Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effective treatment of dyslipidemia improves prognosis. Statin therapy has been documented to decrease the cardiovascular event rate in the setting of elevated low-density lipoprotein (LDL) cholesterol levels and coronary heart disease, but most patients are not treated to the target (LDL <or=100 mg/dL) set by the National Cholesterol Education Program. The triglyceride level is also being increasingly recognized as an important mediator in the process of progressive atherosclerosis and cardiovascular events. Studies suggest the target level for triglycerides should be the same as for LDL cholesterol levels-- no more than 100 mg/dL. In order to achieve these LDL and triglyceride levels, combination therapy is required frequently. Probably the most effective combination for mixed dyslipidemia is a statin with niacin. The use of adjunctive omega-3 supplementation also should be considered especially for patients with elevated triglyceride levels. Other adjunctive agents including sitostanol ester (in the form of a margarine) and a well-tolerated second generation bile acid sequestrant that will lower LDL cholesterol an additional 10% to 18% and will be available soon.
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PMID:Combination drug therapy for dyslipidemia. 1112 91

The triglyceride (TG) level is one of several lipid parameters that can aid prediction of coronary heart disease (CHD) risk. An elevated plasma TG level is strongly associated with an increased risk of CHD. Hypertriglyceridemia, the second most common dyslipidemic abnormality in hypertensive subjects after increased low-density lipoprotein cholesterol (LDL-C), is defined by the National Cholesterol Education Programme (NCEP) as a fasting TG level of > 2.26 mmol/l (> 200 mg/dl) and is recognised as a primary indicator for treatment in type IIb dyslipidemia. Raised TG levels can be present in individuals at risk for CHD when the total cholesterol is normal. However, not all individuals with raised TG levels have increased risk of CHD. Factors such as: diet, age, lifestyle, and a range of medical conditions, drug therapy and metabolic disorders, can all affect the TG level. In some of these circumstances, other factors protect against the risk of CHD, and can minimise or negate the effect of the risk factors present. Although TG reducing therapy has been shown to be associated with an improved clinical outcome, more research is needed to determine whether this is an independent effect of TG reduction or an effect of normalising the overall lipid profile in hypertriglyceridemic patients. Further trials are required to quantify the clinical benefits of lowering TG to 'target' levels and to confirm targets defined by NCEP-II (shown in Table 1). The role of TG in CHD pathogenesis is thought to involve several direct and indirect mechanisms, such as effects on the metabolism of other lipoproteins, transport proteins, enzymes, and on coagulation and endothelial dysfunction. More research is required to fully elucidate the role of TG, the ways in which it can influence other risk factors and the mechanism of its own more direct role in the atherogenic process. Patients with hypertriglyceridemia have been shown to respond well to dietary control and to the use of lipid lowering drugs such as 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG CoA) reductase inhibitors (known as statins), fibrates and nicotinic acids. However, recent retrospective real-life clinical studies show that only 38% of patients receiving some form of lipid-lowering therapy achieved NCEP-defined LDL-C target levels, demonstrating the need for the use of more aggressive treatment. In hypertriglyceridemic patients, the newer statins, cerivastatin and atorvastatin, have shown comparable efficacy in reducing TG compared with the older statins. Achieving NCEP target lipid levels has been shown to reduce the risk of cardiovascular disease in dyslipidemic individuals, including high-risk patient groups such as those with additional risk factors, existing heart disease, diabetes mellitus and metabolic syndrome. Although the latest clinical studies investigating combination therapies, i.e. dual therapy with both a statin and a fibrate, have demonstrated them to be effective for overall control of lipid parameters and reducing coronary events, it is not yet clear whether this offers any significant advantage over monotherapy. Results from ongoing longer-term end-point clinical studies may provide further information in this area and consequent reviews of primary care management policies for dyslipidemia. Statin monotherapy may be a reliable option for primary care treatment of dyslipidemia (including hypertriglyceridemia).
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PMID:Hypertriglyceridemia: a review of clinical relevance and treatment options: focus on cerivastatin. 1146 48

Cardiovascular disease is the most important cause of morbidity and mortality in patients with type 2 diabetes. Endothelial dysfunction predicts cardiovascular outcome. Type 2 diabetes is characterized by endothelial dysfunction, which may be caused by dyslipidemia. Statin therapy restores endothelial function in hyperlipidemic patients. Therefore, we hypothesize a beneficial effect of atorvastatin on NO-dependent vasodilation in patients with type 2 diabetes and mild dyslipidemia (low density lipoproteins >4.0 mmol/L and/or triglycerides >1.8 mmol/L). We evaluated the effect of intensive lipid lowering (4 weeks of 80 mg atorvastatin once daily) on vasoreactivity in 23 patients with type 2 diabetes by using venous occlusion plethysmography. Twenty-one control subjects were matched for age, sex, body mass index, blood pressure, and smoking habits. The ratio of blood flows in the infused (measurement [M]) and noninfused (control [C]) arm was calculated for each recording (M/C ratio), and M/C% indicates the percentage change from the baseline M/C ratio. Serotonin-induced NO-dependent vasodilation was significantly blunted (52+/-30 versus 102+/-66 M/C%, P<0.005), and nitroprusside-induced endothelium-independent vasodilation was modestly reduced (275+/-146 versus 391+/-203 M/C%, P<0.05) in patients with type 2 diabetes compared with control subjects. Despite significant reduction of total cholesterol, low density lipoproteins, and triglycerides (5.8+/-1.0 to 3.2+/-0.6 [P<0.0001], 4.1+/-1.1 to 1.8+/-0.7 [P<0.0001], and 2.2+/-1.3 to 1.4+/-0.5 [P<0.05] mmol/L, respectively), no effect on NO-dependent (59+/-44 M/C%) and endothelium-independent (292+/-202 M/C%) vasodilation was demonstrated. These data suggest that intensive lipid lowering by atorvastatin has no effect on NO availability in forearm resistance arteries in type 2 diabetic patients. Other factors, such as hyperglycemia, may be a more important contributing factor regarding impaired vasoreactivity in this patient group.
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PMID:Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. 1200 93

Patients with combined dyslipidemia are at greatly increased coronary heart disease (CHD) risk. The threat of rhabdomyolysis with dual pharmacologic treatment (hepatic hydroxymethyl glutaryl coenzyme A [HMG-CoA] reductase inhibitors plus fibric acid derivatives) has tended to limit therapy in patients with combined dyslipidemia to a choice of one or the other drug. Judgment of the potential benefits of either agent has rarely taken into account their effect on the postprandial accumulation of highly atherogenic, triglyceride (TG)-rich, remnant lipoprotein particles (RLPs). Because this information could be of substantial clinical relevance, we addressed this question in patients with type 2 diabetes and combined dyslipidemia by comparing the effects of gemfibrozil versus HMG-CoA reductase inhibitors (statins) on both fasting and postprandial lipid and lipoprotein concentrations. For this purpose, 22 patients with type 2 diabetes and combined dyslipidemia were randomized to treatment with either a statin or gemfibrozil for 3 months. Glycemic control was similar in both groups at baseline and did not change in response to treatment. Baseline lipid and lipoprotein concentrations were also similar in the 2 treatment groups, but the responses to therapy were quite different. Statin-treated patients had a statistically significant decrease in low-density lipoprotein (LDL) cholesterol concentration (156 mg/dL to 96 mg/dL, P <.001), whereas there was no change in patients treated with gemfibrozil. In contrast, there was a statistically significant decrease (P <.05) in plasma TG concentrations (116 mg/dL) in gemfibrozil-treated individuals, without any change in subjects treated with statins. However, the decrease in total integrated postprandial plasma RLP response measured hourly from 8 AM to 4 PM was not different in patients treated with either gemfibrozil (-43%) or statins (-34%). These results indicate that statin treatment, in addition to its beneficial effect on hypercholesterolemia, was as effective as gemfibrozil in reducing postprandial accumulation of triglyceride-rich, atherogenic RLPs in patients with type 2 diabetes and combined dyslipidemia. As such, the clinical utility of statin monotherapy in the treatment of combined dyslipidemia may have been underestimated.
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PMID:Comparison in patients with type 2 diabetes of fibric acid versus hepatic hydroxymethyl glutaryl-coenzyme a reductase inhibitor treatment of combined dyslipidemia. 1237 Aug 58

Patients with combined dyslipidemia are at high risk for coronary artery disease and often require combination drug therapy to achieve lipid levels recommended by the US National Cholesterol Education Program's third Adult Treatment Panel (ATP III). In addition to recommendations for low-density lipoprotein (LDL) cholesterol and triglyceride levels, ATP III established non-high-density lipoprotein (HDL) cholesterol goals for individuals with triglycerides >or=2.26 mmol/L (>or=200 mg/dL). It also introduced certain criteria for the diagnosis of the metabolic syndrome, a clustering of risk factors (abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure, impaired fasting glucose) that increases cardiovascular risk and is common in patients with combined dyslipidemia. Statin monotherapy has been shown to benefit these patients, and additional benefit may be obtained by combination therapy that provides greater reductions in both LDL cholesterol and triglycerides as well as greater increases in HDL cholesterol. However, combining a statin with either niacin or a fibrate may increase the risk for myopathy and therefore requires careful monitoring and evaluation of the risk-benefit ratio for each patient. Moreover, combination therapy may be associated with increased drug costs and decreased patient compliance. Recently developed agents that may improve the effectiveness of combination therapy include ezetimibe-a cholesterol absorption inhibitor-and a formulation that combines extended-release niacin and lovastatin in a single pill. Clinical trials are needed to determine the optimal treatment in patients with combined dyslipidemia.
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PMID:Combination therapy for combined dyslipidemia. 1246 37

The significant age-adjusted decline in cardiovascular mortality that has occurred over the past three decades is multifactorial. However, the advent of statin therapy has markedly facilitated the optimization of dyslipidemia in patients at risk for coronary events. Statin therapy has proven to be effective in reducing morbidity and mortality in large-scale primary and secondary prevention trials. As with all therapies, the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co A) reductase inhibitors is not without clinical risks. Myopathy, albeit uncommon, was one of the earliest clinical problems associated with statin therapy. Recent data from the large-scale statin mega-trials have clarified the quantitative clinical risk-benefit relationship of reductase inhibitors relative to the induction of muscle toxicity. Histopathologic studies have clarified the potential role of statins in the syndrome of myalgias and normal creatine kinase levels. However, the precise mechanism of statin-associated muscle toxicity remains unclear and is potentially related to genetically mediated muscle enzyme defects, drug interactions, intracellular depletion of metabolic intermediates, and intrinsic properties of the statins per se.
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PMID:Statins and myotoxicity. 1257 93

The use of niacin, alone and in combination, for the treatment of dyslipidemia in patients with or at risk for coronary heart disease (CHD), is discussed. Cardiovascular risk is independently predicted not only by high levels of low-density lipoprotein cholesterol (LDL-C), but also low levels of high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides. Moreover, we now understand that LDL particle size and number are associated with differing levels of atherogenicity. Metabolic syndrome, increasingly being recognized as a marker for elevated cardiovascular risk, is associated with atherogenic dyslipidemia characterized by low HDL-C, high triglycerides, and small, dense LDL particles. Controlled clinical studies have shown that niacin therapy effectively increases HDL-C and lowers triglyceride and LDL-C levels while causing a shift toward larger, less atherogenic LDL particles. Niacin, alone or in combination, prevents progression and promotes regression of coronary atherogenic lesions and significantly reduces CHD-related morbidity and mortality. Statin monotherapy causes modest increases in HDL-C and decreases triglycerides, while more potently reducing LDL-C. Combinations of lipid-modifying agents may better address the full spectrum of lipoprotein abnormalities in some patients. Investigations have shown that combining statin therapy with niacin results in additive improvement in the major lipids and lipoproteins and improves clinical outcome. With recently broadened treatment recommendations, it seems likely that combination therapy will be increasingly deemed the appropriate choice for addressing a range of lipid abnormalities.
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PMID:Advances in the understanding and management of dyslipidemia: using niacin-based therapies. 1290 Oct 26

Statin/fibrate combinations are frequently used to treat mixed dyslipidemia. However, these combinations may cause life-threatening drug interactions (e.g. rhabdomyolysis) possibly induced by modifications of cytochrome P450 isozyme activities. Some statins are also transported by P-glycoprotein (Pgp) and may act as inhibitors of this drug efflux pump. So far, nothing is known about possible Pgp modulating effects of fibrates. We tested whether gemfibrozil, fenofibrate, fenofibric acid, and bezafibrate inhibit Pgp in vitro using a calcein acetoxymethylester (calcein-AM) uptake assay and confocal laser scanning microscopy with bodipy-verapamil as substrate in L-MDR1 cells, which overexpress human Pgp. In uptake assays in cells with (L-MDR1) and without (LLC-PK1) human Pgp we also investigated whether these compounds are transported by Pgp. Intracellular concentrations were measured by liquid chromatography tandem mass spectrometry. Of the tested fibrates, only fenofibrate increased calcein-AM uptake into cells indicating an inhibition of Pgp mediated transport by this compound. The potency of fenofibrate (mean+/-SD: 7.1+/-3.2 microM), evaluated by calculating the concentration needed to double baseline fluorescence (f2), was similar to that of simvastatin (5.8+/-1.5 microM), lovastatin (10.1+/-1.0), and verapamil (4.7+/-0.8 microM). For simvastatin and fenofibrate Pgp inhibition was confirmed with confocal laser scanning microscopy. Fenofibrate, fenofibric acid, gemfibrozil, and bezafibrate showed no difference in the cellular uptake between LLC-PK1 and L-MDR1, indicating that the tested fibrates are not Pgp substrates. In conclusion, this study demonstrates that fenofibrate inhibits Pgp in vitro with a potency similar to simvastatin.
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PMID:Influence of lipid lowering fibrates on P-glycoprotein activity in vitro. 1469 41

Statins have been proven to reduce cardiovascular risk, and guidelines for cardiovascular prevention recommend statin therapy in a wide range of patients. However, in spite of the dramatic success in large randomized clinical trials, two thirds of patients administered statins are not protected against cardiovascular events. This has prompted a search for additional targets for therapy. The pandemic of metabolic syndrome and type 2 diabetes has led to a dramatic increase in the prevalence of dyslipidemia. This, in turn, has prompted a resurgence of the search for drugs and algorithms that favorably affect high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) metabolism and function. Fibrates are the best-studied class of agents to be used as an addition to statins since they have also been proven to reduce clinical events as a monotherapy. However, there is a need for large safety trials of statin-fibrate combination therapy. Statin-niacin combination therapy has proven to be safe and effective in altering lipoprotein pattern. Randomized clinical trials and more research on the mechanism of action of niacin are necessary. Inhibitors of cholesterol ester transfer protein and HDL therapy drugs are in early developmental stages, and are the most promising potential additions to the current arsenal.
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PMID:Combination therapy for the treatment of dyslipidemia. 1508 97

Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and the progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated a favorable response to administration of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF (5/6 nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg x kg(-1) x day(-1)) groups and observed for 6 wk. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma lecithin:cholesterol acyltransferase (LCAT) and the hepatic LDL receptor, elevated hepatic acyl-CoA:cholesterol acyltransferase (ACAT), and no change in hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol-to-HDL cholesterol ratio, and hepatic LDL receptor but did not significantly change either plasma total cholesterol, hepatic cholesterol 7alpha-hydroxylase, total ACAT activity, or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol-to-HDL cholesterol ratio, hepatic HMG-CoA reductase activity, and cholesterol 7alpha-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.
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PMID:HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure. 1550 47


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