Anna Gdula-Dymek

Pleiotropic Effects of Atorvastatin and Fenofibrate in Metabolic Syndrome and Different Types of Pre-Diabetes

OBJECTIVE To compare extra-lipid effects of statins and fibrates in relation to the baseline metabolic status of patients. RESEARCH DESIGN AND METHODS The study involved a group of 242 metabolic syndrome patients with or without pre-diabetes and randomized to atorvastatin, fenofibrate, or placebo. RESULTS Compared with matched healthy subjects, metabolic syndrome patients exhibited higher plasma levels/activities of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, factor VII, plasminogen activator inhibitor 1, and enhanced monocyte cytokine release. These abnormalities were alleviated by both atorvastatin and fenofibrate treatment. CRP-lowering and monocyte-suppressing actions were more pronounced for atorvastatin in subjects with impaired fasting glucose and for fenofibrate in patients with impaired glucose tolerance. CONCLUSIONS The presence of pre-diabetes potentiates metabolic syndrome–induced abnormalities in plasma markers of inflammation and hemostasis and in monocyte secretory function. Both atorvastatin and fenofibrate exhibit multidirectional pleiotropic effects in subjects with metabolic syndrome, the strength of which seem to be partially determined by the type of pre-diabetes.

Effect of Simvastatin and Fenofibrate on Cytokine Release and Systemic Inflammation in Type 2 Diabetes Mellitus With Mixed Dyslipidemia

The aim of our study was to compare the effect of simvastatin and fenofibrate treatment on the secretory function of human monocytes and lymphocytes and on systemic inflammation in type 2 diabetes and to assess whether their coadministration is superior to treatment with only 1 of these drugs. One hundred ninety-six adult patients with recently diagnosed and previously untreated type 2 diabetes and mixed dyslipidemia, complying throughout the study with lifestyle intervention and treated with metformin, were randomized in a double-blind fashion to receive simvastatin (40 mg), fenofibrate (200 mg), simvastatin plus fenofibrate, or placebo for 90 days. Main outcome measurements were monocyte and lymphocyte release of proinflammatory cytokines and plasma levels of C-reactive protein. One hundred ninety patients completed the study. Simvastatin and fenofibrate decreased monocyte release of tumor necrosis factor-α, interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1 and lymphocyte release of interleukin-2, interferon-γ, and tumor necrosis factor-α, which was accompanied by a decrease in plasma C-reactive protein levels. Anti-inflammatory effects of fenofibrate partly correlated with the improvement in insulin sensitivity. Lymphocyte-suppressing, but not monocyte-suppressing, effect was stronger if these 2 agents were administered together. In conclusion, simvastatin and fenofibrate exhibit a similar effect on the secretory function of human monocytes and lymphocytes and on systemic inflammation in type 2 diabetic subjects with mixed dyslipidemia. This effect may be clinically relevant in the prevention of vascular complications in metformin- and diet-treated subjects with newly diagnosed diabetic dyslipidemia.

Hemostatic effects of bezafibrate and ω-3 fatty acids in isolated hypertriglyceridemic patients

This study aimed to compare the effects of ω-3 fatty acids and fibrate treatment on plasma levels and activities of hemostatic risk factors on glucose and lipid metabolism in subjects with isolated hypertriglyceridemia. Seventy-three subjects with elevated triglyceride levels were allocated into one of the following treatment options: bezafibrate (200 mg twice daily), ω-3 fatty acids (1 g twice daily) or placebo. Plasma lipids, glucose homeostasis markers (fasting and 2-h post-glucose load plasma glucose levels and HOMA), as well as plasma levels/activities of fibrinogen, factor VII and PAI-1 were determined at baseline, on the day of randomization, and after 4 and 12 weeks of the treatment. Not only did bezafibrate improve plasma lipids, but it also increased glucose sensitivity and tended to reduce post-glucose loads of plasma glucose. Except for the reduction in plasma triglycerides, ω-3 fatty acids produced no effect on the lipid profile and insulin sensitivity. Both treatment options reduced, to similar extents, plasma levels of fibrinogen and PAI-1 and factor VII coagulant activity. Our study indicates that, although fibrates exhibit more-pronounced metabolic effects than do ω-3 fatty acids, both these treatment options are equipotent in producing a complex beneficial effect on hemostasis in isolated hypertriglyceridemic subjects.

The Effect of Fenofibrate on Lymphocyte Release of Proinflammatory Cytokines and Systemic Inflammation in Simvastatin-Treated Patients with Atherosclerosis and Early Glucose Metabolism Disturbances

This study was designed to investigate whether fibrates produce lymphocyte‐suppressing and systemic anti‐inflammatory effects in statin‐treated pre‐diabetic patients. The study included 47 atherosclerotic patients with the concomitant presence of impaired fasting glucose and impaired glucose tolerance already receiving simvastatin treatment (40 mg daily) who were allocated to one of two groups treated for 90 days with, respectively, fenofibrate (200 mg daily) or placebo. Plasma lipids, glucose homoeostasis markers, plasma high‐sensitivity C‐reactive protein as well as lymphocyte release of pro‐inflammatory cytokines were determined on the allocation day and after 90 days of therapy. Compared with placebo, fenofibrate reduced lymphocyte release of interleukin‐2, interferon‐γ and tumour necrosis factor‐α, which was accompanied by a reduction in plasma C‐reactive protein levels. The results obtained indicate that fenofibrate inhibits lymphocyte secretory function and reduces low‐grade inflammation in patients with both impaired fasting glucose and impaired glucose tolerance. Our findings suggest that the combined treatment with simvastatin and fenofibrate may be a better treatment option than simvastatin alone in this group of patients, particularly in those who are at high risk for cardiovascular events.

Anti‐Inflammatory and Monocyte‐Suppressing Effects of Simvastatin in Patients with Impaired Fasting Glucose

The aim of our study was to compare the effect of simvastatin on systemic inflammation and monocyte secretory function between individuals with impaired fasting glucose (IFG) and patients with isolated hypercholesterolaemia. The study included 25 patients with IFG and 23 patients with hypercholesterolaemia. The lipid profile, fasting and 2-hr post-glucose load plasma glucose levels, homeostatic model assessment (HOMA) ratio, glycated haemoglobin, plasma high-sensitivity C-reactive protein (hsCRP) levels and monocyte release of TNF-α, interleukin-1β, interleukin-6 and MCP-1 were assessed at baseline, and after 30 and 90 days of simvastatin treatment (20 mg/daily). Compared to monocytes of the control patients (22 age-, sex- and weight-matched patients without lipid and glucose metabolism abnormalities), monocytes of the patients with hypercholesterolaemia and patients with IFG released greater amounts of all studied cytokines and exhibited higher plasma levels of hsCRP, with no difference between the two groups of patients. Although in both the patients with hypercholesterolaemia and the patients with IFG simvastatin treatment improved lipid profile, it exhibited no effect on glucose metabolism markers. The drug markedly reduced plasma hsCRP and monocyte secretion of TNF-α, interleukin-1β, interleukin-6 and MCP-1 in a lipid- and glucose-independent manner. Our results indicate that low-grade systemic inflammation and monocyte secretory function are disturbed to a similar degree in the patients with isolated hypercholesterolaemia and in the patients with IFG. They also show that simvastatin is an effective anti-inflammatory drug in patients with isolated early glucose metabolism abnormalities.

Hemostatic effects of simvastatin in subjects with impaired fasting glucose.

The aim of our study was to compare the effect of simvastatin on a range of hemostatic variables in subjects with impaired fasting glucose (IFG) and isolated hypercholesterolemia. We enrolled 28 subjects with IFG, 25 primary hypercholesterolemic patients and 24 age-, sex- and weight-matched control subjects with normal lipid profile and glucose metabolism. The tested parameters (lipid profile, fasting and 2-h post-glucose load plasma glucose levels, the homeostasis model assessment (HOMA) ratio, glycated hemoglobin, the prothrombin and partial thromboplastin time, plasma fibrinogen, PAI-1 levels and factor VII coagulant activity) were determined at baseline and after 4 and 12 weeks of simvastatin treatment (20 mg/daily). Compared to the control subjects, hypercholesterolemic and IFG patients exhibited increased plasma levels of fibrinogen and PAI-1 and increased factor VII activity. PAI-1 was higher in hypercholesterolemic than in IFG patients. Simvastatin improved lipid profile in both groups of patients, but it did not influence glucose metabolism. In both IFG and hypercholesterolemic patients, simvastatin reduced fibrinogen and PAI-1 levels and factor VII activity, and it prolonged the prothrombin and partial thromboplastin time in a lipid- and glucose-independent manner. The main conclusion of our study is that early glucose metabolism abnormalities are associated with disturbed coagulation and fibrinolysis, which contribute to the development and progression of atherosclerosis. Treatment with a lipid lowering agent may bring multidirectional beneficial effects on hemostasis in IFG patients.

Effect of metformin on selected parameters of hemostasis in fenofibrate-treated patients with impaired glucose tolerance

BACKGROUND No previous study has assessed whether the addition of metformin potentiates fibrate action on hemostasis in prediabetic subjects. METHODS Our study included 41 fenofibrate-treated patients with impaired glucose tolerance allocated to either metformin (3 g daily) or placebo. RESULTS Twelve-week treatment with fenofibrate and metformin reduced plasma levels of fibrinogen and PAI-1 and tended to change the other hemostatic markers measured, as well as improved insulin sensitivity. CONCLUSIONS Our results show that high-dose metformin exhibits beneficial effects on coagulation and fibrinolysis in isolated IGT patients treated with a fibrate.

Monocyte‐Suppressing Effect of Bezafibrate but not Omega‐3 Fatty Acids in Patients with Isolated Hypertriglyceridaemia

Fibrates and omega-3 fatty acids have been used for many years in the treatment of increased triglyceride levels. Unfortunately, pleiotropic effects of these agents in patients with isolated hypertriglyceridaemia are poorly understood. The aim of this study was to compare the effect of bezafibrate and omega-3 fatty acids on monocyte cytokine release and systemic inflammation in this type of dyslipidaemia. The study included eighty-seven hypertriglyceridaemic subjects randomly allocated to one of three groups, treated respectively with bezafibrate (200 mg twice daily), omega-3 fatty acids (1 g twice daily) or placebo for 90 days. Eighty-three subjects completed the study. Apart from improvement in lipid profile, bezafibrate treatment reduced plasma high-sensitivity C-reactive protein (hsCRP) levels and inhibited monocyte release of interleukin-6, interleukin-1β, monocyte chemoattractant protein-1 and tumour necrosis factor-α. Bezafibrate action on plasma hsCRP and monocyte cytokine release was lipid-independent but correlated with drug-induced improvement in insulin sensitivity. Omega-3 fatty acids reduced plasma triglycerides, but did not induce any significant changes in monocyte secretory function and plasma hsCRP. Our study suggests that bezafibrate is superior to omega-3 fatty acids in reducing systemic inflammation and in producing monocyte-suppressing effects. Anti-inflammatory actions of bezafibrate may contribute to the clinical effectiveness of fibrates in the prevention and treatment of isolated hypertriglyceridaemia.

Comparison of the effects of hypolipidemic treatment on monocyte proinflammatory cytokine release in men and women with type 2 diabetes and atherogenic dyslipidemia.

INTRODUCTION Statins and fibrates reduce monocyte release of proinflammatory cytokines, but it remains unknown whether this effect is sex dependent. MATERIAL AND METHODS We retrospectively analysed age-, weight-, and lipid-matched populations of type 2 diabetic patients of both sexes, who, because of atherogenic dyslipidaemia, were treated with simvastatin (40 mg daily), fenofibrate (200 mg daily), or simvastatin plus fenofibrate. Monocyte release of tumour necrosis factor α (TNF-α), inteleukin-1β, interleukin-6, and monocyte chemoattractant protein-1 (MCP-1), as well as circulating levels of high-sensitivity C-reactive protein (hsCRP) and free fatty acids (FFA) were assessed separately for men and women before and after 12 weeks of treatment. RESULTS Baseline monocyte release of TNF-α, interleukin-1β, interleukin-6, and MCP-1, as well as plasma hsCRP and FFA levels were comparable in both sexes. Simvastatin, fenofibrate, and simvastatin/fenofibrate combination therapy reduced monocyte release of TNF-α, inteleukin-1β, interleukin-6, and MCP-1, with no difference between the treatment groups. The impact of simvastatin and fenofibrate administered alone on monocyte cytokine release and systemic inflammation did not differ between the men and women. The effect of simvastatin/fenofibrate combination therapy on monocyte release of interleukin-6 and MCP-1 was more pronounced in the male population. The impact of simvastatin administered together with fenofibrate on TNF-α, interleukin-1β, and hsCRP was also stronger in the men than in the women, but the difference did not reach the level of significance. CONCLUSIONS The obtained results suggest that sex differences determine the strength of the monocyte-suppressing effect of simvastatin/ /fenofibrate combination therapy in type 2 diabetic patients with atherogenic dyslipidaemia.

The effect of hypolipidemic treatment on monocyte cytokine release in different age groups of patients with type 2 diabetes and atherogenic dyslipidemia

INTRODUCTION Although both statins and fibrates have been found to reduce monocyte cytokine release, no study has investigated whether the effect of hypolipidaemic agents depends on age. MATERIAL AND METHODS This study retrospectively analysed the results of 65 patients with type 2 diabetes and atherogenic dyslipidaemia, complying with lifestyle intervention, and receiving metformin. These patients were then treated with simvastatin (40 mg daily), micronized fenofibrate (200 mg daily), or simvastatin plus fenofibrate. Tumour necrosis factor-alpha (TNF-alpha), inteleukin-1beta, interleukin-6, and monocyte chemoattractant protein-1 (MCP-1) release, as well as circulating levels of high-sensitivity C-reactive protein (hsCRP), were determined separately for patients aged between 20 and 50 years and between 51 and 75 years before the study and after 12 weeks of hypolipidaemic treatment. RESULTS Older adults were characterised by higher monocyte release of TNF-alpha and interleukin-6, as well as higher circulating levels of hsCRP, than the younger subjects. The decrease in monocyte release of all investigated cytokines and in plasma hsCRP was similar in both age groups. In turn, the effect of fenofibrate, alone or in combination with simvastatin, on TNF-alpha, interleukin-6, and hsCRP, but not on interleukin-1beta and MCP-1, was stronger in patients aged between 50 and 75 years, and correlated with an improvement in insulin sensitivity only in this age group. CONCLUSIONS Our results suggest that age may partially determine monocyte-suppressing and systemic anti-inflammatory effects of fenofibrate.