Metabolic and monocyte-suppressing actions of fenofibrate in patients with mixed dyslipidemia and early glucose metabolism disturbances

The aim of this study was to compare the action of fenofibrate on monocyte cytokine release between patients with isolated mixed dyslipidemia and dyslipidemia coexisting with prediabetic states in relationship with its metabolic actions. We compared 96 primary mixed dyslipidemic patients and 29 age-, sex- and weight-matched control subjects with normal lipid profile. Depending on glucose metabolism, dyslipidemic patients were allocated into one of three treatment groups: isolated dyslipidemia, dyslipidemia coexisting with impaired fasting glucose (IFG) and dyslipidemia coexisting with impaired glucose tolerance (IGT). Lipid profile, fasting and 2-h post-glucose load plasma glucose levels, HOMA and monocyte release of interleukin-1β and MCP-1 were assessed at baseline and after 30 and 90 days of micronized fenofibrate treatment (267 mg/daily). Compared to monocytes from control subjects, monocytes of dyslipidemic patients released a greater amounts of interleukin-1β and MCP-1. MCP-1 release was higher in the IFG group than in the remaining groups of dyslipidemic patients. In all groups of dyslipidemic patients, micronized fenofibrate reduced monocyte release of interleukin-1β and MCP-1, and this effect was stronger in prediabetic subjects. Fenofibrate treatment also decreased HOMA in IFG and IGT patients, fasting plasma glucose in IFG subjects and 2-h post-glucose load plasma glucose in IGT patients. The observed differences between the studied groups regarding fenofibrate action on glucose homeostasis and cytokine release suggest that fibrate therapy may bring particular benefits to persons with metabolic syndrome.     

Comparison of micronized fenofibrate and pravastatin in patients with primary hyperlipidemia

Micronized fenofibrate lowers total cholesterol and low-density lipoprotein cholesterol to a similar extent as statins but raises high-density lipoprotein cholesterol and lowers triglycerides to a greater extent. The comparative lipid-modifying efficacy of micronized fenofibrate and pravastatin has not been evaluated in dyslipidemic patients. This prospective, multicenter, randomized trial compared the efficacy of 3 months' treatment with micronized fenofibrate (200 mg once daily) or pravastatin (20 mg once daily) in hypercholesterolemic type IIa and mixed dyslipidemic type IIb patients. Two hundred sixty-five male and female patients (18-75 years) were recruited from 28 European centers, and 151 were analyzed. Micronized fenofibrate was at least as effective as pravastatin in reducing levels of low-density lipoprotein cholesterol and total cholesterol in primary dyslipidemia but was significantly more effective than pravastatin in raising high-density lipoprotein cholesterol (respectively, 13.2% vs. 5.6%; p = 0.0084) and lowering triglycerides (-38.7% vs. -11.8%; p = 0.0001). In type IIa dyslipidemia, micronized fenofibrate was as effective as pravastatin in raising high-density lipoprotein cholesterol (+8.6% vs. +8.0%) but was fivefold more effective in lowering triglycerides (-34.3% vs. -7.2%; p = 0.0001). In type IIb dyslipidemic patients with low baseline high-density lipoprotein cholesterol levels, micronized fenofibrate was 10-fold and nearly 3-fold superior to pravastatin in raising high-density lipoprotein cholesterol and lowering triglycerides, respectively. Micronized fenofibrate may be considered an effective first-line therapy for patients with primary hyperlipidemia, particularly those with type IIb mixed dyslipidemia or type 2 diabetes.     

Beyond Low-Density Lipoprotein

The metabolic syndrome and type 2 diabetes mellitus are both becoming more prevalent, and both increase the risk of cardiovascular disease. Many patients are not receiving appropriate treatment for the type of dyslipidemia that commonly occurs in these disorders--the so-called 'atherogenic lipid triad' of high serum triglyceride levels, low serum high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, dense, low-density lipoprotein cholesterol (LDL-C) particles. All of the processes involved in atherogenesis can be exacerbated by insulin resistance and/or the metabolic syndrome. Hypertriglyceridemia is a strong predictor of coronary heart disease. There is also an inverse relationship between serum levels of HDL-C and triglycerides in diabetic patients, with low serum HDL-C levels possibly representing an independent risk factor for cardiovascular disease. Small, dense, LDL-C particles are also highly atherogenic as they are more likely to form oxidized LDL and are less readily cleared. Insulin resistance, which is central to the metabolic syndrome and type 2 diabetes mellitus, leads to high levels of very low-density lipoprotein (VLDL), which contain a high concentration of triglycerides, resulting in high serum triglyceride levels and low serum HDL-C levels. Even though modification of the atherogenic lipid triad is probably one of the most effective methods of reducing cardiovascular risk, therapy for diabetic dyslipidemia is often directed to first lowering serum LDL-C levels with a HMG-CoA reductase inhibitor. This may leave substantial excess risk for cardiovascular disease in patients with these types of dyslipidemia. The results of recent trials evaluating HMG-CoA reductase inhibitors have been mixed, with two showing no significant effect on cardiovascular outcomes in subgroups of diabetic patients. The recent CARDS (Collaborative Atorvastatin Diabetes Study) showed that atorvastatin can reduce cardiovascular events in a trial specifically designed for a diabetic population, though the population had to have at least one other risk factor in addition to diabetes mellitus. Fibric acid derivatives, such as fenofibrate, bezafibrate and gemfibrozil, are potentially well suited to the treatment of dyslipidemia that is generally associated with type 2 diabetes mellitus and the metabolic syndrome, as they are usually more effective than HMG-CoA reductase inhibitors for normalizing serum levels of HDL-C and triglycerides. Promising results have been obtained from several trials of fibric acid derivatives including the BIP (Bezafibrate Infarction Prevention) study and the VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial; gemfibrozil). The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, a clinical outcomes trial specifically designed to evaluate fenofibrate in a large population of patients with type 2 diabetes mellitus, many of whom have the metabolic syndrome, is underway. The FIELD trial results should shed light on the efficacy and safety of fenofibrate in reducing cardiovascular morbidity in diabetic and metabolic syndrome patients and on the safety profile of combination therapy with fenofibrate and a HMG-CoA reductase inhibitor.     

High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists

Dyslipidemia, a major risk factor for cardiovascular disease, may be directly linked to diabetic hyperglycemia and insulin resistance. An appropriate dyslipidemic animal model that has diabetes would provide an important tool for research on the treatment of diabetic dyslipidemia. Ten days of high fat feeding in golden Syrian hamsters resulted in a significant increase in insulin resistance and baseline serum lipid levels accompanied by a pronounced dyslipidemia. Thirteen days of treatment with fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) selective agonist, produced a dose-dependent decrease in serum lipid levels. The pattern observed was characterized by lowered very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) and raised high-density lipoprotein (HDL) cholesterol in a fashion similar to that seen in man. Diabetic conditions were also significantly improved by fenofibrate with a normalization of impaired glucose tolerance and an improvement of insulin sensitivity during an oral glucose tolerance test. These data suggest that fenofibrate may correct not only the dyslipidemia but also the insulin resistance caused by a high fat diet, and the high fat fed hamster may be a good animal model for research on the treatment of diabetic dyslipidemia with PPARalpha selective agonists.     

Hemostatic effects of fenofibrate in patients with mixed dyslipidemia and impaired fasting glucose

Our study aimed to compare the effect of fenofibrate on hemostasis between patients with isolated impaired fasting glucose (IFG) and isolated mixed dyslipidemia and to examine the action of this agent on glucose and lipid metabolism. Twenty-two IFG and 23 mixed dyslipidemic patients were treated for 90 days with micronized fenofibrate (267 mg/day) and were compared with 22 age-, sex- and weight-matched control subjects without lipid and glucose metabolism abnormalities. The lipid profile, fasting and 2-h post-glucose challenge glucose levels, HOMA and glycated hemoglobin as well as the plasma levels/activities of fibrinogen, factor VII and PAI-1 were determined at the beginning and after 30 and 90 days of treatment. Compared to the control subjects, mixed dyslipidemic and IFG patients exhibited increased plasma levels of fibrinogen and PAI-1 as well as increased factor VII activity. Fibrinogen, factor VII and PAI-1 were higher in mixed dyslipidemic than IFG subjects. Not only did fenofibrate improve plasma lipids, but it also increased glucose sensitivity and normalized the IFG- and mixed dyslipidemia-induced changes in coagulation and fibrinolysis. Our study shows that IFG is associated with abnormal hemostasis, which is disturbed to a lesser extent in IFG than in mixed dyslipidemia. Fenofibrate seems to produce a complex beneficial effect on hemostasis in this group of patients.     

Effect of micronized fenofibrate and losartan combination on uric acid metabolism in hypertensive patients with hyperuricemia.

It has been reported that micronized fenofibrate and losartan can significantly decrease serum uric acid levels by augmenting uric acid excretion. We undertook this study to evaluate the effects of the combination treatment with micronized fenofibrate and losartan in nondiabetic hypertensive dyslipidemic patients with hyperuricemia (serum uric acid, >7 mg/ dl). A total of 25 patients (15 men, 10 women) aged 21-66 years was studied. In all patients, serum lipid parameters, including Lp(a), fibrinogen, and uric acid levels, as well as fractional excretion of uric acid (FEUA) were obtained before treatment, 8 weeks after micronized fenofibrate treatment (200 mg daily), and 8 weeks after combination therapy with micronized fenofibrate (200 mg daily) and losartan (50 mg daily). Fenofibrate alone significantly decreased total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, Apo B, Lp(a), fibrinogen, and uric acid levels (from 7.6+/-0.55 to 5.6 +/-0.5 mg/dl; p < 0.0001) and increased high-density lipoprotein (HDL) cholesterol, Apo A1, and FEUA (from 6.5+/-1.8% to 12.2+/-4%; p < 0.0001). The addition of losartan beyond the decrease in blood pressure values did not significantly alter serum metabolic parameters. However, a small additional decrease in serum uric acid levels (from 5.6+/-0.5 to 4.9+/-1 mg/dl; p < 0.05) was found because of a further increase in FEUA (from 12.2+/-4% to 14+/-5.5%; p < 0.05). It is concluded that the combination of micronized fenofibrate and losartan is useful for the management of patients with multiple metabolic abnormalities, including hyperuricemia.     

Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus

INTRODUCTION: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy. AREAS COVERED: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin-fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial. EXPERT OPINION: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.     

Fenofibrate

Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL-C levels, and promoting a shift to larger low-density lipoprotein particles. In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline. In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy. Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms. In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels.     

Synergistic improvement in insulin resistance with a combination of fenofibrate and rosiglitazone in obese type 2 diabetic mice

Peroxisome proliferator-activated receptor (PPAR) α, which is abundant in the liver, increases lipoprotein lipase activity, resulting in a decrease of triglyceride (TG) levels. PPARγ, which is abundant in adipose tissue, stimulates adipocyte differentiation and adipogenesis, and results in an increase in insulin sensitivity. Fenofibrate, a PPARα agonist, is commonly used to treat dyslipidemia, and rosiglitazone, a PPARγ agonist, is effective in improving glycemic control. To examine the synergistic effects of rosiglitazone in combination with fenofibrate, an obese type 2 diabetes mellitus (DM) mouse model was established by the combined administration of streptozotocin and nicotinamide and fed on a high-fat diet (35% of energy as fat) for 3 weeks. The mice had significantly higher plasma glucose concentrations and insulin resistance, as examined by an oral glucose tolerance test and insulin challenge test compared with normal mice. After establishing a dose-response curve for each drug, the drugs were orally administered for 3 weeks either alone or in combination. After individual administration of fenofibrate, HDL cholesterol levels significantly increased, and plasma glucose and TG levels decreased in obese type 2 DM mice. The individual administration of rosiglitazone showed increased insulin resistance (QUICKI). However, HDL cholesterol and TG levels were not significantly changed. In a combination of fenofibrate at 25 mg/kg and rosiglitazone at 1.25 mg/kg there was a decrease in plasma glucose and TG levels, and a combination of fenofibrate at 50 mg/kg and rosiglitazone at 2.5 mg/kg showed an increase in plasma HDL cholesterol levels. Moreover, parameters related to insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) were improved significantly. Thus, our results show that combination therapy with lower doses of fenofibrate and rosiglitazone ameliorates the type 2 DM condition to a greater extent than high doses of either individual monotherapy.     

Micronized Fenofibrate in Dyslipidemia

▲ The prodrug fenofibrate, a synthetic phenoxy-isobutyric acid derivative, is rapidly hydrolyzed in vivo to form fenofibric acid, which alters plasma lipid levels by activating the peroxisome proliferator-activated receptor α. ▲ The micronized fenofibrate 200mg capsule formulation, and the recently developed micronized fenofibrate 160mg tablet formulation, are bioequivalent. ▲ Micronized fenofibrate 200 mg/day (capsules) increased high density lipoprotein cholesterol (HDL-C) levels significantly from baseline in up to 7098 patients with various dyslipidemias in noncomparative studies. ▲ Micronized fenofibrate 200 mg/day (capsules) produced significantly greater elevations in HDL-C levels than a variety of HMG-CoA reductase inhibitors in small, randomized, double-blind and nonblind studies in patients with dyslipidemia (n = 91 to 227). This formulation of fenofibrate and gemfibrozil produced similar increases in HDL-C levels in a randomized, double-blind study (n = 234). ▲ Micronized fenofibrate 160mg once daily (tablet) increased HDL-C levels significantly from baseline by 10.6 to 14.5% in patients with type IIa or IIb dyslipidemia (n = 353) in two noncomparative studies. Additionally, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and LDL-C to HDL-C and TC to HDL-C ratios were lowered significantly from baseline. ▲ The tablet and capsule formulations of fenofibrate were both generally well tolerated in two noncomparative studies in 375 or 9884 patients. In double-blind, placebo-controlled trials in a total of 804 patients, the pooled incidences of individual adverse events were generally similar with fenofibrate and placebo.     

Extralipid effects of micronized fenofibrate in dyslipidemic patients

The aim of this study was to evaluate the levels of lipid and extralipid parameters in patients with atherogenic dyslipidemia. We investigated the lipid-lowering therapeutic efficacy of fenofibrate and its extralipid influence on oxidized low-density lipoprotein (oxLDL), C-reactive protein (CRP), Fibrinogen, factor VII and plasminogen activator type 1 (PAI-1) during 1-month treatment. Fourteen individuals with HLPIIb were treated with micronized fenofibrate (267 mg/d) for 1 month. The control group included twelve volunteers. Lipidograms were determined with enzymatic kits. ELISA method was used to measure oxLDL and PAI-1. Plasma CRP levels were measured spectrophotometrically. Fibrinogen and factor VII serum levels were evaluated with automatic coagulometer. After 1-month therapy with micronized fenofibrate, we observed a significant reduction of total cholesterol (TC) (277.2 to 217.8 mg/dl, p < 0.05), LDL (183.6 to 129.4 mg/dl, p < 0.05), trigliceryde (TG) (316.7 to 220.6 mg/dl, p < 0.05), oxLDL (68.7 +/- 5.5 to 39.7 +/- 3.7 U/l, p < 0.001) and increase in high-density lipoprotein (HDL) (35.1 to 41.9 mg/dl, p < 0.05). Fibrate treatment also decreased CRP(5.81 +/- 0.26 to 5.08 +/- 0.06 mg/l, p < 0.001), PAI-1 (120.4 +/- 9.7 to 84.7 +/- 5.9 ng/ml; p < 0.05), fibrinogen (3.65 +/- 0.17 to 3.44 +/- 0.16 g/l, ns) and factor VII (159.7% +/- 56.7 to 141% +/- 42.4, ns). The micronized fenofibrate at a daily dose of 267 mg demonstrated a highly beneficial effect on all lipid parameters and advantageous influence on inflammatory and thrombogenic plasma risk factors in patients with dyslipidemia HLPIIb.     

Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance,metabolic syndrome and type 2 diabetes mellitus

Introduction: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy.

Areas covered: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin–fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial.

Expert opinion: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.     

Pharmacologic treatment of type 2 diabetic dyslipidemia

Patients with diabetes mellitus have a higher risk for cardiovascular heart disease (CHD) than does the general population, and once they develop CHD, mortality is higher. Good glycemic control will reduce CHD only modestly in patients with diabetes. Therefore, reduction in all cardiovascular risks such as dyslipidemia, hypertension, and smoking is warranted. The focus of this article is on therapy for dyslipidemia in patients with type 2 diabetes. Patients with the metabolic syndrome (insulin resistance) share similarities with patients with type 2 diabetes and may have a comparable cardiovascular risk profile. Diabetic patients tend to have higher triglyceride, lower high-density lipoprotein cholesterol (HDL), and similar low-density lipoprotein cholesterol (LDL) levels compared with those levels in nondiabetic patients. However, diabetic patients tend to have a higher concentration of small dense LDL particles, which are associated with higher CHD risk. Current recommendations are for an LDL goal of less than 100 mg/dl (an option of < 70 mg/dl in very high-risk patients), an HDL goal greater than 40 mg/dl for men and greater than 50 mg/dl for women, and a triglyceride goal less than 150 mg/dl. Nonpharmacologic interventions (diet and exercise) are first-line therapies and are used with pharmacologic therapy when necessary. Lowering LDL levels is the first priority in treating diabetic dyslipidemia. Statins are the first drug choice, followed by resins or ezetimibe, then fenofibrate or niacin. If a single agent is inadequate to achieve lipid goals, combinations of the preceding Drugs may be used. For elevated triglyceride levels, hyperglycemia must be controlled first. If triglyceride or HDL levels remain uncontrolled, pharmacologic agents should be considered. Fibrates are slightly more effective than niacin in lowering triglyceride levels, but niacin increases HDL levels appreciably more than do fibrates. Unlike gemfibrozil, niacin selectively increases subfraction Lp A-I, a cardioprotective HDL. Niacin is distinct in that it has a broad spectrum of beneficial effects on lipids and atherogenic lipoprotein subfraction levels. Niacin produces additive results when used in combination therapy. Recent data suggest that lower dosages and newer formulations of niacin can be used safely in diabetic patients with good glycemic control. Current evidence and guidelines mandate that diabetic dyslipidemia be treated aggressively, and lipid goals can be achieved in most patients with diabetes when all available products are considered and, if necessary, used in combination.     

Effects of fibrates on plasma prothrombotic activity in patients with type IIb dyslipidemia.

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.     

Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia

Micronised fenofibrate is a synthetic phenoxy-isobutyric acid derivative (fibric acid derivative) indicated for the treatment of dyslipidaemia. Recently, a new tablet formulation of micronised fenofibrate has become available with greater bioavailability than the older capsule formulation. The micronised fenofibrate 160mg tablet is bioequivalent to the 200mg capsule. The lipid-modifying profile of micronised fenofibrate 160mg (tablet) or 200mg (capsule) once daily is characterised by a decrease in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, a marked reduction in plasma triglyceride (TG) levels and an increase in high-density lipoprotein cholesterol (HDL-C) levels. Micronised fenofibrate 200mg (capsule) once daily produced greater improvements in TG and, generally, in HDL-C levels than the hydroxymethylglutaryl coenzyme A reductase inhibitors simvastatin 10 or 20 mg/day, pravastatin 20 mg/day or atorvastatin 10 or 40 mg/day. Combination therapy with micronised fenofibrate 200mg (capsule) once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions from baseline than micronised fenofibrate alone in TC and LDL-C levels. Similar or greater changes in HDL-C and TG levels were seen in combination therapy, compared with monotherapy, recipients. Micronised fenofibrate 200mg (capsule) once daily was associated with significantly greater improvements from baseline in TC, LDL-C, HDL-C and TG levels than placebo in patients with type 2 diabetes mellitus enrolled in the double-blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [> or =3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo. Micronised fenofibrate has also shown efficacy in patients with metabolic syndrome, patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia and patients with dyslipidaemia secondary to heart transplantation. Micronised fenofibrate was generally well tolerated in clinical trials. The results of a large (n = 9884) 12-week study indicated that gastrointestinal disorders are the most frequent adverse events associated with micronised fenofibrate therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, micronised fenofibrate improves lipid levels in patients with primary dyslipidaemia; the drug has particular efficacy with regards to reducing TG levels and raising HDL-C levels. Micronised fenofibrate is also effective in diabetic dyslipidaemia; as well as improving lipid levels, the drug reduced progression of coronary atherosclerosis in patients with type 2 diabetes mellitus. The results of large ongoing studies (e.g. FIELD with approximately 10 000 patients) will clarify whether the beneficial lipid-modifying effects of micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.     

Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)alpha activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFalpha (types IIa and IIb dyslipidemias) and interleukin-1beta (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFalpha and interleukin-1beta, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFalpha and interleukin-1beta production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARalpha activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.     

代谢综合征患者血清脂联素水平与胰岛素抵抗的相关性研究

目的:探讨代谢综合征患者血清脂联素水平与胰岛素抵抗的关系。方法:选取代谢综合征患者35例,另选健康对照组20例,所有实验对象空腹采血离心取血清测定脂联素、胰岛素、血糖、胰岛素敏感性指数、胰岛素抵抗指数。结果:与对照组相比,代谢综合征组血清脂联素水平、胰岛素敏感性指数显著降低(P<0.01),血清胰岛素、血糖显著升高(P<0.01)。在代谢综合征组中,血清脂联素与胰岛素、血糖、胰岛素抵抗指数呈负相关,与胰岛素敏感性指数呈正相关(P<0.05)。结论:低血清脂联素水平与胰岛素抵抗密切相关。     

糖尿病合并促甲状腺激素、甲状腺激素异常28例临床分析

目的分析糖尿病合并甲状腺功能减退或低三碘甲状腺原氨酸（T3）综合征鉴别诊断与治疗。方法对照28例糖尿病合并甲状腺功能减退或低三碘甲状腺原氨酸（T3）综合征患者临床治疗前后血糖、血脂、甲状腺激素水平变化。结果糖尿病合并高胆固醇血症、甲状腺功能减退患者，仅用L型甲状腺素钠片替补治疗，胆固醇恢复正常者占60％，空腹及餐后2h血糖完全正常者20％，餐后2h血糖水平下降70％；糖尿病合并低T3综合征，同时分别合并高胆固醇血症、高三酰甘油血症、酮症酸中毒（DKA）、糖尿病肾病（DA），经控制血糖、血脂，积极治疗DKA及DA后，T3恢复正常。结论甲状腺功能减退可致高胆固醇血症，血脂代谢紊乱而产生胰岛素抵抗，引发2型糖尿病。甲状腺素激素替补治疗纠正甲减后，糖代谢紊乱也可纠正；糖尿病合并低T3综合征，经纠正血糖、血脂代谢紊乱、治疗各种并发症后，甲状腺激素水平也逐渐恢复正常。     

Predictive values of metabolic syndrome in children

Metabolic syndrome is a clinical term encompassing risk factors (obesity, insulin resistance, dyslipidemia and hypertension), which yield an increased risk for the development of diabetes mellitus type 2 and cardiovascular disorders in adolescence. Two sets of criteria for diagnosing metabolic syndrome were applied, the criteria for adults, specifically adapted for children, and the criteria defined by the International Diabetes Federation (IDF). A reliability analysis was conducted; sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) of applying certain criteria of both definitions of metabolic syndrome. Metabolic syndrome in adolescents was diagnosed much more frequently using the specific criteria (41%) in comparison to the IDF criteria (22%). Using the specific criteria for children and adolescents, it was established that the HDL cholesterol was the most specific and had the largest PPV. Using the IDF criteria for diagnosing metabolic syndrome, the reliability analysis established that the highest PPV was recorded with the elevated level of triglycerides. The specific criteria have been found to be more efficient in diagnosing metabolic syndrome in adolescents. The highest predictive value was displayed by dyslipidemic disorders, hypertriglyceridemia and hypo HDL cholesterolemia.     

Effect of monthly atorvastatin and fenofibrate treatment on monocyte chemoattractant protein-1 release in patients with primary mixed dyslipidemia

The aim of this study was to compare the effect of 30-day treatment with atorvastatin and fenofibrate on monocyte release and plasma levels of monocyte chemoattractant protein-1 (MCP-1). We studied 52 atherosclerotic patients with primary mixed dyslipidemia and 16 age-, sex-, and weight-matched control subjects with asymptomatic atherosclerosis. Dyslipidemic patients enrolled into the study were randomly divided into three groups, simultaneously treated with atorvastatin (20 mg/d, n = 18), fenofibrate (267 mg/d, n = 16), or placebo (n = 18). Plasma lipid-profile and content of MCP-1, and monocyte release of this chemokine were measured at baseline and after 30 days of therapy. Compared with the control subjects, dyslipidemic patients exhibited the increased plasma levels and monocyte MCP-1 release. Atorvastatin and fenofibrate not only improved lipid profile but also decreased monocyte secretion of this chemokine. Moreover, hypolipemic agents slightly reduced its plasma levels. MCP-1-lowering effect of atorvastatin and fenofibrate did not correlate with the lipid-lowering potential of these agents. Our results suggest that atorvastatin and fenofibrate produce their antiinflammatory effect partially via inhibiting monocyte release of MCP-1. The treatment-induced reduction in its secretion may contribute to the clinical effectiveness of statins and fibrates in the therapy for atherosclerosis and other chronic fibroproliferative diseases.