitus and decompensation of carbohydrate metabolism; and CHD, circulatory insufficiency, and type 2 diabetes mellitus (without hypercholesterolemia). The content of lipid peroxides in LDL isolated from blood plasma by differential ultracentrifugation in a density gradient was estimated by a highly specific method with modifications (reagent Fe(2+) xylene orange and triphenylphosphine as a reducing agent for organic peroxides). The content of lipid peroxides in LDL from patients was much higher than in controls (patients without coronary heart disease and diabetes). Hypercholesterolemia and diabetes can be considered as factors promoting LDL oxidation in vivo. Our results suggest that stimulation of lipid peroxidation in low-density lipoproteins during hypercholesterolemia and diabetes is associated with strong autooxidation of cholesterol and glucose during oxidative and carbonyl (aldehyde) stress, respectively. These data illustrate a possible mechanism of the progression of atherosclerosis in patients with diabetes mellitus.