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)

Patients with diabetes mellitus are at higher risk for cardiovascular events than those without diabetes. Furthermore, patients with diabetes have a characteristic 'lipid triad' of low high-density lipoprotein-cholesterol (HDL-C) levels, high triglyceride levels, and normal or slightly raised low-density lipoprotein-cholesterol (LDL-C) levels, with a preponderance of small, dense LDL-C particles. Current guidelines on preventing cardiovascular disease recognize the need not only to reduce LDL-C levels, but also to increase HDL-C and decrease triglyceride levels in diabetic patients. Some clinical trials of HMG-CoA reductase inhibitors (statins) have included large populations of diabetic patients. In some of these trials (such as 4S [Scandinavian Simvastatin Survival Study], CARE [Cholesterol and Recurrent Events] trial, and the HPS [Heart Protection Study]), HMG-CoA reductase inhibitor treatment significantly reduced cardiovascular events in diabetic patients, whereas in other trials (ALLHAT-LLT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial], ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial]) the reductions were not significant. In CARDS (Collaborative Atorvastatin Diabetes Study), the first large HMG-CoA reductase inhibitor study to enroll only patients with type 2 diabetes, atorvastatin reduced cardiovascular events by 37% (p=0.001) compared with placebo. Fibric acid derivatives (fibrates), which are agonists of peroxisome proliferator-activated alpha receptors, exert their effects by altering the transcription of genes encoding proteins that control lipoprotein metabolism. Fibric acid derivatives are a valuable tool in the treatment of dyslipidemia in patients with diabetes, as they reduce plasma triglyceride levels by 30--50%, increase HDL-C levels by 10--15%, and shift the distribution of LDL subfractions towards larger, less atherogenic particles. The DAIS (Diabetes Atherosclerosis Intervention Study), which was conducted exclusively in patients with type 2 diabetes, found that fenofibrate reduces the progression of angiographic coronary artery disease. The VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial) showed that gemfibrozil reduced cardiovascular events in subgroups of diabetic patients. A large clinical event study, FIELD (Fenofibrate Intervention and Event Lowering in Diabetes), which is currently being completed, will provide further information on the value of fenofibrate for the reduction of cardiovascular risk in patients with diabetes.
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PMID:A new perspective in the treatment of dyslipidemia : can fenofibrate offer unique benefits in the treatment of type 2 diabetes mellitus? 1618 99

Stroke is the third leading cause of death in the US and a common cause of long-term disability worldwide. Ischemic strokes, which are often atherothrombotic, account for more than 80% of all strokes. Current stroke prevention focuses on optimizing the treatment of modifiable risk factors, such as hypertension, diabetes and dyslipidemia. The epidemiologic association between serum cholesterol levels and adjusted stroke rates is not as strong as the link between serum cholesterol levels and coronary heart disease. Clinical trials of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), which are potent inhibitors of cholesterol synthesis, have demonstrated, however, a marked reduction in stroke risk in hypercholesterolemic and atherosclerotic individuals, with benefits extending to normocholesterolemic individuals. These findings suggest that statins might have additional effects in stroke protection beyond cholesterol reduction. Because statins inhibit the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway, which are important lipid attachments for intracellular signaling molecules, they might have direct noncholesterol-dependent effects on inflammatory and endothelial cells. Here we discuss data from clinical trials assessing the effects of statins on stroke risk, as well as outline the mechanisms underlying the cholesterol-independent effects of statins and provide evidence-based recommendations for stroke prevention, based on achieved serum cholesterol levels in patients at risk of stroke.
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PMID:Drug Insight: statins and stroke. 1625 69

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.
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PMID:Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. 1625 26

Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis.
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PMID:Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice. 1645 17

While diabetes mellitus is most often associated with hypertension, dyslipidemia, and obesity, these factors do not fully account for the increased burden of cardiovascular disease in patients with the disease. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease and, more specifically, diabetes-associated atherosclerosis. In addition to the recognized metabolic abnormalities associated with diabetes mellitus, upregulation of putative pathological pathways such as advanced glycation end products, the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines have been shown to play a causal role in atherosclerotic plaque formation and may explain the increased risk of macrovascular complications. This review discusses the methods used to assess the development of atherosclerosis in the clinic as well as addressing novel biomarkers of atherosclerosis, such as low-density lipoprotein receptor-1. Experimental models of diabetes-associated atherosclerosis are discussed, such as the streptozocin-induced diabetic apolipoprotein E knockout mouse. Results of major clinical trials with inhibitors of putative atherosclerotic pathways are presented. Other topics covered include the role of HMG-CoA reductase inhibitors and fibric acid derivatives with respect to their lipid-altering ability, as well as their emerging pleiotropic anti-atherogenic actions; the effect of inhibiting the renin-angiotensin system by either ACE inhibition or angiotensin II receptor antagonism; the effect of glycemic control and, in particular, the promising role of thiazolidinediones with respect to their direct anti-atherogenic actions; and newly emerging mediators of diabetes-associated atherosclerosis, such as advanced glycation end products, vascular endothelial growth factor and platelet-derived growth factor. Overall, this review aims to highlight the observation that various pathways, both independently and in concert, appear to contribute toward the pathology of diabetes-associated atherosclerosis. Furthermore, it reflects the need for combination therapy to combat this disease.
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PMID:Diabetes mellitus-associated atherosclerosis: mechanisms involved and potential for pharmacological invention. 1648 46

Calcium channel blockers and HMG-CoA reductase inhibitors are widely used for the management of hypertension and dyslipidemia, respectively. The use of these agents in the prevention and treatment of cardiovascular disease remains largely based on their actions in lowering blood pressure and lipids. Recent clinical trials, however, indicate that certain members of these two drug classes may slow progression of disease to an extent that cannot be solely attributed to risk factor reduction. The proposed mechanisms for such pleiotropic actions include enhancement of endothelial-dependent nitric oxide bioavailability, anti-inflammatory activity, and inhibition of oxidative stress. To understand the basis for such effects, along with potential synergies, we will review the basic and clinical evidence that indicate a broader opportunity for treatment and protection of cardiovascular events by atheroprotection with these agents beyond risk factor management.
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PMID:A rationale for combined therapy with a calcium channel blocker and a statin: evaluation of basic and clinical evidence. 1650 69

Hypertension is associated with an increase in cardiovascular events. Pathophysiological mechanisms of this include endothelial damage/dysfunction, inflammatory activation, insulin resistance, platelet activation and alterations in the coagulation cascade leading to a prothrombotic state. Dyslipidaemia acts synergistically with hypertension in increasing cardiovascular risk. HMG CoA reductase inhibitors (statins) are lipid-lowering drugs and more recently have been shown to have a significant pleiotropic effect on endothelial function, inflammation, platelet activation and coagulation. Statins affect the whole pathophysiology of atherogenesis from deposition to plaque rupture and thrombogenesis because of its pleiotropic effects. Therefore it is intuitive that statins may be of benefit in hypertensive patients with conventionally normal lipid levels by preventing the pathological effects of hypertension. There is an increasing clinical evidence base for statins use in patients with hypertension. In this article, the novel pleiotropic and conventional mechanisms of statins, and clinical data of statin therapy in patients with hypertension are reviewed.
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PMID:Novel concepts of statin therapy for cardiovascular risk reduction in hypertension. 1672 72

Hyperlipidemia can be effectively treated either with niacin or HMG-CoA reductase inhibitor (statin), or a combination of both. Few reports showed the effects of the combination regimen with niacin and statin on hemostatic functions. We conducted a single-center, double-blind, double-dummy, randomized, two-arm study to assess the effects of the niacin extended-release/lovastatin therapy in a fixed-dose formulation and of simvastatin on lipid lowering and two fibrinolytic parameters, fibrinogen and d-dimer. All patients were enrolled according to NCEP-ATP III guidelines and underwent a placebo run-in period of 4 weeks before being randomized to either niacin extended-release/lovastatin tablets (500/20 mg) once daily (n = 36) or simvastatin capsule (20 mg) once daily (n = 34). After 16 weeks of treatment, both groups of patients showed significantly reduced low-density lipoprotein cholesterol and total cholesterol (LDL-C, p < 0.001 and < 0.001, respectively, p = 0.159 between the groups; TC, p < 0.001 and < 0.001, respectively, p = 0.018 between the groups). Both drugs were well tolerated. Only in the group treated with niacin extended-release/lovastatin was fibrinogen concentration significantly reduced after treatment (2.48 +/- 0.65 to 1.99 +/- 0.62 g/L, p = 0.008). No difference was found with d-dimer in either group. This study shows that both niacin extended-release/lovastatin and simvastatin are effective and well-tolerated lipid-lowering drugs in Taiwanese patients with dyslipidemia. A combinational treatment with niacin extended-release/lovastatin may provide additional benefit in fibrinolysis.
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PMID:Randomized comparative study of the effects of treatment with once-daily, niacin extended-release/lovastatin and with simvastatin on lipid profile and fibrinolytic parameters in Taiwan. 1679 62

Today atherosclerotic diseases are among the most important causes of death in the world. Epidemiological, clinical, genetic, experimental and pathological studies have clearly shown the role of lipoproteins in atherosclerosis. LDL is the major atherogenic lipoprotein and has been defined as the primary target of lipid lowering treatment by NCEP. Although the level of LDL, the primary target in the treatment of dyslipidemia, has been set as below 100 mg/dl in coronary heart diseases (CHD) and CHD risk equivalents, this level has been pulled down to below 70 mg/dl for the group defined as very high risk group by the ATP (Adult Treatment Panel) guide that has been updated following the new clinical studies. As we already know, cholesterol is the precursor of glucocorticoids, mineralocorticoids and sex steroids, besides being a structural component of the cell membrane. Both adrenal and non-adrenal (ovarian+testicular) all steroid hormones are primarily synthesized using the LDL-cholesterol in the circulation. In addition to this, there is 'de novo' cholesterol synthesis in both the adrenals and gonads controlled by the HMG-CoA reductase enzyme. A third pathway, which under normal circumstances has little contribution as compared to the first two, is the use of circulatory HDL-cholesterol by the adrenal and gonadal tissues for the synthesis of steroids. Our knowledge on extremely lowered LDL levels is quite limited. However, since statins both decrease circulatory LDL and inhibit de novo cholesterol synthesis, they are likely to affect the synthesis of steroid hormones.
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PMID:Is lipid lowering treatment aiming for very low LDL levels safe in terms of the synthesis of steroid hormones? 1723 55

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


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