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)

Although the effect of apolipoprotein E gene polymorphism on the response to treatment with statins has been studied, the results are conflicting. Moreover, little is known about the possible effect of apolipoprotein E alleles on the response to treatment with fibrates. The purpose of this study was to evaluate the effect of apolipoprotein E polymorphism on lipid-lowering response to treatment with atorvastatin and fenofibrate in patients with different types of dyslipidemia. The study population included 136 patients with heterozygous familial hypercholesterolemia (type IIA dyslipidemia) treated with atorvastatin (20 mg/day) and 136 patients with either primary hypertriglyceridemia (type IV dyslipidemia) or mixed hyperlipidemia (type IIB dyslipidemia) treated with micronized fenofibrate (200 mg/day). Overall, no significant associations were detected between apolipoprotein E genotype and response to treatment with atorvastatin. In patients treated with fenofibrate, significant associations were noted between apolipoprotein E genotype and changes in apolipoprotein B, apolipoprotein E and triglyceride levels. Specifically, in apolipoprotein E2, apolipoprotein E3, and apolipoprotein E4 individuals, apolipoprotein B reductions were 22%, 17%, and 8%, respectively (P = .003); apolipoprotein E reductions were 45%, 20%, and 15%, respectively (P = .006); whereas triglyceride reductions reached 53%, 36%, and 33%, respectively (P = .033). In conclusion, apolipoprotein E genotype had no significant effect on the response to treatment with atorvastatin in patients with heterozygous familial hypercholesterolemia, but in patients with primary hypertriglyceridemia or mixed hyperlipidemia, there was a clear association between apolipoprotein E genotype and response to treatment with fenofibrate.
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PMID:The effect of apolipoprotein E polymorphism on the response to lipid-lowering treatment with atorvastatin or fenofibrate. 1705 35

Asian Indian dyslipidemia is characterized by: borderline high low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B; high triglycerides, low high-density lipoprotein (HDL) cholesterol and apoA1; and high lipoprotein(a) (lp[a]). We performed a controlled multicentric trial in India to evaluate the efficacy and safety of a fixed dose combination of lovastatin and niacin extended release (niacin(ER)) formulation in patients with moderate to severe dyslipidemia. Consecutive subjects that satisfied the selection criteria, agreed to an informed consent, and with no baseline presence of liver/renal disease or heart failure were enrolled in the study. After a 4-week run-in period there were 142 patients with LDL levels > or = 130 mg/dL. Eleven patients were excluded because of uncontrolled hyperglycemia and 131 patients were recruited. After baseline evaluation of clinical and biochemical parameters all subjects were administered lovastatin (20 mg) and niacin(ER) (500 mg) combination once daily. Dose escalation was done on basis of lipid parameters at 8 weeks and in 11 patients increased to lovastatin (20 mg) and niacin(ER) (1000 mg). An intention-to-treat analysis was performed and data was analyzed using nonparametric Wilcoxon signed rank test. Thirteen patients (10%) were lost to follow-up and 4 (3%) withdrew because of dermatological adverse effects: flushing, pruritus, and rash. The mean values of various lipid parameters (mg/dL) at baseline, and at weeks 4, 12, and 24 respectively were: total cholesterol 233.9 +/- 27, 206.3 +/- 27, 189.8 +/- 31, and 174.9 +/- 27 mg/dL; LDL cholesterol 153.4 +/- 22, 127.3 +/- 21, 109.2 +/- 27, and 95.1 +/- 23 mg/dL; triglycerides 171.1 +/- 72, 159.5 +/- 75, 149.2 +/- 45, and 135.2 +/- 40 mg/dL; HDL cholesterol 45.6 +/- 7, 48.9 +/- 7, 51.6 +/- 9, and 53.9 +/- 10 mg/dL; lp(a) 48.5 +/- 26, 40.1 +/- 21, 35.4 +/- 21, and 26.9 +/- 19 mg/dL; and apoA1/apoB ratio 0.96 +/- 0.7, 1.04 +/- 0.4, 1.17 +/- 0.5, and 1.45 +/- 0.5 (p < 0.01). The percentage of decline in various lipids at 4, 12, and 24 weeks was: total cholesterol 11.8%, 18.8%, and 25.2%; LDL cholesterol 17.0%, 28.8%, and 38.0%; triglyceride 6.8%, 12.8%, and 21.0%; lp(a) 17.5%, 26.9%, and 44.5% respectively (p < 0.01). HDL cholesterol and apoA1/apoB increased by 7.2%, 13.1%, and 18.2%; and 7.9%, 21.9%, and 51.6% respectively (p < 0.01). Target LDL levels (< 100 mg/dL in subjects with manifest coronary heart disease or diabetes; < 130 mg/dL in subjects with > 2 risk factors) were achieved in 92 (80.7%) patients. No significant changes were observed in systolic or diastolic blood pressure, blood creatinine, transaminases, or creatine kinase. A fixed dose combination of lovastatin and niacin(ER) significantly improved cholesterol lipoprotein lipids as well as lp(a) and apoA1/apoB levels in Asian Indian dyslipidemic patients. Satisfactory safety and tolerability profile in this population was also demonstrated.
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PMID:Evaluation of efficacy and safety of fixed dose lovastatin and niacin(ER) combination in asian Indian dyslipidemic patients: a multicentric study. 1731 73

In order to characterize the metabolic syndrome it becomes necessary to establish a number of diagnostic criteria. Because of its impact on cardiovascular morbidity/mortality, considerable attention has been focussed on the dyslipidemia accompanying the metabolic syndrome. The aim of this review is to highlight the fundamental aspects of the pathophysiology, diagnosis, and the treatment of the metabolic syndrome dyslipidemia with recommendations to clinicians. The clinical expression of the metabolic syndrome dyslipidemia is characterized by hypertriglyceridemia and low levels of high-density lipoprotein-cholesterol (HDL-C). In addition, metabolic syndrome dyslipidemia is associated with high levels of apolipoprotein (apo) B-100-rich particles of a particularly atherogenic phenotype (small dense low-density lipoprotein-cholesterol [LDL-C]. High levels of triglyceride-rich particles (very low-density lipoprotein) are also evident both at baseline and in overload situations (postprandial hyperlipidemia). Overall, the 'quantitative' dyslipidemia characterized by hypertriglyceridemia and low levels of HDL-C and the 'qualitative' dyslipidemia characterized by high levels of apo B-100- and triglyceride-rich particles, together with insulin resistance, constitute an atherogenic triad in patients with the metabolic syndrome. The therapeutic management of the metabolic syndrome, regardless of the control of the bodyweight, BP, hyperglycemia or overt diabetes mellitus, aims at maintaining optimum plasma lipid levels. Therapeutic goals are similar to those for high-risk situations because of the coexistence of multiple risk factors. The primary goal in treatment should be achieving an LDL-C level of <100 mg/dL (or <70 mg/dL in cases with established ischemic heart disease or risk equivalents). A further goal is increasing the HDL-C level to >or=40 mg/dL in men or 50 mg/dL in women. A non-HDL-C goal of 130 mg/dL should also be aimed at in cases of hypertriglyceridemia. Lifestyle interventions, such as maintaining an adequate diet, and a physical activity program, constitute an essential part of management. Nevertheless, when pharmacologic therapy becomes necessary, fibrates and HMG-CoA reductase inhibitors (statins) are the most effective drugs in controlling the metabolic syndrome hyperlipidemia, and are thus the drugs of first choice. Fibrates are effective in lowering triglycerides and increasing HDL-C levels, the two most frequent abnormalities associated with the metabolic syndrome, and statins are effective in lowering LDL-C levels, even though hypercholesterolemia occurs less frequently. In addition, the combination of fibrates and statins is highly effective in controlling abnormalities of the lipid profile in patients with the metabolic syndrome.
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PMID:Management of dyslipidemia in the metabolic syndrome: recommendations of the Spanish HDL-Forum. 1735 65

Dyslipidemia is defined by abnormal levels of plasma lipoproteins. Several different types of dyslipidemia can be distinguished. An important group of drugs used in the treatment of dyslipidemia are the fibrates. Fibrates serve as agonists for the peroxisome proliferator-activated receptor alpha (PPARalpha), a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. By binding to response elements mostly present in the promoter of target genes, PPARalpha governs the expression of numerous genes involved in a variety of metabolic processes. Activation of PPARalpha results in a reduction of plasma TG levels, which is achieved by: (1) induction of genes that decrease the availability of TG for hepatic VLDL secretion, and (2) induction of genes that promote lipoprotein lipase-mediated lipolysis of TG-rich plasma lipoproteins. The stimulatory effect of PPARalpha on plasma HDL levels in humans, which is opposite to what is observed in mice, appears to be mainly mediated via increased production of APOA1 and APOA2, the apolipoprotein constituents of HDL. Apart from its major actions outlined above, PPARalpha modulates lipoprotein metabolism in several other ways, mostly via direct up-regulation of specific PPARalpha target genes. By taking into account novel insights into the metabolism of plasma lipoproteins and by considering the latest information on PPARalpha-dependent gene regulation, a fresh perspective on the molecular mechanisms underlying the plasma lipoprotein modulating effect of PPARalpha is presented.
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PMID:PPARalpha and dyslipidemia. 1760 18

Tesaglitazar (GALIDA; AstraZeneca, Wilmington, DE) is a dual peroxisome proliferator-activated receptor alpha/gamma agonist previously in clinical development for the treatment of glucose and lipid abnormalities associated with type 2 diabetes mellitus and insulin resistance. This study compared the efficacy of tesaglitazar with that of pioglitazone as adjunctive therapy to atorvastatin in subjects with abdominal obesity and dyslipidemia. In this open-label, 3-way crossover study, 58 subjects received atorvastatin 10 mg once daily in a 6-week run-in period, followed by tesaglitazar 3 mg, pioglitazone 45 mg, or placebo, as adjunctive therapy to atorvastatin, in a randomized sequence for 6 weeks each. Serum triglycerides and other lipids, apolipoproteins, glucose, and insulin concentrations were compared between treatments. Tesaglitazar adjunctive therapy reduced serum triglycerides significantly more from baseline (-1.07 mmol/L) than pioglitazone (-0.33 mmol/L; P = .007) or placebo (-0.09 mmol/L; P < .0001). Tesaglitazar also resulted in significantly greater improvements in free fatty acids, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, low-density lipoprotein particle size, apolipoprotein (apo) B, apo C-III, and the apo B/apo A-I ratio compared with pioglitazone or placebo. Tesaglitazar adjunctive therapy also reduced fasting plasma glucose, fasting plasma insulin, and insulin resistance (homeostasis model assessment index) significantly more than pioglitazone or placebo (P < .0001 for all comparisons). Tesaglitazar was generally well tolerated in combination with atorvastatin, but hemoglobin and absolute neutrophil count decreased and serum creatinine increased more with tesaglitazar than with pioglitazone or placebo. These effects, also shown in previous trials, led to the discontinuation of the clinical development of the drug. In conclusion, the addition of tesaglitazar to a background of atorvastatin therapy further improved the dyslipidemia associated with insulin resistance.
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PMID:The dual peroxisome proliferator-activated receptor alpha/gamma agonist tesaglitazar further improves the lipid profile in dyslipidemic subjects treated with atorvastatin. 1769 74

Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acyl-CoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets.
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PMID:Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. 1800 Sep 63

The aim of the study was to investigate the role of serum C-reactive protein (CRP) level as a risk factor in predicting metabolic syndrome (MS), hypertension, atherogenic dyslipidemia, type 2 diabetes mellitus, and coronary heart disease. We prospectively evaluated 1270 men and 1320 women, aged 30 to 89 years, who had serum CRP determinations and a mean 4.3 years' follow-up. The CRP values were log-transformed for calculations. Metabolic syndrome was defined by the Adult Treatment Panel III criteria modified for male abdominal obesity. Prediction of outcome was performed by excluding from analysis the particular outcome variable existing at baseline examination. Smoking men had higher age-adjusted estimated CRP concentrations (P < .001), whereas smoking women had lower CRP (P = .027) than never smokers. Risk of developing an elevated (> or =2 mg/L) CRP was predicted significantly by baseline CRP in both sexes and by apolipoprotein (apo B), current smoking, and family income in men, when adjusted for 5 further variables. Baseline CRP levels predicted atherogenic dyslipidemia when adjusted for age, baseline dyslipidemia values, and apo B tertiles and predicted incident hypertension independent of age, waist circumference, and smoking status. After adjustment for sex, age, and the 5 MS components, CRP predicted newly developing MS, with a hazard ratio (HR) of 1.16 (95% confidence interval, 1.02-1.32). When adjusted for sex, age, baseline glucose, waist circumference, and apo B tertiles, diabetes was significantly predicted by CRP in women (HR, 1.31) alone. Sex- and age-adjusted CRP level identified also those that progressed to diabetes independent of a fasting glucose >100 mg/dL (HR, 1.39; 95% confidence interval, 1.21-1.59), although not in men. In the prediction of incident coronary heart disease, CRP contributed to 7 established risk factors including waist circumference with a significant 1.18-fold HR. C-reactive protein is both an independent significant predictor and a risk factor of cardiometabolic risk among Turkish adults, additive to MS components, whereby risk is modulated by sex, smoking habit, and apo B.
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PMID:Serum C-reactive protein is an independent risk factor predicting cardiometabolic risk. 1819 Oct 50

Dyslipidaemia is a common and consistent abnormality in insulin resistant subjects with obesity and type 2 diabetes mellitus associated with increased risk of cardiovascular disease. Lipoprotein metabolism is complex and abnormal plasma concentrations can result from alterations in the rates of production and/or catabolism of diverse lipoprotein particles. Our understandings of the dysregulation and therapeutic regulation of lipoprotein transport in insulin resistant states has relied on the application of advances in stable isotope and modelling methods. Dysregulation of lipoprotein metabolism in these circumstances may be caused by a combination of overproduction of VLDL apolipoprotein (apoB) B-100 and VLDL-apoC-III, 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 and accumulation of visceral fat. Several pharmacological treatments, such as statins, fibrates or fish oil can correct the dyslipidaemia by diverse kinetic mechanisms of action, including decreased secretion of apoB and apoC-III, and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. Newer agents, including insulin sensitizers, cholesterol absorption inhibitors, CETP inhibitors, peroxisome proliferator-activated receptor-delta agonists and endocannabinoid-1 receptor blockers, have also been shown to improve plasma lipid and lipoprotein abnormalities in insulin resistant states; their mechanisms of action are at present being investigated. Rimonabant is the endocannabinoid receptor blocker shown to decrease cardiometabolic risk in insulin resistant subjects. The complementary mechanisms of action of different agents support the use of combination regimens in treating dyslipoproteinaemia in subjects with central obesity and type 2 diabetes.
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PMID:Pharmacological regulation of dyslipoproteinaemia in insulin resistant states. 1822 Sep 42

It has been proposed that nephrotic syndrome is a consequence of an imbalance between oxidant/antioxidant statuses. The present study aimed to assess oxidant and antioxidant status in relation to dyslipidemia in children during remission and relapse phases of steroid sensitive nephrotic syndrome (SSNS). The study dealt with 40 children diagnosed as SSNS. They were categorized into two subgroups. The first subgroup included 25 children during remission stage. The second subgroup included 15 children during relapse. Control group consisted of age and gender-matched 15 healthy children. Significantly higher serum levels of malondialdehyde, oxidized LDL, total cholesterol, LDL cholesterol, triglycerides, apolipoprotein A-I, and apolipoprotein-B were observed in patients with SSNS especially in the relapsers. The serum levels of albumin, glutathione peroxidase activity, vitamin C, A, and E, and HDL cholesterol were significantly lower in patients especially among relapsers. In conclusion, a strong relationship between the oxidant/antioxidant status and dyslipidemia is documented in patients with SSNS, especially among relapsers. No normalization of the biochemical indices was observed despite the use of glucocorticoids. Therefore, the combined use of steroid, antioxidant therapy, and lipid lowering therapy can be recommended in such children.
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PMID:Oxidative modification of low-density lipoprotein in relation to dyslipidemia and oxidant status in children with steroid sensitive nephrotic syndrome. 1835 47

Atherosclerosis is an example of an inflammatory disorder. During the acute phase and under inflammatory conditions, high-density lipoprotein (HDL), which is normally anti-inflammatory, can become proinflammatory. Reactive oxygen species generated by several enzyme systems can modify phospholipids and sterols, producing oxidized phospholipids and oxidized sterols that reduce the capacity of HDL to protect against undesirable oxidative modifications of molecules. In animal models of dyslipidemia, diabetes, vascular inflammation, and chronic rejection, it is observed that reducing oxidative and inflammatory pressure will help HDL regain its protective role. One way to accomplish this is through the use of apolipoprotein A-I mimetic peptides, which remove oxidation products from lipoproteins and cell membranes, returning normal structure and function to low-density lipoprotein and HDL. These mimetic peptides markedly reduce atherosclerosis in animal models. Published studies of apolipoprotein mimetic peptides in models of inflammatory disorders other than atherosclerosis suggest that they have efficacy in a wide range of inflammatory conditions.
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PMID:Proatherogenic high-density lipoprotein, vascular inflammation, and mimetic peptides. 1841 73


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