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)

Dyslipidemia, characterized by elevated serum levels of triglycerides and reduced levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol, has been recognized in patients with human immunodeficiency virus (HIV) infection. It is thought that elevated levels of circulating cytokines, such as tumor necrosis factor-alpha and interferon-alpha, may alter lipid metabolism in patients with HIV infection. Protease inhibitors, such as saquinavir, indinavir and ritonavir, have been found to decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with a syndrome of fat redistribution, insulin resistance, and hyperlipidemia. Elevations in serum total cholesterol and triglyceride levels, along with dyslipidemia that typically occurs in patients with HIV infection, may predispose patients to complications such as premature atherosclerosis and pancreatitis. It has been estimated that hypercholesterolemia and hypertriglyceridemia occur in greater than 50% of protease inhibitor recipients after 2 years of therapy, and that the risk of developing hyperlipidemia increases with the duration of treatment with protease inhibitors. In general, treatment of hyperlipidemia should follow National Cholesterol Education Program guidelines; efforts should be made to modify/control coronary heart disease risk factors (i.e. smoking; hypertension; diabetes mellitus) and maximize lifestyle modifications, primarily dietary intervention and exercise, in these patients. Where indicated, treatment usually consists of either pravastatin or atorvastatin for patients with elevated serum levels of LDL-C and/or total cholesterol. Atorvastatin is more potent in lowering serum total cholesterol and triglycerides compared with other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but it is also associated with more drug interactions compared with pravastatin. Simvastatin and lovastatin are significantly metabolized by cytochrome P450 enzymes (CYP3A4) and are therefore not recommended for coadministration with protease inhibitors. A fibric acid derivative (gemfibrozil or fenofibrate) should be used in patients with primary hypertriglyceridemia. However, it must be kept in mind that protease inhibitors, such as nelfinavir and ritonavir, induce enzymes involved in the metabolism of the fibric acid derivatives and may, therefore, reduce the lipid-lowering activity of coadministered gemfibrozil or fenofibrate. In certain patients HMG-CoA reductase inhibitors may be used in combination with fibric acid derivatives but patients should be carefully monitored for liver and skeletal muscle toxicity. Select patients may experience improvements in serum lipid levels when their offending protease inhibitor(s) is/are exchanged for efavirenz, nevirapine, or abacavir; however each patient's virologic and immunologic status must be taken closely into consideration.
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PMID:Management of protease inhibitor-associated hyperlipidemia. 1472 85

The availability of highly active antiretroviral therapy (HAART) has resulted in dramatic declines in morbidity and mortality in patients infected with human immunodeficiency virus-1 (HIV-1). However, the success of HAART has been tempered by the recognition of adverse metabolic effects clearly associated with its use. These "metabolic complications" include dyslipidemia, changes in body fat distribution, insulin resistance and glucose intolerance, metabolic bone disease, and lactic acidosis. Guidelines to assist clinicians in the management of these complications have been put forth by various organizations, including the International AIDS Society, the HIV Medicine Association of the Infectious Disease Society of America, and the Adult AIDS Clinical Trials Group.
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PMID:Metabolic complications associated with the use of highly active antiretroviral therapy in HIV-1-infected adults. 1525 41

This report reviews current data pertaining to the development of dyslipidemia during treatment with protease inhibitors and the associated risk for cardiovascular disease in patients who have the human immunodeficiency virus. Most protease inhibitors used to manage the human immunodeficiency virus and the acquired immunodeficiency syndrome are associated with prompt, marked, and sustained increases in serum lipid levels that are consistent with an increased 10-year risk for coronary heart disease as determined in the Framingham Heart Study. Management of lipid elevations in patients who use protease inhibitors is discussed. Novel protease inhibitors, which have minimal effects on lipid profiles, may have a role in the long-term management of the human immunodeficiency virus.
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PMID:Long-term cardiovascular risk with protease inhibitors and management of the dyslipidemia. 1546 73

Current antiretroviral therapy protocols enable long-term survival of HIV-infected patients, decreasing the risk of infectious complications. Three classes of anti-HIV treatments are available. With longer survival, unusual cardiovascular complications related to iatrogenic biological anomalies (dyslipidemia and impaired glucose tolerance) have appeared among this young population which is exposed to usual risk factors of atherosclerosis. Antiretroviral therapies are suspected to cause these complications, inducing maturity-onset diabetes in 4 to 20% of patients, impaired glucose tolerance in 15 to 60%, hypertriglyceridemia in 15 to 74% depending on the survey, and hypercholesterolemia in 20 to 60%, especially in case of associated lipodystrophia. A lipid battery including total cholesterol, HDL, and triglycerides, and 12-h fasting blood glucose should be obtained before initiating antiretroviral therapy. Any anomalous finding should be followed carefully with regular surveillance every 3 to 6 months and search for other causes of secondary dyslipidemia. In the event of casual and persisting elevation of LDL-cholesterol levels, a statin treatment can be introduced. For secondary prevention, irrespective of the context, recommendations currently merge with the consensus applying to the general population. These patients require careful surveillance of cardiovascular risk factors and a specific care in addition to treatment of their immunodeficiency.
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PMID:[Antiretroviral therapy and cardiovascular risk]. 1552 82

Atazanavir (formerly BMS-232632), an azapeptide protease inhibitor (PI), is a new human immunodeficiency virus (HIV) treatment that has recently received marketing approval from the FDA. It has a pharmacokinetic profile that supports once-daily dosing and has demonstrated a unique resistance profile and superior virologic potency compared with other antiretrovirals in vitro. In subjects with HIV, atazanavir (400 mg once daily) produced rapid and sustained improvements in viral load and CD4 counts in both antiretroviral-naive as well as previously treated patients when used in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) treatment. In these studies atazanavir demonstrated comparable anti-HIV efficacy to nelfinavir (twice or three times daily), efavirenz and the combination of ritonavir and saquinavir. However, unlike these comparator agents, atazanavir did not adversely affect the plasma lipid profile, an advantage that sets it apart from other currently available PIs. Atazanavir was inferior to lopinavir/ritonavir in patients who previously failed an initial protease inhibitor containing regimen. Preliminary results in multiple PI-experienced patients indicate comparable efficacy to lopinavir/ritonavir in subjects receiving a boosted regimen of atazanavir plus ritonavir. In summary, atazanavir offers several therapeutic advantages, including a convenient once-daily dosing schedule, neutral lipid effects and a distinct resistance profile. These characteristics may ultimately help improve adherence, reduce the potential risk of long-term cardiovascular events associated with dyslipidemia, and increase the range of therapeutic options available for patients failing other antiretroviral regimens.
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PMID:Atazanavir: A novel once-daily protease inhibitor. 1564 3

Dyslipidemia and coronary heart disease (CHD) are of increasing concern in persons with human immunodeficiency virus (HIV) infection who are living longer because of the benefits of highly active antiretroviral therapy (HAART). All classes of drugs used in HAART have been associated with atherogenic changes in lipid profiles. The management of HIV-infected persons with dyslipidemia and/or CHD currently emphasizes the importance of monitoring and optimizing lipid levels through lifestyle changes, switching antiretrovirals (ARVs), and lipid-lowering treatments utilizing guidelines developed for persons without HIV infection. In HIV-infected persons, the use of lipid-lowering drugs may result in pharmacokinetic interactions with ARVs, complicating the management of patients. Recent advances in our understanding of the differential effects of specific ARVs on lipids is beginning to alter the clinical approach to management. In the absence of randomized clinical trials, clinicians should aggressively treat atherogenic dyslipidemia by primarily utilizing or switching to ARVs with the lowest potential to induce CHD or, when this is not possible or is ineffective, secondarily by the addition of lipid-lowering therapy. The current optimal management of HIV infection requires careful selection of ARVs with consideration given to the potential development of CHD and an understanding of how to manage dyslipidemia.
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PMID:Coronary heart disease risk, dyslipidemia, and management in HIV-infected persons. 1568 55

We investigated the effect of dyslipidemia associated with highly active antiretroviral therapy on cardiovascular risk and life expectancy among patients who had the human immunodeficiency virus. Dyslipidemia estimates were based on results from a phase 2 randomized trial that compared lipid changes after 32 weeks of therapy with atazanavir with those with nelfinavir (each in combination with stavudine and lamivudine). The resultant increased coronary risk was estimated using Framingham risk equations, and change in life expectancy (after adjustment for mortality due to human immunodeficiency virus) was based on the cardiovascular life expectancy model, which is based on a published Markov's model. Levels of total cholesterol and low-density lipoprotein cholesterol increased significantly more among patients who used nelfinavir (+24% and +28%) than among those who used atazanavir (+4% and +1%). This dyslipidemia increased the risk of coronary disease by 50% over 10 years. The absence of dyslipidemia was estimated to preserve life expectancy 0.15 to 1.53 additional years depending on a patient's age, gender, and other risk factors. There are increasing reports of dyslipidemia and cardiovascular events associated with highly active antiretroviral therapy. Significant increases in blood lipid levels observed with some protease inhibitors are associated with an increase in calculated 10-year coronary risk. Accordingly, minimizing dyslipidemia associated with highly active antiretroviral therapy may preserve life expectancy among adults who have the human immunodeficiency virus.
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PMID:Impact of dyslipidemia associated with Highly Active Antiretroviral Therapy (HAART) on cardiovascular risk and life expectancy. 1572 Oct 96

The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, time-dependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.
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PMID:Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors. 1575 8

Type 2 diabetes mellitus and obesity have reached epidemic proportions in many developing and developed nations, leading to talk of the "twin epidemics." The latest projections from the International Diabetes Federation suggest that 190 million people worldwide currently have type 2 diabetes. In addition, > or = 300 million people worldwide have impaired glucose tolerance (IGT). These statistics represent an epidemic of major proportions--possibly the largest epidemic in human history--in terms of glucose intolerance and cardiovascular disease (CVD) risk because individuals with IGT are at substantially higher risk for diabetes and CVD than are members of the general population. Along with IGT, the metabolic syndrome comprises other major CVD risk factors, including insulin resistance, central obesity, and dyslipidemia; insulin resistance has been implicated as the single most common cause of the syndrome. Although the exact prevalence of the metabolic syndrome is unknown, the syndrome is widespread among adults in developed nations, becoming more prevalent with age. Epidemiologic data suggest that in patients with schizophrenia or affective disorders, both diabetes and obesity are 1.5 to 2.0 times more prevalent than in the general population. Furthermore, because adverse effects of certain therapies for human immunodeficiency virus (HIV) infection and psychiatric disorders increase the risk for developing diabetes, obesity, and the metabolic syndrome, such therapies should be carefully chosen, particularly considering CVD risk. Appropriate therapy may be determined via screening of patients for levels of fasting blood glucose and lipids, as well as other CVD risk factors, before initiating use of second-generation antipsychotic agents or highly active antiretroviral therapy.
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PMID:Epidemiology of diabetes mellitus and associated cardiovascular risk factors: focus on human immunodeficiency virus and psychiatric disorders. 1590 89

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


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