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)

Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia, producing a desirable normalization of a range of cardiovascular risk factors. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a Gi-type G protein-coupled receptor, resulting in the inhibition of adipocyte lipolysis, may contribute. This review describes the identification of this elusive receptor, and outlines the evidence suggesting that this may be the molecular target for the clinical effects of nicotinic acid.
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PMID:Identification of a nicotinic acid receptor: is this the molecular target for the oldest lipid-lowering drug? 1508 92

Nicotinic acid effectively treats each of the common lipid abnormalities found in the metabolic syndrome, and much progress has recently been made in understanding its mechanisms of action. Early concern that nicotinic acid can precipitate or worsen diabetes has been eased with recent trials, which demonstrated its safety and effectiveness in insulin-resistant states. Furthermore, nicotinic acid prevents cardiovascular disease and death in persons with a high prevalence of risk factors for the metabolic syndrome. When used by an experienced physician and taken by a motivated patient, nicotinic acid can be safe and effective in treating the dyslipidemia of the metabolic syndrome.
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PMID:Management of the metabolic syndrome-nicotinic acid. 1526 97

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

Nicotinic acid is a unique cholesterol modifying agent that exerts favorable effects on all cholesterol parameters. It holds promise as one of the main pharmacological agents to treat mixed dyslipidemia in metabolic syndrome and diabetic patients. The use of nicotinic acid has always been haunted with concerns that it might worsen insulin resistance and complicate diabetes management. We will discuss the interaction between phosphorous metabolism and carbohydrate metabolism and the possibility that worsening of insulin resistance could be related to a drug induced alteration in phosphorous metabolism, and the implications of that in medical management of diabetes and metabolic syndrome patients with mixed dyslipidemia.
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PMID:Are the effects of nicotinic acid on insulin resistance precipitated by abnormal phosphorous metabolism? 1551 Dec 97

Cardiovascular disease is the leading cause of mortality among people with diabetes mellitus, accounting for 70% of all deaths. As the prevalence of diabetes increases significantly worldwide, greater attention must be focused on preventing cardiovascular events in this group. One contributor to this increased event rate is the characteristic pattern of dyslipidemia in diabetic patients, consisting of elevated serum triglyceride levels, decreased high-density lipoprotein levels, and an increased proportion of small, dense, low-density lipoproteins. Several pharmacologic agents have been used to treat this dyslipidemia including HMG-CoA reductase inhibitors, fibric acid derivatives, niacin (nicotinic acid), thiazolidinediones, and fish oils, as well as other non-pharmacologic measures. Currently, the most extensive data for a reduction in cardiovascular events in patients with diabetes exist for HMG-CoA reductase inhibitors. The results of these trials indicate that HMG-CoA reductase inhibitor therapy should be considered for all patients with diabetes at sufficient risk for cardiovascular events, regardless of serum low-density lipoprotein-cholesterol level. Several ongoing trials of various pharmacologic agents should help clarify the role of these agents alone and in combination with HMG-CoA reductase inhibitors in the management of diabetic dyslipidemia.
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PMID:Management of diabetic dyslipidemia: need for reappraisal of the goals. 1572 39

The lipid hypothesis, which was proposed over 100 years ago, is based on the premise that dyslipidemia is central to the process of atherosclerosis. Low-density lipoprotein and lipoprotein(a) are clearly atherogenic, whereas the role of very low-density lipoprotein as an independent factor is controversial. The only lipoprotein that is clearly antiatherogenic is high-density lipoprotein (HDL), which is thought to reduce coronary risk by mediating cholesterol efflux from the periphery by way of transportation to the liver for excretion. Traditionally, fibric acid derivatives and nicotinic acid were the major pharmacologic agents used to raise circulating levels of HDL. Recent therapeutic advances have been made in the ability to increase HDL. Apolipoprotein A-I Milano and cholesterol ester transfer protein represent novel approaches to the pharmacologic therapy of individuals with low HDL levels. The mechanisms and clinical implications of these interventions are discussed here.
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PMID:Raising high-density lipoprotein cholesterol: innovative strategies against an old adversary. 1572 22

Use of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) infection is associated with the development of cardiovascular risk factors, including dyslipidemia, insulin resistance, fat redistribution, and hypertension. The results of the Data Collection on Adverse Events of Anti-HIV Drugs study showed that HAART therapy is associated with a 26% relative risk increase in the rate of myocardial infarction per year of HAART exposure. A number of studies have shown that insulin resistance often precedes lipodystrophy, suggesting that insulin resistance may be a primary feature of the metabolic syndrome in this population. The rate-limiting step in the uptake of glucose is glucose transport, and the predominant glucose transporter (GLUT) in muscle and fat is GLUT-4. Specific protease inhibitors (PIs) have been associated with decreased GLUT-4-mediated glucose transport and insulin resistance both in vitro and in vivo, whereas newer protease inhibitors may have fewer effects on insulin sensitivity. Data also suggest that endothelial dysfunction, impaired fibrinolysis, and excess inflammation may contribute to increased cardiovascular risk in the population infected with HIV. Moreover, recent data suggest that evidence for coronary atherosclerotic disease can be revealed by means of carotid intimal medial thickness (IMT) assessments in specific groups of HIV patients. Pharmacologic strategies for the prevention and/or treatment of HAART-induced dyslipidemia and abnormal glucose homeostasis include 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), resins, nicotinic acid, fibrates, and insulin-sensitizing agents. However, newer PIs such as atazanavir may result in less insulin resistance and dyslipidemia and, as part of a HAART regimen, use of atazanavir may reduce the metabolic complications associated with HAART.
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PMID:Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. 1590 92

Nicotinic acid has favorable effects on atherogenic dyslipidemia. However, in some patients who have diabetes, crystalline nicotinic acid decreases glycemic control; this effect could be due to a marked rebound of nonesterified fatty acids (NEFAs) observed after nicotinic acid suppression of lipolysis in adipose tissue. Recent reports have indicated that small doses of extended-release nicotinic acid do not cause a substantial decrease in glucose levels. Therefore, in this study, we examined whether 2 g/day of extended-release nicotinic acid abolishes the NEFA rebound that is reported with crystalline nicotinic acid. Seventeen men who had the metabolic syndrome (8 did not have type 2 diabetes and 9 did) were treated for 4 months. At baseline and at 4 months, measurements were made of plasma glucose, insulin, and NEFA during an oral glucose tolerance test. At 3 months, effects of extended-release nicotinic acid on NEFA levels and flux rates were determined on 3 separate days at 3 separate intervals after the final dose of nicotinic acid (4, 9, and 28 hours). Values obtained at 28 hours were taken as baseline (i.e., no nicotinic acid remaining in the circulation). After 4 hours (percent baseline), NEFA levels were -30% without diabetes and -37% with diabetes, and flux rates were -21% without diabetes and -25% with diabetes; after 9 hours, NEFA levels were 43% without diabetes and 50% with diabetes, and flux rates were 38% without diabetes and 70% with diabetes. Extended-release nicotinic acid did not abolish NEFA rebound. Nonetheless, the rebound was much less than previously reported for crystalline nicotinic acid. Moreover, after 4 months of nicotinic acid therapy, levels of NEFA, glucose, and insulin during the oral glucose tolerance test were not significantly different from those before institution of nicotinic acid therapy, suggesting minimal changes in insulin sensitivity.
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PMID:Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia. 1590 34

The metabolic syndrome is defined as a condition characterized by a set of clinical criteria: insulin resistance, visceral obesity, atherogenic dyslipidemia, and hypertension. The major risk factors leading to the epidemic of this syndrome in the United States are visceral obesity, physical inactivity, and an atherogenic diet. The available current evidence suggests that the first step in management of patients with metabolic syndrome should be focused on lifestyle modifications (eg, weight loss and physical activity). The treatment should be based on two major components: behavioral change to reduce caloric intake and an increase in physical activity. A realistic goal for weight reduction should be 7% to 10% over 6 to 12 months. The general dietary recommendations include low intake of saturated fats, trans fats and cholesterol, and diets with low glycemic index. Soy protein could be more beneficial than animal protein in weight reduction and correction of dyslipidemia. Physical activity is associated with successful weight reduction and these therapeutic lifestyle changes can reduce by half the progression to new-onset diabetes in patients with metabolic syndrome. Physical activity recommendations should include practical, regular, and moderated regimens of exercise, with a daily minimum of 30 to 60 minutes. An equal balance between aerobic exercise and strength training is advised. Medication therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. There is no single best therapy and the treatment should consist of treatment of individual component(s). Atherogenic dyslipidemia should be controlled with statins if there is concomitant increase in low-density lipoprotein cholesterol and if indicated with combination therapy, including fibrates, nicotinic acid, bile acid-binding resins, or ezetimibe. Drugs such as thiazolidinediones and renin-angiotensin system blockers are a few of the available agents in this category. Some evidence suggests that angiotensin-converting enzyme inhibitors and b blockers are more beneficial for treatment of hypertension in patients with metabolic syndrome. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor agonists, will broaden the horizons of the current treatment options in metabolic syndrome.
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PMID:Current Treatment Options for the Metabolic Syndrome. 1591 5

As a treatment for dyslipidemia, oral doses of 1-3 grams of nicotinic acid per day lower serum triglycerides, raise high density lipoprotein cholesterol, and reduce mortality from coronary heart disease (Tavintharan, S., and Kashyap, M. L. (2001) Curr. Atheroscler. Rep. 3, 74-82). These benefits likely result from the ability of nicotinic acid to inhibit lipolysis in adipocytes and thereby reduce serum non-esterified fatty acid levels (Carlson, L. A. (1963) Acta Med. Scand. 173, 719-722). In mice, nicotinic acid inhibits lipolysis via PUMA-G, a Gi/o-coupled seven-transmembrane receptor expressed in adipocytes and activated macrophages (Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., and Offermanns, S. (2003) Nat. Med. 9, 352-355). The human ortholog HM74a is also a nicotinic acid receptor and likely has a similar role in anti-lipolysis. Endogenous levels of nicotinic acid are too low to significantly impact receptor activity, hence the natural ligands(s) of HM74a/PUMA-G remain to be elucidated. Here we show that the fatty acid-derived ketone body (D)-beta-hydroxybutyrate ((D)-beta-OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid, (D)-beta-OHB inhibits mouse adipocyte lipolysis in a PUMA-G-dependent manner and is thus the first endogenous ligand described for this orphan receptor. These findings suggests a homeostatic mechanism for surviving starvation in which (D)-beta-OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.
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PMID:(D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. 1592 91


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