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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic syndrome consists of a cluster of metabolic disorders, many of which promote the development of atherosclerosis and increase the risk to develop cardiovascular disease. The metabolic syndrome is characterized by atherogenic dyslipidemia (elevated triglycerides, increased small dense low-density lipoproteins, and decreased high-density lipoproteins), hypertension, insulin resistance and obesity. To decrease the risk of cardiovascular disease events decreasing body weight by ingesting a healthy diet, increasing physical activity, cessation of smoking and managing dyslipidemia are recommended. Pharmacological treatment of dyslipidemia is based on different drug classes. For LDL-cholesterol-lowering mainly statins and for triglyceride-lowering mainly fibrates are used. In primary and secondary prevention trials of heart disease they have shown to reduce the incidence of coronary artery disease or coronary events by 25-60 percent. Statins reduce mainly LDL-cholesterol levels by competitive inhibition of HMG-CoA reductase but have also shown to reduce fasting and postprandial triglyceride levels. Fibrates effectively reduce fasting and postprandial lipemia, shift the distribution of LDL particles towards less dense particles and increase HDL-cholesterol. Thus fibrates particularly address components of the metabolic syndrome and features of diabetic dyslipidemia. However studies still are needed showing definite evidence on differential therapy in lipid lowering based on prospective controlled trials with endpoints of macro- and microangiopathy in diabetic patients.
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PMID:Treatment of dyslipoproteinemia in the metabolic syndrome. 1145 42

Compelling evidence from meta-analysis of a number of clinical studies on a large aggregate of patients has established an increased level of triglycerides as an independent risk factor for atherosclerotic heart disease. The finding of triglyceride-rich lipoproteins in human atheromata has provided substantial pathophysiologic evidence for a direct role in atherogenesis. Hypertriglyceridemia is commonly embedded in the context of a metabolic syndrome that includes central obesity, insulin resistance, low levels of HDL cholesterol, and often hypertension. Hypertriglyceridemia also appears to underlie the phenomenon of small dense LDL in most instances. Therapeutic interventions must be directed at underlying obesity, insulin resistance, and diabetes when present, as well as addressing metabolic determinants of dyslipidemia per se. Diet, exercise, weight loss, and avoidance of alcohol are the cornerstones of treatment. The choice of medication should be based on the lipoprotein phenotype. Niacin, fibric acid derivatives, and omega-3 fatty acids are most useful in treating severe hypertriglyceridemia. HMG-CoA reductase inhibitors are useful in some phenotypes with moderately increased triglyceride levels. Evidence from a number of clinical trials indicates that mitigation of risk of coronary heart disease, and possibly stroke, can be effected by reducing levels of plasma triglycerides.
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PMID:A risk factor for atherosclerosis: triglyceride-rich lipoproteins. 1179 72

Rosuvastatin, a new statin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG-CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome p450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug-drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Dose-ranging studies in hypercholesterolemic patients demonstrated dose-dependent effects in reducing low-density lipoprotein cholesterol (LDL-C) (up to 63%), total cholesterol, and apolipoprotein (apo) B across a 1- to 40-mg dose range and a significant 8.4% additional reduction in LDL-C, compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has also been shown to be highly effective in reducing LDL-C, increasing high-density lipoprotein cholesterol (HDL-C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia, rosuvastatin has been shown to produce large decreases in LDL-C at starting doses, thus reducing the need for subsequent dose titration, and to allow greater percentages of patients to attain lipid goals, compared with available statins. The substantial LDL-C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. In addition, rosuvastatin's effects in reducing triglycerides, triglyceride-containing lipoproteins, non-HDL-C, and LDL-C and increasing HDL-C in patients with mixed dyslipidemia or elevated triglycerides should be of considerable value in enabling achievement of LDL-C and non-HDL-C goals in the numerous patients with combined dyslipidemias or metabolic syndrome who require lipid-lowering therapy. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended-release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins. A large, long-term clinical trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.
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PMID:Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. 1248 Dec 2

Plasma levels of high-density lipoprotein-cholesterol (HDL-C) are a powerful independent cardiovascular risk factor, bearing an inverse relationship with atherosclerotic cardiovascular disease (with risk rising sharply when levels are <1.04 mmol/L). Apart from its protective role in atherosclerosis, HDL-C increases fibrinolysis, is an antioxidant to low density lipoprotein-cholesterol (LDL-C), and decreases platelet aggregability. Up to a third of patients with atherosclerotic cardiovascular disease have 'desirable' plasma levels of total cholesterol but low HDL-C levels. Benefits of treating low plasma HDL-C levels were clearly demonstrated in the Veterans Affairs HDL Intervention Trial (VA-HIT) where gemfibrozil reduced nonfatal infarcts and coronary deaths by 22%. This was achieved by a 6% increase in plasma HDL-C levels, and a 24.5% decrease in plasma levels of triglycerides, without any significant decrease in LDL-C levels. Multivariate analyses revealed the rise in plasma HDL-C levels after treatment, but not decreases in plasma levels of triglycerides or LDL-C, predicted coronary artery disease events. The typical patient under consideration in this article is one with plasma levels of HDL-C <1 mmol/L, LDL-C <3.37 mmol/L [either receiving therapeutic lifestyle changes or or LDL-C-lowering therapy comprising a hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor or bile acid sequestrant] and fasting triglycerides <2.26 mmol/L. We propose this dyslipidemia be classified as Type VI phenotype following the Frederickson and Lees classification. High-risk patients (with >/=2 risk factors for atherosclerotic cardiovascular disease, or 10-year cardiovascular risk >20%), patients with established atherosclerotic cardiovascular disease, or type 2 diabetes mellitus, or metabolic syndrome should receive pharmacotherapy. Plasma HDL-C levels >1.16 mmol/L may be considered optimal and between 1 and 1.16 mmol/L as desirable. Fibric acid derivatives, nicotinic acid, HMG-CoA reductase inhibitors, estrogens, and ethanol (not recommended as therapy) increase plasma HDL-C levels. Nicotinic acid is the most potent agent and recent reports indicate that, in contrast to gemfibrozil, it selectively increases antiatherogenic HDL subfraction, lipoprotein (Lp) AI (without apolipoprotein AII), in patients with low plasma HDL-C levels. An extended-release formulation, administered once daily, has improved the tolerability of nicotinic acid. Recent evidence also indicates that nicotinic acid may effectively correct dyslipidemia in patients with diabetes mellitus without significantly compromising glycemic control. Fibric acid derivatives and estrogen raise plasma HDL-C levels by different mechanisms of action, and these agents may be used with nicotinic acid. Combination therapy (especially HMG-CoA reductase inhibitor and nicotinic acid) should be considered in patients with atherosclerotic cardiovascular disease and low plasma HDL-C levels.
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PMID:Optimal therapy of low levels of high density lipoprotein-cholesterol. 1472 46

Combined hyperlipidemia is increasing in frequency and is the most common lipid disorder associated with obesity, insulin resistance and diabetes mellitus. It is associated with other features of the metabolic syndrome including hypertension, hyperuricemia, hyperinsulinemia and highly atherogenic subfractions of lipoprotein remnant particles including small dense low density lipoprotein-cholesterol. This review examines the mechanisms by which combined hyperlipidemia arises and the various drugs including fibric acid derivatives, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and nicotinic acid which can be used either as monotherapy or in combination to manage it and to improve prognosis from atherosclerotic disease in diabetes mellitus, insulin resistant states and primary combined hyperlipidemia. The therapeutic approach to combined hyperlipidemia involves determination of whether the cause is hepatocyte damage or metabolic derangements. Combined hyperlipidemia due to hepatocyte damage should be treated by attention to the primary cause. In the case of metabolic dysfunction because of imbalance in glucose and fat metabolism, therapy of diabetes mellitus and obesity should be optimised prior to commencement of lipid lowering drugs. Both fibric acid derivatives and HMG-CoA reductase inhibitors can be used in the treatment of combined hyperlipidemia with fibric acid derivatives having greater effects on triglycerides and HMG-CoA reductase inhibitors on LDL-C though both have effects on the other cardiovascular risk factors. There is some evidence of benefit with both interventions in mild combined hyperlipidemias and large scale trials are underway. Fibric acid derivatives and HMG-CoA reductase inhibitor therapy can be combined with care, provided that gemfibrozil is avoided, fibric acid derivatives are given in the mornings and shorter half -life HMG-CoA reductase inhibitors are used at night. Combined hyperlipidemia emergencies occur with predominant hypertriglyceridemia in pregnancy or as a cause of pancreatitis. Therapy in the former should aim to reduce chylomicron production by a low fat diet and intervention to suppress VLDL-C secretion using omega-3 fatty acids. In the latter case, fluid therapy alone and medium chain plasma triglyceride infusions usually reduce levels satisfactorily though apheresis may be required. Blood glucose levels also need aggressive management in these conditions. Combined hyperlipidemia is likely to become an increasing problem with the increase in the prevalence of obesity and diabetes mellitus and needs aggressive management to reduce cardiovascular risk.
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PMID:Drug treatment of combined hyperlipidemia. 1472 15

Rosuvastatin (Crestor, AstraZeneca) is a synthetic statin that represents an advance on the pharmacologic and clinical properties of other agents in this class. Relative to other statins, rosuvastatin possesses a greater number of binding interactions with HMG-CoA reductase and has a high affinity for the active site of the enzyme. Rosuvastatin is relatively hydrophilic and is selectively taken up by, and active in, hepatic cells. Rosuvastatin has the longest terminal half-life of the statins and is only minimally metabolized by the cytochrome P450 (CYP 450) enzyme system with no significant involvement of the 3A4 enzyme. Consistent with this finding is the absence of clinically significant drug interactions between rosuvastatin and other drugs known to inhibit CYP 450 enzymes. In patients with hypercholesterolemia, rosuvastatin 10-40 mg has been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels by 52-63%, as well as increase high-density lipoprotein cholesterol (HDL-C) levels by up to 14% and reduce triglycerides (TG) by up to 28%. Studies have shown that rosuvastatin is superior to atorvastatin, simvastatin and pravastatin in reducing LDL-C and favorably modifying other components of the atherogenic lipid profile. The significant decreases in LDL-C with rosuvastatin treatment should help to improve attainment of lipid goals and reduce the requirement for dose titration. In addition, the effects of rosuvastatin on HDL-C and TG levels will be of benefit in treating patients with abnormalities such as mixed dyslipidemia and the metabolic syndrome. Rosuvastatin is well tolerated, with a safety profile comparable with that of other currently available statins.
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PMID:Rosuvastatin: a new inhibitor of HMG-coA reductase for the treatment of dyslipidemia. 1503 Feb 49

The prevalence of obesity has become increasingly common worldwide, in particular western countries. Obesity, together with insulin resistance, leads to metabolic syndrome in which other coronary risk factors including hyperlipidemia and hypertension cluster in one individual. Hyperlipidemia in metabolic syndrome is characterized increased triglyceride(TG), decreased HDL-C, and small dense LDL, called dyslipidemic triad. Dyslipidemia is attributable to increased flux of free fatty acids to the liver, which promotes TG synthesis, thus VLDL production. Increased VLDL, together with decreased lipoprotein lipase activity due to insulin resistance, causes accumulation of TG-rich lipoproteins, including proatherogenic remnants. Further, increased activities of cholesteryl ester transfer protein and hepatic triglyceride lipase results in low HDL-C and small dense LDL. Initial treatment should be directed to modify life style(weight loss and increased physical activity). Then, pharmacological intervention should be considered when the initial treatment is not fully successful. Fibrate derivatives are considered to be ideal to correct dyslipidemic triad. In addition, potent statins(HMG-CoA reductase inhibitor) can be alternative in metabolic syndrome subjects with elevated LDL-C levels.
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PMID:[Dyslipidemia in metabolic syndrome]. 1520 47

Visceral obesity is frequently associated with high plasma triglycerides and low plasma high density lipoprotein-cholesterol (HDL-C), and with high plasma concentrations of apolipoprotein B (apoB)-containing lipoproteins. Atherogenic dyslipidemia in these patients may be caused by a combination of overproduction of very low density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles, and increased catabolism of HDL-apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance. Weight reduction, increased physical activity, and moderate alcohol intake are first-line therapies to improve lipid abnormalities in visceral obesity. These lifestyle changes can effectively reduce plasma triglycerides and low density lipoprotein-cholesterol (LDL-C), and raise HDL-C. Kinetic studies show that in visceral obesity, weight loss reduces VLDL-apoB secretion and reciprocally upregulates LDL-apoB catabolism, probably owing to reduced visceral fat mass, enhanced insulin sensitivity and decreased hepatic lipogenesis. Adjunctive pharmacologic treatments, such as HMG-CoA reductase inhibitors, fibric acid derivatives, niacin (nicotinic acid), or fish oils, may often be required to further correct the dyslipidemia. Therapeutic improvements in lipid and lipoprotein profiles in visceral obesity can be achieved by several mechanisms of action, including decreased secretion and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. Clinical trials have provided evidence supporting the use of HMG-CoA reductase inhibitors and fibric acid derivatives to treat dyslipidemia in patients with visceral obesity, insulin resistance and type 2 diabetes mellitus. Since drug monotherapy may not adequately optimize dyslipoproteinemia, dual pharmacotherapy may be required, such as HMG-CoA reductase inhibitor/fibric acid derivative, HMG-CoA reductase inhibitor/niacin and HMG-CoA reductase inhibitor/fish oils combinations. Newer therapies, such as cholesterol absorption inhibitors, cholesteryl ester transfer protein antagonists and insulin sensitizers, could also be employed alone or in combination with other agents to optimize treatment. The basis for a multiple approach to correcting dyslipoproteinemia in visceral obesity and the metabolic syndrome relies on understanding the mechanisms of action of the individual therapeutic components.
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PMID:Dyslipidemia in visceral obesity: mechanisms, implications, and therapy. 1528 98

Although elevated low-density lipoprotein (LDL)-cholesterol is a well established coronary heart disease (CHD) risk factor, the ability to adequately discriminate high-risk individuals by this risk factor alone is limited and other metabolic risk variables are known to modulate CHD risk. For instance, it has been reported that the cluster of metabolic disturbances observed among individuals with abdominal obesity, the so-called metabolic syndrome, is associated with a substantially increased risk of CHD. Among the features of the dyslipidaemic profile observed in these individuals, the high triglyceride-low high-density lipoprotein (HDL)-cholesterol dyslipidaemia is predictive of an elevated risk of CHD. Fibric acid derivatives (fibrates) have been used in clinical practice for more than 2 decades as a class of agents known to decrease triglyceride levels while substantially increasing HDL-cholesterol levels, with a limited but significant additional lowering effect on LDL-cholesterol levels. Although the clinical benefits of HMG-CoA reductase inhibitors (statins) have been well documented by primary and secondary prevention trials that justify their widespread use, it was not until the publication of the VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial) that the relevance of identifying HDL-cholesterol as a therapeutic target to reduce the risk of recurrent CHD events was finally confirmed. The clinical benefits of fibrate therapy are especially important in the subpopulation of patients with low HDL-cholesterol levels with the metabolic syndrome, particularly in patients with type 2 diabetes mellitus or in abdominally obese, hyperinsulinaemic patients. Evidence also suggests that there is a 'fibrate effect' that mediates the reduction in CHD risk beyond the favourable impact of these agents on HDL-cholesterol levels. This last notion is consistent with the pleiotropic effects of fibrates which are known to be related to their mechanisms of action. Through peroxisome proliferator-activated alpha-receptors, fibrates have a significant impact on the synthesis of several apolipoproteins (apo) and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Fibrate therapy has been reported to decrease apo CIII levels (a powerful inhibitor of lipoprotein lipase) and increase apo AI levels, as well as to increase lipoprotein lipase activity. Such changes contribute to improve the catabolism of triglyceride-rich lipoproteins, leading to a substantial increase in HDL-cholesterol levels accompanied by a shift in the size and density of LDL particles (from small, dense LDL particles to larger, more buoyant cholesteryl ester-rich LDL). It is proposed that some of these pleiotropic effects could explain some of the clinical benefits of fibrate therapy beyond its HDL-raising properties, particularly among patients with abdominal obesity, hyperinsulinaemia or type 2 diabetes with both low HDL- and low/normal LDL-cholesterol levels.
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PMID:Role of fibric acid derivatives in the management of risk factors for coronary heart disease. 1545 34

1. Expression levels of four key enzymes of cholesterol metabolism, namely 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lanosterol 14-demethylase (CYP51), cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12alpha-hydroxylase (CYP8B1), in metabolic syndrome model rats (SHR/NDmcr-cp) were examined. 2. Decreased expression of CYP51, which may be linked to the development of obesity, was found in the rats. 3. Expression of CYP8B1 was significantly higher in young rats. 4. No substantial change was observed in the mRNA levels of the dominant rate-limiting enzymes of sterol metabolism, namely HMG-CoA reductase and CYP7A1, in the rats. 5. These findings suggest that the expression levels of two key enzymes managing the downstream parts of the cholesterol-metabolizing pathways are altered in the rats, although little change was observed in the expression levels of the dominant rate-limiting enzymes of cholesterol metabolism.
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PMID:Studies on the expression levels of sterol-metabolizing enzymes in the obese model SHR/NDmcr-cp rats. 1564 92


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