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Background The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. Methods We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). Results The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. Conclusions Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Background and objective: Metabolic syndrome is characterized by insulin resistance (IR) as well as dyslipidemia, ventral overweight, hypertension and elevated fasting plasma glucose. Since diabetic and prediabetic statesare commonly associated with hypertriglyceridemia, fenofibrates have been used in such patients. The aim of this pilot open trial was to study the influence of micronized fenofibrate on insulin resistance and plasma insulin levels in prediabetic and diabetic patients. Subjects: From 114 dyslipidemic patients, 31 with dyslipidemia and insulin resistance were selected to take part in the study. Of the 31 patients, 20 were nondiabetic and only 11 had noninsulin-dependent diabetes mellitus. Eighteen dyslipidemic patients acted as controls. Methods: Insulin resistance was assessed in a short-term insulin tolerance test. Plasma insulin, antiinsulin antibodies, lipid parameters and the insulin sensitivity index (ISI) were measured at entry and after a 3-month therapy with 200 mg micronized fenofibrate daily. Results: Three-month therapy with micronized fenofibrate resulted in significant ISI increase and was accompanied by a decrease in plasma insulin levels in dyslipidemic patients with metabolic syndrome. ISI also improved in patients with type 2 diabetes mellitus and there was an unexpected increase in plasma insulin levels. Antiinsulin antibodies were unchanged throughout the trial. Reductions in plasma triglycerides and total cholesterol exceeding 50% and 20%, respectively, were observed in patients with metabolic syndrome. These changes were accompanied by an increase in mean levels of plasma high-density lipoprotein (HDL) cholesterol (above 35%). Conclusions: Micronized fenofibrate is an effective drug in normalizing lipid-lipoprotein levels in patients with metabolic syndrome. After a 3-month fenofibrate therapy, insulin resistance was reduced in a group of patients with dyslipidemia and metabolic syndrome.

OBJECTIVE Increased levels of fibrinogen and plasminogen activator inhibitor 1 (PAI-1) are associated with an increased risk of ischemic coronary disease and its complications. Since atherogenic dyslipidemias are well-known risk factors for coronary heart disease, this study aimed to determine whether Type IIb dyslipidemia, one of the most atherogenic dyslipidemias, is accompanied by increased PAI-1 and fibrinogen synthesis. The additional aim of this study was to evaluate the effect of micronized fibrates on the levels of PAI-1 and fibrinogen in patients with Type IIb dyslipidemia. SUBJECTS Thirty patients with Type IIb dyslipidemia and 12 age-matched control subjects were studied. Fourteen patients were treated with fenofibrate and 16 were treated with ciprofibrate for 1 month. METHODS Plasma PAI-1 levels were measured by the ELISA method with Diagnostica Stago kit. The level of fibrinogen was measured by the Clauss method. RESULTS PAI-1 levels in dyslipidemic patients before treatment differed significantly in both the fenofibrate and ciprofibrate treatment groups (101.18 +/- 36.47 ng/ml, 87.64 +/- 32.06 ng/ml, respectively) from those in the control group (32.32 +/- 7.39 ng/ml, p < 0.001). Compared with the control subjects (2.91 +/- 0.35 g/l), fibrinogen levels before treatment were higher in patients with dyslipidemia treated with ciprofibrate (3.42 +/- 0.59 g/l, NS) and fenofibrate (3.65 +/- 1.10 g/l, p < 0.05). One-month ciprofibrate treatment resulted in an insignificant decrease in PAI-1 levels (76.28 21.60 ng/ml, NS) and in a significant decrease in fibrinogen levels (2.73 +/- 0.40 g/l, p < 0.01). After one-month fenofibrate treatment PAI-1 levels (81.22 +/- 25.01 ng/ml, p < 0.01) and fibrinogen levels (2.95 0.72 g/l, p < 0.01) decreased significantly. CONCLUSION Type IIb dyslipidemic patients have increased levels of PAI-1 and fibrinogen. Micronized fibrates decreased not only lipid levels but also the levels of fibrinogen and PAI-1 in these patients.

OBJECTIVE The most important mechanism through which high plasma lipid levels trigger the formation of atherosclerotic lesions involves a change in the expression of adhesion molecules on endothelial and smooth muscle cells. The aim of this study was to evaluate an extralipid effect of fenofibrate and simvastatin by examination of MCP-1 and ICAM-1 plasma concentration after 1-month hypolipemic therapy as well as MCP-1 and ICAM-1 plasma concentration after 1-month therapy with low-fat diet alone. METHODS Twenty patients with HLPIIb or HLPIIa, who did not respond to a low-fat diet, were treated with micronized fenofibrate or simvastatin, respectively, for 1 month. The control group included 18 normo-lipidemic, healthy age-matched participants; 10 patients with HLPIIa were effectively treated with a low-fat diet for 1 month. This group was compared to a control group of 10 healthy subjects. The plasma adhesion molecule levels were measured by an ELISA method before and after the treatment. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. RESULTS sICAM-1 levels were significantly higher in HLPIIa and HLPIIb patients (331 +/- 19 ng/ml and 423 +/- 23 ng/ml, respectively) compared with the control group (236 +/- 12 mg/ml). MCP-1 levels were also significantly higher in HLPIIa and HLPIIb patients (170 +/- 9 pg/ml and 183 +/- 15 pg/ml, respectively) compared with the control group (100 +/- 4 pg/ml). Fenofibrate (200 mg daily) significantly decreased sICAM-1 (by 17%) and MCP-1 levels (by 12.5%). Simvastatin (20 mg daily) caused a significant decrease (by 10.5%) in sICAM-1 levels only. Restriction in dietary lipids resulted in a significant decrease in the levels of cholesterol (8%), LDL cholesterol (14.9%) and ApoB (12.7%), which was accompanied by a significant decrease in the levels of sICAM-1 (8.7%) and MCP-1 (16.1%). CONCLUSION The results of this study suggest that high lipid levels are accompanied by increased levels of sICAM-1 and MCP-1 and that hypolipidemic therapy only slightly decreases the levels of these molecules compared with plasma lipids. The hypolipidemic diet-related decrease in the levels of lipids, ICAM-1 and MCP-1 suggests that it is a drug-induced decrease in lipid levels but not a direct action of the drugs on endothelial cells, smooth muscle cells or macrophages that leads to a decrease in the levels of adhesion molecules.

Monocytes that migrate into the arterial wall participate in the development and, eventually, rupture of the atherosclerotic plaque. The aim of this study was to evaluate the secretion of monocyte chemoattractant protein-1 (MCP-1) by monocytes from hyperlipidemic patients treated with hypolipidemic drugs, namely fenofibrate, simvastatin, or atorvastatin to determine what role is played by these drugs in the development and stabilization of the atherosclerotic plaque.Fifty-four hyperlipidemic patients, who did not respond to a low-fat diet, were treated with fenofibrate, simvastatin, or atorvastatin (18 patients in each group) for 1 month. The control group included 18 normolipidemic, healthy, age-matched participants. Ten hyperlipidemic patients were effectively treated with hypolipidemic diet alone for 1 month. This group was compared with a control group of ten healthy subjects. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. Before and after treatment, monocytes were isolated from peripheral blood. After stimulation with lipopolysaccharide (LPS), MCP-1 secretion was measured by enzyme-linked immunosorbent assay (ELISA).MCP-1 levels were significantly higher in hyperlipidemic patients than controls: 15.8+/-0.47, 16.7+/-0.23, and 14.9+/-0.45 compared with 12.36+/-0.42 ng/ml. Fenofibrate, atorvastatin, and simvastatin significantly decreased MCP-1 levels from 15.8+/-0.47 to 8.79+/-0.89, from 16.7+/-0.23 to 7.46+/-0.73, and from 14.9+/-0.45 to 10.3+/-0.8 ng/ml, respectively. In the diet-treated group of hyperlipidemic patients, the level of MCP-1 before therapy was significantly higher than in controls (16.89+/-0.31 vs 12.45+/-0.36 ng/ml). The diet therapy caused a significant decrease in levels of MCP-1 to 15.1+/-0.36 ng/ml. There was a correlation between the decreased levels of lipids and the decreased release of MCP-1 in the patients treated with hypolipemic drugs.The drug-induced decrease in MCP-1 secretion in hyperlipidemic patients suggests that, apart from acting on lipids, the hypolipidemic drugs studied may directly inhibit the activity of monocytes.

OBJECTIVE Hyperlipoproteinemia is one of the factors that are involved in the development of atherosclerosis. One of the mechanisms through which these high plasma lipid levels trigger the formation of atherosclerotic lesions is a change in the expression of adhesion molecules on endothelial and smooth muscle cells. The aim of this study was to evaluate the plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and monocyte chemoattractant protein-1 (MCP-1) in patients with Type IIa (HLP-IIa) and IIb (HLP-IIb) hyperlipoproteinemias. SUBJECTS Twenty patients with HLP-IIa, 20 patients with HLP-IIb and 23 control subjects were studied. To accurately evaluate adhesion molecule levels, we excluded those hyperlipemic patients and control subjects who had an inflammatory disease. METHODS Plasma sICAM-1, sVCAM-1 and MCP-1 levels were measured by the ELISA method. RESULTS sVCAM-1 levels in HLP-IIa and HLP-IIb patients (535 +/- 27 ng/ml and 545 +/- 22 ng/ml, respectively) did not differ significantly from those in the control group (558 +/- 20 ng/ml). sICAM-1 levels were significantly higher in patients with HLP-IIa and HLP-IIb (279 +/- 10 ng/ml and 322 +/- 12 ng/ml, respectively) compared to the control group (226 +/- 10 ng/ml). MCP-1 levels were significantly higher in HLP-IIa and HLP-IIb patients (151 +/- 12 pg/ml vs 154 +/- 12 pg/ml, respectively) compared to healthy controls (98 +/- 4 pg/ml). sICAM-1 levels in the HLP-IIb group were significantly higher than in the HLP-IIa group. CONCLUSION The results of the study suggest that lipid abnormalities affect the levels of adhesion molecules and chemokines in plasma.

Tumor necrosis factor alpha (TNF alpha) secreted by activated macrophages stimulates proliferation and migration of vascular smooth muscle in atherogenesis. Up to now, the effect of fibrates on concentration of TNF-alpha has not been investigated. The aim of this study was to estimate TNF-alpha plasma concentration in healthy subjects before and after fenofibrate therapy in patients with hyperlipoproteinaemia IIb and to correlate their levels with plasma concentration of total cholesterol (TC), low density lipoproteins (LDL) and apolipoprotein B (ApoB).10 patients with hyperlipoproteinaemia IIb were treated with micronized fenofibrate (Lipanthyl 200 m-Fournier) for 1 month. Cytokines levels before and after therapy was measured by the ELISA method with Genzyme kits.The levels of lipid parameters at the onset study were as follows: TC: 265.4 +/- 9.4 mg%, TG: 344 +/- 53 mg%, LDL: 167.2 +/- 4.7 mg%, and ApoB: 1.62 +/- 0.05 g/l. After 1-month therapy with Lipanthyl 200 m the parameters decreased: TC 206 +/- 16 mg% (p0.05), TG: 194 +/- 30 mg% (p0.05), ApoB: 1.43 +/- 0.04 g/l (p0.01), and LDL: 144.4 +/- 12.9 mg% (ns). The decreased level of TC, TG and LDL correlated with the decreased concentration of TNF alpha. Before treatment the TNF concentration was 19.2 +/- 1.6 pg/ml and was higher than the concentration of control subjects (9.9 +/- 1.1 pg/ml, p0.01). After 1-month therapy the level of TNF alpha in blood from patient was 9.2 +/- 1.0 pg/ml (p0.01). The results of this study indicate that the concentrations of TNF alpha in plasma from hyperlipidemic patients are higher than concentrations of healthy subjects. Fenofibrate decreased the levels of this cytokine. This effect may be of significance for the treatment of HLPIIb and of atherosclerosis prevention.

The present study was undertaken to evaluate the efficacy and safety of amlodipine for hypertension treatment in comparison with nifedipine retard.We examined 31 patients with arterial blood pressure approximately 155-165 mmHg/100-105 mm Hg at the beginning of the trial. It was a randomized double-blind, parallel-group trial including two groups of patients. Patients of the first group were given active amlodipine and nifedipine retard placebo during 6 weeks, while the second group was given active nifedipine retard and amlodipine placebo. Statistical analysis was made using the paired Student's t-test, chi-square test and ANOVA test.At end point we observed significant decrease in arterial blood pressure after treatment of both drugs. The treatment with nifedipine retard increased the mean heart rate of patients. Amlodipine therapy in comparison to nifedipine retard did not change the heart rate in treated patients. Safety parameters: SGOT, SGTP, creatinine and others were in laboratory norms ranges.Amlodipine proved to be an effective, more safe and better-tolerated therapeutical alternative for hypertension management than nifedipine retard.

Growing body of evidence explicitly suggests the significant role of inflammatory processes in vascular diseases related to atherosclerosis. Monocytes, present in every phase of atherogenesis, are the principal cells accumulating in atherosclerotic plaque. Monocyte Chemotactic Protein 1 (MCP-1) seems to influence firm adherence of rolling monocytes and infiltration into the artery wall. Although the significant meaning of inflammation in atherogenesis has been proved, potential role of antiinflammatory cytokines remains unknown. Interleukin 10 (IL-10) is a major cytokine of pleiotropic antiinflammatory function known to exert inhibitory effects on monocytes. Recent data emerging from clinical and pathological studies suggest important role of thrombosis and fibrinolytic disorders in atherosclerosis complications especially in coronary heart disease (CHD). Individuals with greater Plasminogen Activator Inhibitor 1 (PAI-1) level are believed to be more susceptible to cardiovascular disease.In our study we measured the plasma levels of MCP-1, IL-10 and PAI-1 in 10 patients with stable angina and 10 healthy subjects. We also estimated its mutual correlations. The plasma levels of MCP-1, IL-10 and PAI-1 were determined with RD kits (ELISA).Plasma levels of MCP-1 were significantly higher (261.5+/-40.7 pg/mL vs 73.3+/-3.05 pg/mL; p0.0002) and also levels of PAI-1 were higher (79.36+/-5.8 ng/mL vs 35.88+/-1.38 ng/mL; p0.0001) in patients with SA compared with the healthy control subjects. Whereas plasma levels of IL-10 were lower (11.6+/-0.5 pg/mL vs 16.5+/-0.4 pg/mL; p0.0001) compared with control group and correlated with both MCP-1 plasma level (r=-0.67; p0.0015) and PAI-1 concentration (r=-0.69; p0.0008).The data obtained confirm the predictive role of cytokines in patients with stable coronary heart disease. The negative correlation of anti-inflammatory IL-10 and PAI-1 was also found.

In recent studies atherosclerosis has often been referred to as immune disease. The atherosclerotic plaque consists of large amounts of inflammatory cells, mainly monocytes/macrophages and T lymphocytes. Macrophages activated by low-density lipoproteins (LDL) secrete tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) in vitro, while LDL-stimulated T lymphocytes release interferon gamma (IFN-gamma). The aim of this study was to estimate the plasma levels of TNF-alpha, IL-1, IFN-gamma in patients with hyperlipoproteinemia IIb (HLPIIb) and atherosclerosis. Since the fibrates are drugs of choice in HLPIIb, we additionally evaluated the effect of fibrates on the cytokine levels.Ten patients with HLPIIb were treated with micronized fenofibrate for 1 month. Before and after treatment, the cytokine levels were measured by the ELISA method. To accurately evaluate cytokine levels, we excluded atherosclerotic patients and control subjects with any inflammatory disease.The initial lipid parameters were as follows: total cholesterol (TC): 6.9 +/- 0.24 mmol/l, triglycerides (TG): 3.44 +/- 0.53 mmol/l, LDL: 4.35 +/- 0.12 mmol/l, and apolipoprotein B (ApoB): 1.62 +/- 0.05 g/l. After 1 month of fenofibrate treatment the parameters decreased to the following values: TC 5.36 +/- 0.42 mmol/l (p0.05), TG 1.94 +/- 0.30 mmol/l (p0.05), ApoB 1.43 +/- 0.04 g/l (p0.01), and LDL 3.75 +/- 0.34 mmol/l (p0.05). Before therapy, TNF-alpha levels in atherosclerotic patients were higher than in control subjects, 19.2 +/- 1.6 and 9.9 +/- 1.1 pg/ml, respectively (p0.01). After 1-month therapy, TNF-alpha levels in atherosclerotic patients were 9.2 +/- 1.0 pg/ml (p0.01). Similarly, the initial levels of IFN-gamma were higher in atherosclerotic patients compared with healthy subjects, 44.4 +/- 5.3, and 19.4 +/- 2.1 pg/ml, respectively (p0.01). After fenofibrate therapy, IFN-gamma levels decreased to 24.8 +/- 2.9 pg/ml (p0.01). The decreased levels of TC, TG, and LDL correlated with the decreased levels of TNF-alpha and IFN-gamma.The results of this study indicate that plasma TNF-alpha and IFN-gamma levels in hyperlipidemic patients are higher than in healthy subjects, and that fenofibrate is effective in decreasing lipids and cytokines in plasma.