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)

Smoking is a major cause of chronic obstructive pulmonary disease (COPD) and cardiovascular disorders, including coronary heart disease (CHD) and peripheral arterial disease. Smoking-induced inflammation and other risk factors like dyslipidemia cause vascular endothelial damage via oxidative stress, and a vicious cycle with the characteristics of atherosclerosis ensues. Inflammatory cytokines stimulate hepatic acute-phase protein production, and C-reactive protein is now used widely to assess inflammation in the arterial wall. Smoking is associated with many alterations in lipids and lipoproteins, and is also prothrombotic. Global risk assessment, which determines the absolute risk for developing CHD in 10 years, is used widely to determine who should receive lipid-lowering therapy. Major CHD risk factors include age, sex, smoking, blood pressure, lipoproteins, and cholesterol, but COPD is not among them. Future studies should determine the absolute risk for developing CHD in patients with COPD. The 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are used widely to treat and prevent cardiovascular disease. The statins may also produce other beneficial pleiotropic effects, including increased nitric oxide and prostacyclin, antithrombosis, and decreased inflammation, perhaps indicating utility in the therapy for COPD. Efforts are currently underway to determine if such antiinflammatory effects are independent of or in addition to simply lowering low-density lipoprotein cholesterol.
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PMID:Cardiovascular disease in chronic obstructive pulmonary disease. 1611 68

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.
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PMID:Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates. 1611 45

HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors (statins) have been shown to reduce serum cholesterol and cardiovascular morbidity and mortality. The mechanisms of these beneficial effects are reviewed. Altered inflammatory responses and improved endothelial function mediated by statins are thought to be, in part, responsible for the reduction in cardiovascular events. It has not been well established whether statins confer similar benefits to the kidney. In this review, we critically consider the available data whereby dyslipidemia mediates renal dysfunction by modulating the inflammatory response to diverse cytokines. We also review the emerging database suggesting that statins may modulate renal dysfunction by altering the response of the kidney to dyslipidemia, particularly in patients with end-stage renal disease (ESRD) and post-kidney transplant.
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PMID:HMG-CoA reductase inhibitors and the kidney. 1615 74

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was the first trial of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) to assess the benefits of lipid lowering in the primary prevention of coronary heart disease (CHD) in patients with hypertension who were not deemed to have dyslipidemia by conventional measures. A total of 19,342 patients with hypertension and > or =3 cardiovascular risk factors, but without CHD, were enrolled in ASCOT. Of these, 10,305 patients with a serum cholesterol level of < or =250 mg/dL (< or =6.5 mmol/L) were randomized to either atorvastatin (10 mg/day) or placebo in the ASCOT lipid-lowering arm (ASCOT-LLA). Follow-up was planned for an average of 5 years. The ASCOT-LLA was stopped after 3.3 years owing to the superiority of atorvastatin 10 mg over placebo in reducing the primary end point of nonfatal myocardial infarction (MI) and fatal CHD. Patients receiving atorvastatin experienced a significant reduction in total cholesterol (50 mg/dL [1.3 mmol/L]) and low-density lipoprotein cholesterol (46 mg/dL [1.2 mmol/L]) levels after 1 year compared with those who received placebo. Cholesterol lowering with atorvastatin was associated with a highly significant reduction in the primary end point of nonfatal MI and fatal CHD (36%, P = 0.0005). The observed benefit was consistent across the secondary end points and the 18 prespecified subgroups. The ASCOT-LLA findings have influenced lipid-lowering guidelines and support the concept that treatment strategies to reduce cardiovascular disease should be based on the assessment of all cardiovascular risk factors, rather than on numerical thresholds of individual risk factors, to determine treatment strategies.
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PMID:Lipid-lowering therapy and the patient with multiple risk factors: what have we learned from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)? 1635 1

The incidence of type 2 diabetes mellitus is expected to increase dramatically over the next decade. Patients with type 2 diabetes are at a much greater risk for cardiovascular disease (CVD) than are nondiabetic individuals. Consequently, the treatment of CVD risk factors is a healthcare priority in this patient population. Dyslipidemia is a major cardiovascular (CV) risk factor in patients with type 2 diabetes, and it is characterized by elevated triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, and a preponderance of small, dense low-density lipoprotein (LDL) particles. Subgroup analyses of clinical trial data suggest that treatment of the entire range of lipid abnormalities may reduce CV risk in this patient population. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the best therapy for LDL cholesterol reduction. A number of statin trials have shown significant CV risk reduction through LDL cholesterol lowering in subgroups of patients with diabetes. The recently published Collaborative Atorvastatin Diabetes Study (CARDS), a placebo-controlled trial conducted solely in patients with type 2 diabetes, terminated 2 years earlier than its anticipated length owing to the significant reduction in number of CV events observed in patients randomized to receive low-dose atorvastatin versus placebo. These results suggest that low-dose statin therapy with atorvastatin results in significant reduction of CV events in patients with type 2 diabetes without prior CVD or high LDL cholesterol levels. Based on this evidence, patients with type 2 diabetes may be candidates for statin therapy regardless of LDL cholesterol level and in the absence of a previous CV event.
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PMID:Benefits of lipid-lowering therapy in patients with type 2 diabetes mellitus. 1635 2

Atherogenic dyslipidemia is one of the major components of the metabolic syndrome, a complex cluster of several risk factors within a single patient that according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III includes at least 3 of the following: large waist circumference, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose levels, which are directly related to the incidence of coronary heart disease. Atherogenic dyslipidemia clinically presents as elevated serum triglyceride levels, increased levels of small dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL-C. An important component of atherogenic dyslipidemia is central obesity, which is defined as increased waist circumference and has recently been identified as a chief predictor of the metabolic syndrome in certain patients. Another recent study found that both body mass index and waist circumference were highly predictive of eventual development of the metabolic syndrome. Because atherogenic dyslipidemia usually precedes the clinical manifestation of the metabolic syndrome, strategies to treat it are the focus of pharmacologic intervention. For example, the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, commonly known as statins, benefit hypercholesterolemic patients who have atherogenic dyslipidemia that is associated with the metabolic syndrome. Pioglitazone, an antidiabetic agent that acts primarily by decreasing insulin resistance, improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. The investigational agent, rimonabant--a centrally and peripherally acting, selective cannabinoid type-1 receptor blocker--is the first therapy developed for managing several cardiovascular risk factors at one time. Rimonabant has shown promise in attacking atherogenic dyslipidemia from several vantage points by affecting glucose, HDL-C, triglycerides, and waist circumference in patients who are prone to atherogenic dyslipidemia.
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PMID:The metabolic basis of atherogenic dyslipidemia. 1647 58

This report reviews data on the development of proteinuria in patients with chronic kidney disease who are treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for dyslipidemia. Although subgroup analyses of statin trials have shown cardiovascular benefits in subjects with chronic kidney disease, concern about statin-induced proteinuria remains high. Experimental studies have suggested that the proteinuria seen with statin treatment results from the inhibition of receptor-mediated endocytosis, the likely mechanism of protein uptake in proximal tubular cells. Transient proteinuria may signify little more than the effective inhibition of cholesterol synthesis at this site. The blockade of protein trafficking in tubular cells is thought to reduce inflammation, slow fibrosis, and diminish proteinuria in the long term. Post hoc analyses of large clinical trials in subjects without overt renal disease have generally supported this notion, showing that statins most benefit patients with the greatest baseline renal deficits. Statins have also been shown to preserve glomerular filtration rate and reduce proteinuria in subjects with nondiabetic renal disease. In conclusion, in the absence of prospective, randomized trials in renally impaired patients, the collective evidence indicates that statin therapy may slow the decrease in renal function that generally attends atherosclerotic disease. The incidence of proteinuria with potent statins is only 1% to 2% when these drugs are given in recommended doses. Several large trials are currently under way to examine the safety and efficacy of statins in renally compromised patients at high risk for cardiovascular disease.
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PMID:Effects of statins on renal function. 1649 Apr 50

Safety has become a central issue in the management of dyslipidemia with statins. A review of New Drug Applications (NDAs) and the US Food and Drug Administration (FDA) Web site was conducted for all 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, with a major focus on cerivastatin and rosuvastatin. The findings provide insight into the incidence of adverse events for this class of drugs and support the significant benefits of statins relative to associated risks. These data delineate the nature of statin associated liver, muscle, and renal adverse events. Although transaminase levels increase in a dose-related fashion with statins, a definitive correlation between statin therapy and hepatotoxicity is not supported by statin NDA data. Statin-induced myopathy is a relatively rare event (1 in 1,000) and rhabdomyolysis is even rarer (1 in 10,000). The cerivastatin NDA, along with its supplementary NDA, was the first to demonstrate a clear statin dose-response relation with myopathy and a threshold effect above which myotoxicity increases significantly. Proteinuria was identified as a consequence of statin therapy with data from the rosuvastatin NDA, and subsequent analysis suggests a class effect that is dose related but transient. Studies in cell culture suggest the mechanism is a pharmacologic effect on the proximal renal tubule. The available evidence suggests no clear renal toxicity with currently approved statins, because no declines in renal function or glomerular filtration rate have been documented over time. Overall, currently marketed statins have a very favorable benefit-to-risk relation with respect to liver, muscle, and renal issues.
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PMID:Statin safety: lessons from new drug applications for marketed statins. 1658 28

The large administrative databases of health plans contain information on drug-related medical adverse events (AE) and constitute an increasingly powerful tool for the assessment of drug safety. We conducted a retrospective observational study using an administrative managed care claims database covering 9 million members from diverse regions of the United States. Patients aged >or=18 years who received >or=2 prescriptions for lipid-lowering drugs between July 1, 2000 and December 1, 2004 were included in the study. Hospitalizations with diagnosis codes (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9]) related to muscle, kidney, and liver were determined for patients exposed to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), fibrates, extended-release niacin, cholesterol absorption inhibitors, or statin combination therapy. A total of 473,343 patients contributed 490,988 person-years of monotherapy and 11,624 person-years of combination dyslipidemia therapy. Rates of hospitalization due to AEs in patients on monotherapy with currently available statins were similar, whereas the incidence of hospitalization for muscle disorders increased 6.7-fold with cerivastatin therapy. Patients who received a lipid-lowering medication with a concomitant cytochrome P450 3A4 (CYP3A4) inhibitor had a 6-fold increased rate of muscle disorders, including rhabdomyolysis. Hypertension was associated with a 5-fold increase in both muscle and renal events, whereas patients with diabetes mellitus had a 2.5-fold increased risk of renal events. No hospitalized cases of the index AEs were observed in study subjects during the 6-month period before initiation of the lipid-lowering drug. Statin monotherapy as currently prescribed is generally well tolerated and safe.
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PMID:Statin safety: an assessment using an administrative claims database. 1658 31

The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.
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PMID:Statins for diabetic cardiovascular complications. 1684 42


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