[Comparative Randomized Study of the Effects of Long-Term Therapy With Rosuvastatin and Combination of Atorvastatin and Ezetimibe on Carbohydrate Metabolism and Adipokines Levels in Patients With Coronary Artery Disease and Diabetes Mellitus].

OBJECTIVE: This open randomized study compares the effects of 24-week-long treatment with rosuvastatin and with atorvastatin coadministered with ezetimibe on the parameters of carbohydrate metabolism and the plasma levels of adipokynes in patients with coronary artery disease and type 2 diabetes mellitus or impaired glucose tolerance (IGT). METHOD: A total of 31 patients with coronary artery disease and type 2 diabetes mellitus or IGT were recruited in the study. Patients were randomized into two groups: group 1 included patients who received rosuvastatin therapy in an average dose of 12.5 mg/day (n = 16); group 2 included patients who received combination treatment with atorvastatin in an average dose of 13.3 mg/day and ezetimibe (10 mg) (n = 15). Plasma levels of lipids, apoB, apoA1, glucose, insulin, leptin, and adiponectin were evaluated; HOMA-IR index (an empty stomach insulin, mu/l x fasting glucose, mmol/l)/22.5) was calculated. RESULTS: During the therapy, the LDL-C and apoB levels decreased by 51.7% and 42.3% in group 1 and by 51.8% and 44.9% in group 2, respectively. Reduction in the triglyceride levels was significantly more pronounced in group 2 than in group 1: 43.2% vs 17.4% (p < 0.02), whereas we did not observed significant changes of HDL-C and apoA1 in either group. The increases in basal glycemia, basal insulinemia, HbA1c levels (from 6.47% [6.10-7.02%] to 6.98% 16.23-8.18%]), and HOMA-IR (from 2.14 [1.68-3.51] to 4.30 [2.31-5.77]) were found only in group 2 (p < 0.05 for all). These changes were observed in 75% of patients of group 2 independently of the presence of diabetic state or IGT, but the changes were more pronounced in patients with disturbed carbohydrate metabolism. Changes of leptin levels during the therapy were diverse: 73% patients of group 1 demonstrated decrease in the leptin levels, whereas 67% of patients in group 2 experienced 57%-increase in the leptin concentrations. Degree of increased basal glycemia was associated with increase in the leptin levels (r = 0.37, p = 0.04) in the entire group of patients (n = 31). Furthermore, changes in leptin levels were negatively associated with decreased adiponectin levels (r = -0.57, p = 0.034). CONCLUSIONS: In case of equivalent degree of the decrease in LDL-C levels, 24-week combination therapy with atorvastatin and ezetimibe, unlike rosuvastatin treatment, induced increases in basal glycemia, insulinemia, HbA1c, and HOMA-IR index irrespective of the presence of carbohydrate metabolism disturbances before treatment. Our data suggest that adiponectin and leptin are involved in the mechanisms of adverse metabolic effects of the combination of atorvastatin and ezetimibe.

[Trends in subclinical atherosclerosis in patients with arterial hypertension associated with diabetes mellitus: a relationship between blood pressure achieved with antihypertensive therapy and body weight].

AIM: To analyze carotid artery morphofunctional changes in patients with arterial hypertension (AH) associated with type 2 diabetes mellitus (CD2) on regular antihypertensive and sugar-lowering therapy in relation with the changes in the diurnal blood pressure (BP) profile, the quality of metabolic control, and baseline clinical and laboratory data. MATERIALS AND METHODS: Seven-six patients with CD2-associated AH who had received regular antihypertensive and sugar-lowering treatment without statins for 12 months were examined. The intima-media thickness (IMT) in the common carotid artery (CCA) was estimated by ultrasound scanning; the compliance and stiffness indices were calculated. The values of 24-hour BP monitoring, glycemic control, and blood lipids were studied. RESULTS: Among the patients with increased CCA IMT (Group 1), women were three times more than among those without it (Group 2). Subclinical atherosclerosis progression as an annual average CCA IMT increment of 0.08 mm was detected in the absence of a less than 7-mm Hg decrease in 24-hour mean systolic BP and/or a 24-hour mean BP of less than 134/80 mm Hg or if, during adequate BP control, HbA1 exceeded 9%. Group 1 women showed increased body mass index and a trend for worse vascular elastic properties. Group 2 displayed not only a CCA IMT reduction (from 0.94 +/- 0.03 to 0.83 +/- 0.03 mm; p < 0.01), but also a CCA decrease that seemed to show reduced vessel wall thickness. There were no changes in the CCA lumen in Group 1. Comparable control of glycemia and blood lipid-transport system indices was achieved in both groups. The magnitude for 24-hour BP reduction in which there was no subclinical atherosclerosis under stable glycemic control was determined. CONCLUSION: The results of the study suggest a correlation between a inadequate BP reduction, worse elastic properties of large-sized arteries, and higher body mass index in patients (mainly women) with CD2 and underline the importance of correcting body weight and achieving goal BP in this group of patients.

[A circadian profile of arterial pressure in hypertensive patients with diabetes mellitus: relation with affected renal circulation].

AIM: To study a circadian profile of blood pressure (BP) in normotensive patients with diabetes mellitus type 2 (DM-2) and hypertensive patients with DM-2; to examine BP circadian rhythm disorders for correlation with dopplerographic indices of intrarenal blood circulation. MATERIAL AND METHODS: A total of 35 normotensive diabetics and 309 hypertensive diabetics were examined. Control groups consisted of 90 patients with essential hypertension (EH) and normal carbohydrate tolerance (CT) and 34 healthy subjects, respectively. Patients with hypertension and DM-2 and EH patients had no differences by duration of hypertension and office BP. The following methods of examination were used: outpatient 24-h BP monitoring, tests for glycemia, insulinemia and microalbuminuria (MAU), duplex scanning with colour impulse doppler mapping of blood flow in the arcuate intrarenal arteries to measure intrarenal resistance. RESULTS: A circadian BP profile in normotensive diabetics is characterized by insufficient fall of nocturnal BP and indirect signs of neurohumoral hyperactivation--high mean diurnal variability and morning rise of systolic BP. Hypertensive diabetics had more pronounced neurohumoral hyperactivation, lower drop of nocturnal BP. EH patients with normal CT had higher and longer diastolic diurnal hypertension. In combination of hypertension with DM-2 pulse blood pressure (PBP) rises earlier, in duration of hypertension up to 10 years nocturnal PBP rise was more pronounced. Circadian PBP rose significantly later. CONCLUSION: Stepwise regression analysis has revealed that a nocturnal PBP rise in line with postprandial insulinemia contributes significantly to growth of intrarenal vascular resistance in combination of hypertension with DM-2.

[Left ventricular remodeling in association of arterial hypertension with diabetes mellitus type 2: correlation with gender and disease duration].

AIM: To study specific features of left ventricular remodeling (LVR) in patients with hypertension and diabetes mellitus type 2 (DM-2). MATERIAL AND METHODS: The study group comprised 290 patients, the control group consisted of 79 patients with essential hypertension free of carbohydrate tolerance impairment. The age of the examinees ranged from 35 to 60 years. Structural-geometric left ventricular model was determined by echocardiography. Estimation of significant determinants of myocardial mass index (MMI) and types of left ventricular remodeling was made with multiple regression analysis and logistic regression. The parameters of 24-h monitoring of blood pressure, glycemic control, blood lipid-transport function, plasma insulin, aldosteron, hydrocortisone levels, blood rennin activity were used as independent variants. Incidence of registration of left ventricular excentric hypertrophy (LVEH) in the study group was higher as compared to control (27.6 and 16.5%, respectively; p < 0.05). A rise of left ventricular MMI in the study group was related to 24-h systolic arterial pressure and basal insulinemia (R2 = 0.4229). Development of left ventricular structural-geometric model in the study group depended on the gender, duration of diabetes, 24-h systolic blood pressure (direct correlation) and 24-h diastolic blood pressure (inverse correlation), R2 = 0.6500. In DM duration about 5 years, percentage of males with concentric left ventricular hypertrophy (CLVH) and LVEH was 63% versus 37% (chi-square 5.0815, p < 0.03). In longer diabetes LVEH was seen more frequently than CLVH (73.3 and 26.7%, respectively). Among women with left ventricular hypertrophy and hypertension under 10 years LVEH and CLVH were detected in 69.1 and 30.9% cases, respectively (chi-square 7.9356, p < 0.01). Later, these differences became less obvious (41.7 and 58.3%, respectively). CONCLUSION: Hypertensive patients with diabetes mellitus type 2 develop structural-geometric changes of the heart earlier. LVR in such patients is associated with gender, duration of DM and non-proportional growth of 24-h systolic blood pressure leading to gender-related differences in the time of formation of LVEH and CLVH.

[Effect of 6-month therapy with simvastatin on lipid transport function of the blood and the state of endothelium in patients with diabetes and hypertension].

The state of lipid transport function of the blood, blood contents of stable nitrogen metabolites, and proinflammatory cytokines (TNF-a and IL-1b) during therapy with simvastatin were studied in 29 patients receiving combination antihypertensive therapy with angiotensin converting enzyme inhibitors (ACEI) and verapamil. Lipid lowering action of simvastatin was realized just in 1 month of treatment and remained sustained for half a year (average duration). 6 months after addition of simvastatin to antihypertensive therapy substantial (58.4%, p=0.044) rise of plasma content of stable nitrogen metabolites took place. At the same time therapy with metoprolol in a similar group of patients exerted no considerable effect on blood plasma concentration of nitrate and nitrite anions. Lowering of median values of TNF-alpha from 20.13 (12.67-52.80) to 11.34 (3.31-31.29) pg/ml (p<0.0038) was also noted at the background of combination antihypertensive therapy. This happened without distinct affair with degree of lipid lowering action of simvastatin. The results of the study document positive effect of half year treatment of patients with concomitant hypertension and diabetes with simvastatin (10-20 mg/day) in combination with ACEI and verapamil on metabolism of nitric oxide and plasma content of TNF-alpha which realizes independently from degree of hypolipidemic action of simvastatin.

[ACE and AGTR1 genes polymorphisms in left ventricular hypertrophy pathogenesis in humans]. / Polimorfizm genov ACE i AGTR1 v patogeneze gipertorofii levogo zheludochka serdtsa u cheloveka.

The role of A2350G polymorphism in exon 17 of the ACE gene and A1166C - in 3'-UTR of the AGTR1 in the pathogenesis of left ventricular hypertrophy was studied in patients with essential hypertension (EH) and arterial hypertension combined with diabetes mellitus type 2 (AH + DM2). Patients with EH and AH + DM2 did not differ from the control sample of healthy individuals by allele or genotype frequencies. However, an association of both polymorphisms with LVH was detected in EH patients. The frequency of 1166C allele was higher in patients with LVH (33.6% vs 20.7% without LVH). A1166C polymorphism determined the magnitude of left ventricular mass index (LVMI) in EH patients as well (p = 0.007). 2350G allele frequency of the ACE gene was in 1.5, and GG genotype--in 3.5-fold higher in EH patients with LVH, as compared without LVH. LVMI was significantly higher in patients with GG genotype as compared with heterozygotes and AA homozygotes (p = 0.002). Thus the presence of 1166C allele of AGTR1 and 2350G allele of ACE can be considered as predisposing factors for LVH development in EH. In contrast, association of studied polymorphisms with presence or LVH degree was not detected in patients with arterial hypertension combined with DM2. This may indicate another structure of genetic component of predisposition to LVH in different causes.

[Effect of long term therapy with captopril on dopplerographic parameters of intrarenal blood flow and renal function in patients with hypertension and diabetes]. / Vliianie dlitel'noi antigipertenzivnoi terapii kaptoprilom na dopplerograficheskie pokazateli vnutripochechnogo krovotoka i funktsiiu pochek u bol'nykh arterial'noi gipertoniei na fone sakharnogo diabeta.

Effect of 9-12 month treatment with captopril on dopplerographic parameters of intrarenal blood flow and renal function was studied in 30 hypertensive diabetics without clinical signs of nephroangiopathy. There was an interrelationship between strict blood pressure (BP) control (average 24-hour BP below 135/83) and improvement of parameters of intrarenal hemodynamics. BP normalization and most pronounced positive changes of renal perfusion during therapy with captopril were achieved in patients with mild hypertension and initially high intrarenal resistance yet at the stage of normo- or microalbuminuria. In moderate hypertension with microalbuminuria treatment with captopril was associated with stabilization of parameters of renal blood flow and rate of 24-hour albumin excretion at their initial level despite less strict control of BP and unsatisfactory compensation of diabetes. BP response to captopril in patients with hypertension and diabetes was related to initial state of intrarenal hemodynamics. In patients with mild hypertension indexes of resistance of renal and intrarenal arteries could be used for prediction of sensitivity to antihypertensive action of captopril.

[Clinical Efficacy of Combination Therapy With Trimetazidine and Angiotensin Converting Enzyme Inhibitors in Patients With Hypertension and Ischemic Heart Disease Associated With Type II Diabetes]. / Klinicheskaia éffektivnost' kombinirovannoi terapii trimetazidinom i ingibitorami angiotenzinprevrashchaiushchego fermenta u bol'nykh arterial'noi gipertoniei i ishemicheskoi bolezn'iu serdtsa, assotsiirovannykh s sakharnym diabetom 2-go tipa.

AIM: To assess in a randomized open study effect of 12-15 week use of angiotensin converting enzyme inhibitors (ACEI) with and without trimetazidine on myocardial perfusion reserve in patients with ischemic heart disease (IHD) and/or hypertension associated with type II diabetes. MATERIAL: Patients (n=69) receiving long term ACEI therapy with transient myocardial perfusion defects during dipyridamole stress test. METHODS: Control patients (n=29, including 15 with IHD) continued to receive an ACEI, while in trimetazidine group (n=40, including 21 IHD patients) trimetazidine (60 mg/day) was added to ACEI. Single photon emission computer tomography with (199)Thallium Chloride was used for measurement of myocardial perfusion reserve. Changes of physical working capacity, intracardiac hemodynamics and glycemia were studied only in trimetazidine group. RESULTS AND CONCLUSION: Significant 52% (mean) decrease (32.5% in IHD patients) of perfusion defects and acceleration on total clearance of Tl-199 were registered in trimetazidine group while no considerable changes of myocardial perfusion were revealed in control group. Most substantial changes of myocardial blood flow reserve occurred in patients with moderate alterations of left ventricular diastolic filling, and among IHD patients - in those without cardiac dilatation and pronounced diastolic left ventricular dysfunction. Significant increase (45.9 and 23.9% in patients with and without IHD, respectively) of total work performed during bicycle exercise was registered in trimetazidine treated patients. In IHD patients decline of initially elevated intramyocardial tension was also observed.

[The clinical instrumental evaluation of treatment efficacy in patients with concomitant atherosclerosis of the coronary, cerebral and peripheral arteries]. / Kliniko-instrumental'naia otsenka éffektivnosti lecheniia bol'nykh s sochetannym aterosklerozom koronarnykh, mozgovykh i perifericheskikh arterii.

The loading tests, instrumental and biochemical methods were employed to study the effect of mildronate, dalargin, rokornal, gevilon, dibunol, emoxipine and plasmapheresis on the coronary, cerebral, peripheral circulation, the level of cholesterol, its fractions and triglycerides in 247 patients suffering from atherosclerosis. Mildronate, dalargin, rokornal, emoxipine and plasmapheresis were shown to exert a beneficial effect on the regional circulation, lipid metabolism and can be used in the treatment of patients with concomitant forms of atherosclerosis.

[Effect of long-term antihypertensive therapy on vaso-regulating function of the brachial artery in patients with arterial hypertension associated with type 2 diabetes mellitus]. / Vliianie dlitel'noi antigipertensivnoi terapii na sostoianie vazoreguliruiushei funktsii plechevoi arterii u bol'nykh arteial'noi gipertoniei, assotsiirovannoi s sakharnym diabetom tipa 2.

AIM: To evaluate the impact of 6-month-to-one-year antihypertensive therapy on the vasoregulating junction of the brachial artery and predictors of its efficiency in 75 patients with stages I-II arterial hypertension associated with type 2 diabetes mellitus. MATERIALS AND METHODS: An open randomized study of parallel groups of patients receiving angiotensin-converting enzyme (ACE) inhibitors, calcium blockers (verapamil) and their combination and in those who did not take antihypertensive therapy examined endothelium-dependent vasodilation (EDVD) according to the data of ultrasound scanning and Doppler study of brachial arterial blood flow as compared with changes in metabolism and 24-hour blood pressure profile. RESULTS: A positive effect of verapamil on the baseline impaired EDVD is realized only in the presence of an adequate compensation of glycemia, at the normal blood level of cortisol, occurs in parallel with increased nonendothelium-dependent vasoreactivity, and associates with the magnitude of an antihypertensive effect. ACE inhibitors improve decreased EDVD irrespective of the degree of glycemic control, the blood level of cortisol without a clear correlation with the altered non-endothelium-dependent vasoreactivity and with the degree of an antihypertensive effect. Combined therapy with these agents causes decreases in baseline insulinemia and the athoregenicity index and it can improve impaired vasoreactivity even in case of incomplete antihypertensive therapeutic effect. CONCLUSION: The differences found in the effect of ACE inhibitors and verapamil on baseline decreased EDVD provide evidence for differential use of these drugs to correct impaired vasoreactivity in patients with AH associated with DM. The combined antihypertensive therapy fails to produce a positive impact if significant hypercholesterolemia (total blood cholesterol being more than 6.5 mmol/l) and stenosing peripheral atherosclerosis are present.

[Polymorphic markers of GNB3 (C825T), AGTR1 (A1166C) and ACE (A2350G and I/D) genes in patients with arterial hypertension combined with diabetes mellitus type 2]. / Polimorfnye markery genov GNB3(C825T), AGTR1(A1166C), and ACE(A2350G and I/D) u bol'nykh arterial'noi gipertoniei, sochetaiushcheisia s sakharnym diabetom tipa 2.

AIM: To elicit correlations of polymorphic markers of GNB3 (C825T), AGTR1 (A1166C), ACE (A2350G and I/D) genes with arterial pressure, left ventricular hypertrophy (LVH) and blood concentrations of proinflammatory cytokines in hypertensive patients with diabetes mellitus type 2 (DM2). MATERIAL AND METHODS: Clinical parameters (24-h arterial pressure profile, echocardiographic findings, immunoenzymes level) were studied in 89 hypertensive patients with DM2. These patients had different genotypes by the studied allele variants of the genes determined by polymerase chain reaction. RESULTS: Polymorphism of A1166C gene of type 1 vascular receptor of angiotensin II (AGTR1) contributes to formation of arterial hypertension (AH) signs diversity in DM2 patients. GNB3, a gene C825T polymorphic marker, showed a correlation with diastolic arterial pressure but this variant of the gene locus is not associated with LVH. However, G-allele of ACE gene contributes much to appearance of this pathological sign. Mean values of IL-1beta and TNF-alpha as well as the presence of LVH depended on genotypes by ACE gene (polymorphism I/D). CONCLUSION: Polymorphic markers of ACE and GNB3 candidate genes influence clinical diversity of pathological signs in DM2 patients through modification of AH and LVH severity and the level of proinflammatory cytokines.

[Coronary flow vasodilator reserve in patients with type 2 diabetes mellitus-associated arterial hypertension]. / Vazodilatatsionnyi rezerv koronarnogo krovotoka u bol'nykh arterial'noi gipertoniei, assotsiirovannoi s sakharnym diabetom tipa 2.

The coronary flow vasodilator reserve (CFVR) in the proximal segment of the anterior descending coronary artery was studied in 50 patients with diabetes mellitus (DM), by Doppler study via transesophageal approach. Group 1 included 39 patients with DM concurrent with Stages 1-2 arterial hypertension (AH), of them 14 patients were documented as having coronary heart disease (CHD) in the presence of coronary atherosclerosis (Subgroup 1A) and CHD was excluded in the remaining 25 patients (Subgroup 1B). Group comprised 11 patients with normal blood pressure (BP). For comparison, 6 healthy individuals were examined. CFVR was calculated as a ratio of the peak diastolic coronary flow (CF) velocity during infusion of dipyridamole (0.56 mg/kg) to the baseline CF. CDVR was significantly decreased as compared with the controls (2.07 +/- 0.73 in Subgroup 1A, 2.15 +/- 0.67 in subgroup 1B, 1.78 +/- 0.33 in Group 2, and 3.68 +/- 0.26 in the controls), this decrease being due to low CF velocities in hyperemia in the majority of patients in Subgroup 1A and Group 2 and to higher baseline CF velocity in most patients from Subgroup 1B. In Group 1 patients, CFVR was not linear with age, the duration of the disease, BP and HbA1 levels, but it was related to the carotid distensibility coefficient (rho = 0.60, p = 0.004) and to the blood level of total cholesterol (rho = -0.43, p = 0.0107). In Group 2 patients, the least CF velocities in the presence of vasodilatation were detectable in older patients and in patients with hypercholesterolemia. An all the patients with left ventricular hypertrophy (LVH) had decreased CFVR whose values with the myocardial mass index above 130 g/m2 were significantly less than those in the absence of LVH. Thus, the limited reserve of coronary vasodilatation was detectable in patients with DM irrespective of BP levels and the status of epicardial arteries and it was most pronounced in LVH and hypercholesterolemia. The impaired elastic properties of peripheral arteries in the presence of cholesterolemia may be regarded as a marker of the low reserve of coronary vasodilatation in patients with DM concurrent with AH.

[The use of mildronat with stenocardia patients]. / Primenenie mildronata u bol'nykh stenokardiei.

Against placebo background 50 patients with effort stenocardia received mildronate, a new native cardioactive drug and its effects on the clinical course in conditions of spirometric bicycle ergometry were studied. It was found that monotherapy with mildronate is accompanied by an antianginal effect and an increase of the physical working capacity of patients.