[Fibrates - the present state of art]. / Fibraty - aktualny stan wiedzy.

Peroxisome proliferator-activated receptor (PPAR)α activators (fibrates) are one of the major group of hypolipidemic agents. Apart from lowering plasma lipid levels, fibrates produce many other favourable effects that may potentially contribute to their clinical effectiveness. Administered to patients with abnormal glucose and lipid homeostasis participating in our studies, these agents reduced monocyte and lymphocyte secretory function, systemic inflammation, hemostasis and normalized adipose tissue function and these effects did not correlate with their lipid-lowering properties. These beneficial pleiotropic effects were observed in patients with mixed dyslipidemia, isolated hypertriglyceridemia, impaired glucose tolerance, metabolic syndrome and type 2 diabetes mellitus and their strength was similar to that of statins. However, large clinical trials assessing fibrate effectiveness in the primary and secondary prevention of cardiovascular diseases provided contrasting results. In our article, we summarise the present state of knowledge on the role of fibrates in the treatment of metabolic disorders, which leads to the conclusion that fibrates are most probably efficient in primary and secondary prevention of cardiovascular diseases, particularly in patients with mixed dyslipidemia and lipid abnormalities coexisting with disorders of carbohydrate metabolism.

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.

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-1ß, 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-1ß, 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-1ß, 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-1ß, 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.

[Fibrates in the light of large clinical trials]. / Fibraty w Swietle duZych badaN klinicznych.

Peroxisome proliferator-activated receptor (PPAR)α activators (fibrates) are one of the major group of hypolipidemic agents, that have been presented to have clinical benefits in prevention and treatment of cardiovascular disorders. Apart from their well-known hypolipidemic properties, fibrates produce other so-called pleiotropic effects, including anti-inflammatory and anti-oxidant action, as well as reduction in procoagulant activity and improvement in endothelial function. These observations are in line with some of the results from large randomised clinical trials, which indicated the benefits from therapy with fibrates other than we could expect from their hypolipidemic properties. Nevertheless, the analysis of these studies supports the argument that patients with mixed dyslipidemia and carbohydrate metabolism disturbances are the group, which benefits the most from fibrate therapy. In this article, particular attention is devoted to the results of the large clinical trials. We try to explain the differences between the results of various studies.

Lymphocyte-suppressing, endothelial-protective and systemic anti-inflammatory effects of metformin in fenofibrate-treated patients with impaired glucose tolerance.

BACKGROUND: No previous clinical study has been designed to assess the additive effect of metformin and a fibrate on lymphocyte secretory function. The aim of our study was to investigate whether metformin produces any effect on lymphocyte cytokine release in fibrate-treated patients with early glucose metabolism abnormalities. METHODS: The study included 80 patients with isolated impaired glucose tolerance and normal plasma lipids who complied with lifestyle modifications and received chronic fenofibrate treatment. These subjects were randomly assigned to 90 days' treatment with either high-dose metformin (3 g daily in three divided doses) or placebo. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and intercellular adhesion molecule-1 levels, as well as lymphocyte release of proinflammatory cytokines were determined before randomization and at the end of the treatment. RESULTS: Beyond improving glucose homeostasis, metformin reduced plasma C-reactive protein levels and lymphocyte release of tumor necrosis factor-α and interferon-γ, as well as tended to reduce interleukin-2 release and plasma intercellular adhesion molecule-1. CONCLUSIONS: Our study shows that metformin potentiates lymphocyte-suppressing, endothelial-protective and systemic anti-inflammatory effects of fenofibrate, and suggests that patients with impaired glucose tolerance may benefit the most from the combined treatment with a fibrate and high-dose metformin.

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.

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.

Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance.

BACKGROUND: Fibrates were found to reduce cytokine release and low-grade inflammation in patients with impaired glucose tolerance. The aim of this study was to investigate whether these effects of fibrates may be potentiated by metformin treatment. METHODS: The study included 43 patients with isolated impaired glucose tolerance and normal plasma lipids who had been treated for at least 6 months with micronized fenofibrate (200 mg daily). These subjects were randomly assigned to 12 weeks' treatment with either high dose metformin (3 g daily in three divided doses) or placebo. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C-reactive protein levels were determined before randomization and at the end of the treatment. RESULTS: Metformin treatment reduced plasma C-reactive protein levels and monocyte release of tumor necrosis factor-α and interleukin-6, as well as tended to reduce monocyte release of interleukin-1ß and monocyte chemoattractant protein-1, which was accompanied by an improvement in insulin sensitivity. CONCLUSIONS: Our results show that high-dose metformin produces monocyte-suppressing and systemic anti-inflammatory effects in fibrate-treated patients with isolated impaired glucose tolerance. This suggests that fibrate-metformin combination therapy may bring clinical benefits to impaired glucose tolerance patients at high cardiovascular risk.

[Beta-adrenolitics in therapy of cardiovascular diseases in patients with type 2 diabetes mellitus]. / Zastosowanie leków beta-adrenolitycznych w terapii schorzen ukladu sercowo-naczyniowego u pacjentów z cukrzyca typu 2.

The recent years have brought about a marked increase in the number of people suffering from carbohydrate metabolism disturbances. This is primarily due to adverse changes in lifestyle, which consists of an improper diet, rich in simple carbohydrates and fats, and low physical activity. An increasing number of patients with diabetes resulted in the growth of a number of individuals suffering from diabetes-related complications, including cardiovascular diseases. Although, the first line treatment of cardiovascular disorders are beta-blockers, for many years their use in diabetic patients was questioned to the extent that diabetes was one of the major contraindication to these agents. These concerns stemmed primarily from the proven negative impact of first generation beta-blockers on carbohydrate metabolism. The aim of this study was to summarize the possibility of beta-blocker applications in type 2 diabetic patients suffering from cardiovascular disorders, which, in a non-diabetic population, are commonly treated with these agents, taking into account the diversity between various classes of beta-blockers. On the basis of published clinical trials and meta-analyses we discuss the impact of this group of agents on the development of new-onset diabetes, worsening of existing diabetes control, and the development and progression of diabetes-induced complications.

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 bezafibrate and omega-3 fatty acids on lymphocyte cytokine release and systemic inflammation in patients with isolated hypertriglyceridemia.

PURPOSE: The aim of this study was to compare the effects of fibrates and omega-3 fatty acids on lymphocyte secretory function and systemic inflammation in patients with isolated hypertriglyceridemia. METHODS: The study included 107 patients with isolated hypertriglyceridemia who received bezafibrate (200 mg twice daily), omega-3 fatty acids (1 g twice daily) or placebo for 12 weeks. The lipid profile, fasting and 2-h post-glucose load plasma glucose levels, homeostasis model assessment index (HOMA), plasma high-sensitivity C-reactive protein (hsCRP) levels and lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α were assessed at baseline, on the day of randomization, and after 4 and 12 weeks of treatment. RESULTS: Both bezafibrate and omega-3 fatty acids reduced plasma triglyceride levels. Bezafibrate additionally decreased total and low-density lipoprotein-cholesterol levels and the HOMA and insignificantly decreased post-glucose load plasma glucose, as well as increased high-density lipoprotein-cholesterol. Bezafibrate treatment was associated with a reduction in lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α, which was accompanied by a reduction in plasma hsCRP levels. Omega-3 fatty acid did not significantly reduce lymphocyte cytokine release and plasma hsCRP. The anti-inflammatory effects of both drugs did not correlate with their action on plasma lipids, but in the case of the former the effect was related to the improvement in insulin sensitivity. CONCLUSION: Our results indicate that bezafibrate is superior to omega-3 fatty acid in inhibiting systemic inflammation and lymphocyte secretory function.

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-1ß, 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.

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-1ß, 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.

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-1ß, 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-1ß, 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.

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.

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.

Growth hormone therapy in children and adults.

Growth hormone (GH) is a polypeptide hormone, secreted by somatotropic cells of the anterior part of the hypophysis. Its application in therapy, first limited to GH deficient children, has now been widened to various other clinical conditions, not necessarily related to short stature. Clinical trials conducted in recent years have proved the safety of its administration in both children and adults. The efficacy of this form of therapy varies, according to different authors, from enthusiastic data to very critical opinions. For many pediatric diseases, such as GH deficiency or Turner syndrome, GH is regarded by many experts, despite the high costs of the therapy, as the first-line treatment. Mounting evidence suggests that GH is safe and effective also in children with chronic renal failure and cystic fibrosis. Recently, it has also been administered to adults with GH deficiency and short bowel syndrome. The aim of this paper is to summarize the current data on GH administration in modern pharmacotherapy. In this paper we have included the results of the recently published studies and discussed not commonly known indications for GH therapy, as well as its experimental administration in both children and adults.

[Growth hormone therapy]. / Terapia hormonem wzrostu.

Growth hormone (GH) is a polypeptide secreted by somatotropic cells of the anterior part of the hypophysis. Its usage was firstly restricted to children with growth hormone deficiency. Because of molecular biology development and greater availability of GH, the range of its therapeutic applications has widened. Apart from supplementary management of GH deficiency in children and adults, nowadays it is commonly used as first-line therapy in many disorders associated with short height. The aim of this paper is to present the exact role of GH in contemporary pharmacotherapy and adverse effects of treatment with GH. We review both well-known and less-commonly known indications for this form of treatment. Suggested dosage and the time of the beginning and duration of therapy are also discussed.