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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARalpha in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.
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PMID:Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates. 1765 32

Evidence of the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) within continuum of atherothrombotic conditions and particularly in the treatment and prevention of coronary heart disease (CHD) is well established. Large-scale, randomized, prospective trials involving patients with CHD have shown that statins reduce the clinical consequences of atherosclerosis, including cardiovascular deaths, nonfatal myocardial infarction and stroke, hospitalization for acute coronary syndrome and heart failure, as well as the need for coronary revascularization. Direct testing of varying degrees of low-density lipoprotein (LDL)- cholesterol lowering has now been carried out in 4 large outcomes trials: PROVE IT-TIMI 22, A to Z, TNT and IDEAL. However, the question whether more aggressive LDL-cholesterol lowering by high-dose statins monotherapy is an appropriate strategy is still open: higher doses of statins are more effective mainly for the prevention of the nonfatal cardiovascular events but such doses are associated with an increase in hepatotoxicity, myopathy and concerns regarding noncardiovascular death. Moreover, despite the increasing use of statins, a significant number of coronary events still occur and many such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is now being paid to combined atherogenic dyslipidemia which typically presented in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or 'lipid quartet') - hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, a preponderance of small, dense LDL particles and an accumulation of cholesterol-rich remnant particles - emerged as the greatest 'competitor' of LDL-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP, HHS, VAHIT and FIELD) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants, CETP inhibitors and omega-3 fatty acids. Particularly, ezetimibe/statins combinations provide superior lipid-modifying benefits compared Tenenbaum/Fisman/Motro/Adler 128 with any statins monotherapy in patients with atherogenic dyslipidemia. Atherogenic dyslipidemia is associated with increased levels of chylomicrons and their remnants containing 3 main components: apolipoprotein B-48, triglycerides and cholesterol ester of intestinal origin. Reduction in accessibility for one of them (specifically cholesteryl ester lessening due to ezetimibe administration) could lead to a decrease of the entire production of chylomicrons and result in a decrease of the hepatic body triglycerides pool as confirmed in number of clinical studies. However, the ENHANCE study showed no difference in the progression of carotid atherosclerosis between ezetimibe/simvastatin vs. simvastatin alone over a 2-year period. Conclusions regarding ezetimibe/statins combinations should not be made until the three large clinical outcome trials will be completed within the next 2-3 years. In addition, bezafibrate as a pan-PPAR activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism, insulin sensitivity and pancreatic beta cell protection. Because fibrates, niacin, ezetimibe, omega-3 fatty acids and statins each regulate serum lipids by different mechanisms, combination therapy - selected on the basis of their safety and effectiveness, could be more helpful in achieving a comprehensive lipid control as compared with statins monotherapy.
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PMID:Optimal management of combined dyslipidemia: what have we behind statins monotherapy? 1823 Sep 60

Hypolipemic agents, both statins and fibrates, may cause a spectrum of side-effects, including the transient increase in creatine phosphokinase (CPK) activity. Muscle injury may present as common myalgia, non-specific myositis with normal CPK levels, myopathy and in the most serious cases, as rhabdomyolysis. Muscle damage is much more probably in patients with concomittant kidney and liver diseases, hypothyroidism, and serious infections or after some injuries or a heavy physical effort. On the other hand, one of the most common causes of secondary hypercholesterolemia and myopathy is hypothyroidism. This condition, which may enhance the risk of muscle damage in the course of hypolipemic treatment, may sometimes present with an atypical clinical presentation, making its diagnosis challenging. In this article, we present the case of a 50-year-old male physical worker presented with marked dyslipidemia, in whom myopathy was diagnosed during therapy with hypolipemic agents. Cessation of the treatment resulted in the only moderate reduction of CPK activity. Only just the introduction of thyroid hormone supplementation led to regression of symptoms and normalization of abnormalities found in laboratory examinations including remarkable improvement in lipid profile. After several months of observation we consider that hypolipemic treatment probably revealed previously occult autoimmune thyroid disease in this patient.
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PMID:[Is every case of muscle damage during hypolipemic therapy the side effect of this therapy? A case report]. 1832 Jul 90

Therapeutic use of certain peroxisome proliferator-activated receptor (PPAR) alpha agonists (fibrates) for the treatment of dyslipidemia has infrequently been associated with the untoward side effect of myopathy. With interest in PPAR-delta as a therapeutic target, this study assessed whether a PPAR-delta agonist induced similar hepatic and skeletal muscle alterations as noted with some fibrates. PPAR-alpha null (KO) and corresponding wild-type (WT) mice were administered toxicological dosages of a potent PPAR-delta agonist tool ligand (GW0742; which also has weak PPAR-alpha agonist activity) or a potent PPAR-alpha agonist (WY-14,643) for 10 days. Increases in liver weights and clinical chemistry indicators of skeletal muscle damage and/or liver injury were more pronounced in WT mice compared with KO mice administered the PPAR-delta agonist. Likewise, the incidence and severity of skeletal myopathy were greater in WT mice given GW0742 compared with KO mice. Ultrastructural and immunohistochemical analyses revealed significant peroxisome proliferation in muscle and liver of WT mice treated with each agonist; however, KO animals showed little or no evidence of hepatic and muscle peroxisome proliferation. PMP-70 protein expression in liver was consistent with these results. The hepatomegaly, hepatic and skeletal muscle peroxisome proliferation, and skeletal myopathy induced by this PPAR-delta ligand was predominantly mediated by its cross-activation of PPAR-alpha, though PPAR-delta agonism contributed slightly to these effects.
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PMID:PPAR alpha, more than PPAR delta, mediates the hepatic and skeletal muscle alterations induced by the PPAR agonist GW0742. 1859 27

The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.
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PMID:Efficacy and safety of a potent and selective peroxisome proliferator activated receptor alpha agonist in subjects with dyslipidemia and type 2 diabetes mellitus. 1867 1

This case study explores the incidence of rhabdomyolysis in a HIV positive patient that was taking a lipid lowering drug and a protease inhibitor concurrently while under chiropractic treatment for generalized muscular soreness. Dyslipidemia is a very common problem both in the general and HIV population, with many patients being prescribed lipid lowering drugs. While extremely rare, adverse effects of lipid lowering drugs have been documented to include myopathy such as rhabdomyolysis. It is imperative that chiropractors are aware of the possible adverse side effect of lipid lowering drug therapy in their patients complaining of musculoskeletal pain. It is even more important that chiropractors treating the HIV population are aware of the potential interactions between these medications and protease inhibitors to cause myopathy.
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PMID:Rhabdomyolysis: a case study exploring the possible side effect of lipid lowering medication by a HIV positive patient taking a protease inhibitor. 1906 98

Many patients who receive statin therapy for hyperlipidemia-such as patients with diabetes mellitus and metabolic syndrome--have residual cardiovascular risk. These patients often have dyslipidemia, including low levels of HDL cholesterol and elevated levels of triglycerides and small, dense LDL. For such patients, combination treatment with statins and fibrates is a potentially useful strategy to improve lipid and lipoprotein profiles and reduce cardiovascular risk. However, statin-fibrate combination regimens have potential adverse effects on skeletal muscle, including myopathy. To date, no large-scale, prospective, randomized, controlled trial has evaluated the safety and efficacy of statin-fibrate combination therapy; one such trial is underway but will not report data until 2010. Until then, clinicians need to consider pharmacokinetic, pharmacodynamic, metabolic, pathophysiologic and other factors that can increase the systemic exposure of statins and/or fibrates and hence heighten the risk of toxic effects on muscles, as well as data from clinical trials and recommendations of consensus panels to optimize the safety of such combination regimens. On the basis of currently available data, fenofibrate or fenofibric acid is the fibrate of choice when used in combination with a statin because each is, in theory, associated with a lower risk of myopathy than gemfibrozil.
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PMID:Myopathy with statin-fibrate combination therapy: clinical considerations. 1963 24

Fibrates, the ligands of peroxisome proliferator-activated receptor alpha (PPARalpha), are used as a class of lipid-lowering drugs in clinical practice for the treatment of dyslipidemia. Fibrates are well tolerated in most cases concomitantly with occasional adverse reactions including muscular toxicity, which is enhanced by the combination with statins. This study was designed to investigate the effects of bezafibrate as a PPARalpha agonist on human embryo rhabdomyosarcoma (RD) cells and possible mechanisms responsible for bezafibrate-mediated myopathy. The results revealed that bezafibrate caused a dose-dependent decrease in cell viability, which was fortified in association with atorvastatin at a pharmacological dose. Bezafibrate at toxic doses of 300 and 1000microM upregulated PPARalpha at the mRNA level, counteracted by a PPARalpha antagonist (MK886). Bezafibrate at a toxic dose induced typical apoptotic characteristics related to the inhibition of phosphorylation of Akt which was blocked by PPARalpha antagonist. Toxic doses of bezafibrate initiated a significant increase in pyruvate dehydrogenase kinase 4 mRNA and protein levels, compromised by MK886. These results suggest the critical roles of PPARalpha signaling in bezafibrate-induced myotoxicity and the involvement of apoptosis through Akt pathway.
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PMID:Bezafibrate induces myotoxicity in human rhabdomyosarcoma cells via peroxisome proliferator-activated receptor alpha signaling. 1968 50

Despite its low frequency, endogenous Cushing's syndrome is not an exceptional clinical entity. A growing number of cases are currently derived to specialized centers suggesting an increasing knowledge of the clinical features of hypercortisolism by specialists of diverse branches of clinical medicine. Clinical signs derive from an exaggeration of the physiological actions of cortisol inducing protein breakdown, hyperglycemia, fat mobilization, dyslipidemia, hydrosaline retention, immunosuppression and increased susceptibility to infection. Despite its low specificity, symptoms such as unexplained development of central obesity, mood changes, fatigue, weakness, myopathy, easy bruisability, red striae, arterial hypertension, diabetes and hyperlipidemia, are suggestive of the diagnosis. From an epidemiological point of view, Cushing's syndrome is to be suspected and consequently searched for among patients with uncontrolled high blood pressure or diabetes mellitus, metabolic syndrome, polycystic ovarian syndrome, osteoporosis, depression or adrenal incidentaloma. True Cushing's syndrome has to be differentiated from pseudo syndromes. Most sensitive physical signs for discriminating Cushing's syndrome from pseudo-Cushing states are the presence of supraclavicular fat pads, myopathy, thin skin and easy bruising. The recognition of the clinical manifestations of Cushing's syndrome and of the sub-populations at risk of contracting the disease should be improved through medical education at the medical school and at postgraduate levels. Clinical detection of Cushing's syndrome must be performed mainly by non-endocrinologists, yet its etiological diagnosis and therapeutic management is to be carried out in highly experienced and specialized centers, to ensure the best results in the treatment of this really challenging endocrine disturbance.
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PMID:In what clinical settings should Cushing's syndrome be suspected? 2005 13

HMG-CoA reductase inhibitors (statins) are the mainstay in the pharmacologic management of dyslipidemia. Since they are widely prescribed, their safety remains an issue of concern. Rosuvastatin has been proven to be efficacious in improving serum lipid profiles. Recently published data from the JUPITER study confirmed the efficacy of this statin in primary prevention for older patients with multiple risk factors and evidence of inflammation. Rosuvastatin exhibits high hydrophilicity and hepatoselectivity, as well as low systemic bioavailability, while undergoing minimal metabolism via the cytochrome P450 system. Therefore, rosuvastatin has an interesting pharmacokinetic profile that is different from that of other statins. However, it remains to be established whether this may translate into a better safety profile and fewer drug-drug interactions for this statin compared with others. Herein, we review evidence with regard to the safety of this statin as well as its interactions with agents commonly prescribed in the clinical setting. As with other statins, rosuvastatin treatment is associated with relatively low rates of severe myopathy, rhabdomyolysis, and renal failure. Asymptomatic liver enzyme elevations occur with rosuvastatin at a similarly low incidence as with other statins. Rosuvastatin treatment has also been associated with adverse effects related to the gastrointestinal tract and central nervous system, which are also commonly observed with many other drugs. Proteinuria induced by rosuvastatin is likely to be associated with a statin-provoked inhibition of low-molecular-weight protein reabsorption by the renal tubules. Higher doses of rosuvastatin have been associated with cases of renal failure. Also, the co-administration of rosuvastatin with drugs that increase rosuvastatin blood levels may be deleterious for the kidney. Furthermore, rhabdomyolysis, considered a class effect of statins, is known to involve renal damage. Concerns have been raised by findings from the JUPITER study suggesting that rosuvastatin may slightly increase the incidence of physician-reported diabetes mellitus, as well as the levels of glycated hemoglobin in older patients with multiple risk factors and low-grade inflammation. Clinical trials proposed no increase in the incidence of neoplasias with rosuvastatin treatment compared with placebo. Drugs that antagonize organic anion transporter protein 1B1-mediated hepatic uptake of rosuvastatin are more likely to interact with this statin. Clinicians should be cautious when rosuvastatin is co-administered with vitamin K antagonists, cyclosporine (ciclosporin), gemfibrozil, and antiretroviral agents since a potential pharmacokinetic interaction with those drugs may increase the risk of toxicity. On the other hand, rosuvastatin combination treatment with fenofibrate, ezetimibe, omega-3-fatty acids, antifungal azoles, rifampin (rifampicin), or clopidogrel seems to be safe, as there is no evidence to support any pharmacokinetic or pharmacodynamic interaction of rosuvastatin with any of these drugs. Rosuvastatin therefore appears to be relatively safe and well tolerated, sharing the adverse effects that are considered class effects of statins. Practitioners of all medical practices should be alert when rosuvastatin is prescribed concomitantly with agents that may increase the risk of rosuvastatin-associated toxicity.
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PMID:Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia. 2010 31


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