Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three categories of highly active antiretroviral therapy (HAART)-associated major toxic effects have been identified: nucleoside-related toxic effects (e.g., neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis, and possibly lipoatrophy), metabolic complications (e.g., fat redistribution, insulin resistance, and hyperlipidemia), and bone disease (e.g., osteopenia and/or osteoporosis). The toxic effects caused by nucleosides are hypothesized to be a result of mitochondrial injury and include myopathy, pancreatitis, liver failure, and lactic acidosis. Alterations in lactic acid metabolism range from common instances of asymptomatic lactic acidemia to rare occurrences of life-threatening lactic acidosis with hepatic steatosis. A metabolic syndrome consisting of lipodystrophy (i.e., fat redistribution), hyperlipidemia and insulin resistance has been observed, particularly with protease inhibitor treatment. Some additive interaction between protease inhibitors and nucleosides has also been described. The potential relationship of these metabolic abnormalities to increased risk of cardiovascular disease and diabetes has broad implications on long-term patient management. Lipodystrophy associated with HAART is generally accompanied by potentially serious abnormalities, including dyslipidemia (i.e., hypercholesterolemia and hypertriglyceridemia) and altered glucose metabolism (i.e., insulin resistance). Regimens of HAART may have adverse effects on bone metabolism, as indicated by emerging reports of osteopenia, osteoporosis, and avascular necrosis.
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PMID:Long-term exposure to lifelong therapies. 1183 99

Insulin resistance is a common metabolic disorder. It plays an important role in the metabolic syndrome (or syndrome X), type 2 diabetes, obesity and in the lipodystrophic syndromes recently described, associated with treatments of HIV disease and represent a worrying cardiovascular risk. However, its pathophysiology remains poorly understood in these situations. Syndromes of major insulin resistance, although rare, allow investigations of the mechanisms leading to alterations in the insulin transduction pathways. Mutations of the insulin receptor gene have been discovered in rare patients. Therefore alterations at the post-receptor level are probably causative in other cases. Furthermore, the role of body fat repartition seems determinant in the apparition of insulin resistance, as attested by the clinical characteristics of lipodystrophies, either congenital or acquired. The two lipodystrophic syndromes which molecular defect is identified are the familial partial lipodystrophy of the Dunnigan type, due to mutations of the lamin A/C gene, and the congenital generalized lipodystrophy, linked to alterations in the protein seipin. However, their physiopathology remains mysterious. Lamin A/C is indeed an ubiquitous nuclear protein, which is also mutated in a genetic squelettic and/or cardiac myopathy, and seipin is a protein of unknown function mainly expressed in brain. Progresses in the understanding of these syndromes, in particular lipodystrophies which can be considered as caricatural models of the metabolic syndrome, will probably allow to clarify the physiopathology of the more common forms of insulin resistance.
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PMID:[Major insulin resistance syndromes: clinical and physiopathological aspects]. 1183 62

Advicor (lovastatin and extended-release niacin) is the first cholesterol-lowering combination product to become available for the management of hyperlipidemia. Lovastatin significantly lowers low-density lipoprotein cholesterol, whereas niacin significantly lowers triglycerides and lipoprotein (a) and markedly increases high-density lipoprotein cholesterol. These effects are ideal for managing a variety of lipid disorders, including metabolic syndrome. Lovastatin and niacin reduce coronary heart disease mortality in primary and secondary prevention patients, respectively. The extended-release niacin component uses a unique technology to minimize adverse effects (e.g., flushing and hepatotoxicity) while retaining the same lipid-altering effects as immediate-release niacin. The combination product appears to be well tolerated, with discontinuation due to adverse effects other than flushing occurring in a similar percent of patients as for lovastatin in clinical trials. Approximately 9% of patients discontinued the combination product due to flush. No confined cases of myopathy or hepatotoxicity have been reported with this product. Once-daily dosing provides ease of administration that should improve compliance and result in a greater proportion of patients meeting their low-density lipoprotein cholesterol goals. The nomenclature surrounding niacin products used to treat dyslipidemias is confusing. While only two types of niacin formulations exist (immediate-release formulations and formulations which dissolve more slowly than immediate-release formulations), government regulations allow for slowly dissolved niacin formulations to be divided into two types of niacin products; those that are available over-the-counter (OTC) and those that are available by prescription only. Over-the-counter slowly dissolved niacin preparations are not classified as OTC per se, but are considered "nutritional supplements". For this reason, they fall under the jurisdiction of the Federal Trade Commission and do not fall under the umbrella of the FDA branch that controls dyslipidemic products (Endocrine and Metabolic Division of the Center for Drug Evaluation and Research). The slowly dissolved niacin nutritional supplements have not been reviewed by the FDA for safety nor efficacy in the treatment of dyslipidemia nor are they required to meet generic drug rules (even though various brands are available). These brands are described on their labels as "sustained-release", "timed-release", and "slow-release" for example. Only two slowly absorbed niacin products have been approved by the FDA for the treatment of dyslipidemia; they are Niaspan (Kos Pharmaceuticals, Inc., Miami, FL) and Advicor (Kos Pharmaceuticals, Inc., Miami, FL). The term "extended-release" has been given to these two products to simplify the terminology and differentiate the products from immediate-release niacin. In this review, we will use "extended-release" to refer to the FDA approved slowly dissolving niacin preparation and "sustained-release" to refer to the nutritional supplements (not FDA approved).
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PMID:Lovastatin and extended-release niacin combination product: the first drug combination for the management of hyperlipidemia. 1197 44

Patients with combined dyslipidemia are at high risk for coronary artery disease and often require combination drug therapy to achieve lipid levels recommended by the US National Cholesterol Education Program's third Adult Treatment Panel (ATP III). In addition to recommendations for low-density lipoprotein (LDL) cholesterol and triglyceride levels, ATP III established non-high-density lipoprotein (HDL) cholesterol goals for individuals with triglycerides >or=2.26 mmol/L (>or=200 mg/dL). It also introduced certain criteria for the diagnosis of the metabolic syndrome, a clustering of risk factors (abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure, impaired fasting glucose) that increases cardiovascular risk and is common in patients with combined dyslipidemia. Statin monotherapy has been shown to benefit these patients, and additional benefit may be obtained by combination therapy that provides greater reductions in both LDL cholesterol and triglycerides as well as greater increases in HDL cholesterol. However, combining a statin with either niacin or a fibrate may increase the risk for myopathy and therefore requires careful monitoring and evaluation of the risk-benefit ratio for each patient. Moreover, combination therapy may be associated with increased drug costs and decreased patient compliance. Recently developed agents that may improve the effectiveness of combination therapy include ezetimibe-a cholesterol absorption inhibitor-and a formulation that combines extended-release niacin and lovastatin in a single pill. Clinical trials are needed to determine the optimal treatment in patients with combined dyslipidemia.
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PMID:Combination therapy for combined dyslipidemia. 1246 37

Updated guidelines from the National Cholesterol Education Program give greater emphasis to lipoproteins other than low-density lipoprotein cholesterol (LDL) than previous guidelines. Although statins remain first-line therapy for most patients to lower LDL, combination therapy is the next logical step in achieving goals in patients with mixed dyslipidemia or elevated LDL despite statin therapy. As the prevalence of diabetes, metabolic syndrome, and atherogenic dyslipidemia rises, the importance of treating the total lipid profile becomes even more crucial. Niacin, fibrates, and bile acid sequestrants are effective in combination with statins in lowering LDL, triglycerides, and total cholesterol levels and increasing high-density lipoprotein cholesterol (HDL). Although combination therapies may increase the risk of myopathy, both fibrate-statin and niacin-statin combinations are considered safe. In addition, niacin-statin therapy reduces atherosclerotic progression and coronary events. New pharmacologic formulations exist that will further affect treatment: a single-tablet combination of lovastatin and extended-release niacin is available, as is ezetimibe, a cholesterol-absorption inhibitor. In all, both HDL and triglyceride levels correlate with cardiovascular risk and should be considered secondary targets of therapy. Combination therapy can be safe and effective and can be constructed to affect all lipoprotein parameters.
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PMID:Treating dyslipidemic patients with lipid-modifying and combination therapies. 1274 37

Cardiovascular disease is responsible for a large proportion of morbidity and mortality in people with type 2 diabetes, who typically have a clustering of risk factors for coronary heart disease (CHD), including dyslipidaemia. Intensive single-factor interventions to lower blood glucose have not eliminated the increased risk of adverse cardiovascular outcomes in patients with diabetes. In comparison, multifactorial interventions, which include normalizing blood lipids with statins, appear to be more effective in reducing CHD. However, risk reductions in patients with type 2 diabetes are often no better than those seen in people without diabetes, despite the much greater baseline risk in the former group. High-density lipoprotein cholesterol (HDL-C) is an independent risk factor for CHD, but is only minimally improved by statin therapy. Additional interventions aimed at increasing HDL-C can further reduce cardiovascular morbidity and mortality in patients with type 2 diabetes. However, use of fibrates in combination with statins may pose an unacceptable risk of myopathy. Therefore, other strategies for combination therapy are needed to normalize lipids in patients with type 2 diabetes or metabolic syndrome.
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PMID:Is dyslipidaemia important if we control glycaemia? 1605 91

Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.
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PMID:Overcoming 'ageism' bias in the treatment of hypercholesterolaemia : a review of safety issues with statins in the elderly. 1668 57

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are the most successful cardiovascular drugs of all time. By interrupting cholesterol synthesis in the liver, they activate hepatocyte low-density lipoprotein (LDL) receptors and produce consistent and predictable reductions in circulating LDL cholesterol with resulting reproducible improvements in cardiovascular risk by retarding or even regressing the march of atherosclerosis in all major arterial trees (coronary, cerebral and peripheral). Clinical trials have demonstrated their capacity not only to extend life, but also to improve its quality by retarding the progression of diabetes mellitus and chronic renal disease and by enhancing central and peripheral blood flow. They are amongst the most extensively investigated pharmaceutical agents in current clinical use. In cardiovascular end-point trials they have proven ability to help prevent that first and all important myocardial infarction and to reduce the likelihood of a recurrence in those who do succumb. They are equally effective in men and women of all ages and at all levels of cardiovascular risk, whether caused by hypercholesterolaemia, hypertension, cigarette smoking, diabetes mellitus or the metabolic syndrome. In addition, they improve the outlook of patients with familial hypercholesterolaemia whose LDL receptor function is deficient or defective; and all of this comes at minimal risk to the recipient. Their most important potential side effect is myopathy, which on very rare occasions may lead to rhabdomyolysis. Clinical experience shows that myopathic symptoms with creatine kinase levels raised to more than 10 times the upper limit of normal is seen in <0.01% of recipients and progression to fatal rhabdomyolysis because of renal failure has been recorded in only 0.15 cases per million prescriptions. Liver function abnormalities are also, rarely, seen. Again, the frequency of raised aspartate or alanine aminotransferase to more than three times the normal limit is encountered in no more than 1-2% of all treated patients and is completely reversible upon withdrawal of treatment. Progression to hepatitis or liver failure does not occur. This constellation of benefits with little side effect penalty has resulted in the comparison of statins with antibiotics in the global battle against cardiovascular disease.
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PMID:Who should receive a statin these days? Lessons from recent clinical trials. 1696 68

Dyslipidaemia is an important risk factor for the development of chronic kidney disease (CKD) and cardiovascular disease (CVD). CKD generates an atherogenic lipid profile, characterised by high triglycerides, low high-density lipoprotein (HDL) cholesterol and accumulation of small dense low-density lipoprotein (LDL) particles, comparable to that in the metabolic syndrome. These changes are due specifically to the effects of CKD on key enzymes, transfer proteins and receptors involved in lipid metabolism. Dyslipidaemia is further compounded by dialysis, immunosuppressive drugs, and concomitant diseases such as diabetes mellitus. Post hoc analyses from large intervention trials suggest the benefit of statins in patients with early CKD, but prospective clinical trials in haemodialysis (HD) and renal transplant recipients have not conclusively shown improvements in hard cardiovascular end-points. The lack of efficacy of statins in late-stage CKD could be a consequence of other disease processes, such as calcific arteriopathy and insulin resistance, which are not modified by lipid-lowering agents. Despite uncertainty and pending the results of ongoing statin trials such as Study of Heart and Renal Protection (SHARP) and AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events), major international guidelines continue to support statin therapy in CKD and renal transplant patients to reduce cardiovascular risk burden. Because of increased risk of toxicity, particularly myopathy, statins and other lipid-regulating agents should be used cautiously in CKD and renal transplant recipients.
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PMID:Dyslipidaemia and cardiorenal disease: mechanisms, therapeutic opportunities and clinical trials. 1734 61

Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARalpha agonists, such as the already available fibrates, improve dyslipidemia, while PPARgamma agonists, such as thiazolidinediones, improve insulin resistance and diabetes. The complementary action of simultaneous activation of each PPAR in patients suffering from metabolic syndrome and type 2 diabetes has led to new pharmacological strategies focused on the development of agonists targeting more than one receptor such as the dual PPARalpha/gamma agonists. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various PPAR agonists including novel specific PPARgamma agonists and dual PPARalpha/gamma agonists. These safety concerns include potential carcinogenicity in rodents, signs of myopathy and rhabdomyolysis, increase in plasma creatinine and homocysteine, weight gain, fluid retention, peripheral edema and potential increased risk of cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects which have motivated the discontinuation could be either due to the activation of PPARgamma, PPARalpha or both (class effect) or due to a PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative PPAR-related mechanism of action. This review mainly focuses on the preclinical and clinical adverse events of PPAR agonists that could be of concern when considering the development of new PPAR agonists. The selective modulation of PPAR activities is a promising approach to develop new drugs with preserved efficacy but diminished adverse effects.
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PMID:Safety issues and prospects for future generations of PPAR modulators. 1742 30


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