Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ezetimibe potently and selectively inhibits cholesterol absorption in the intestine, thereby reducing plasma cholesterol in preclinical models of hypercholesterolemia. Clinical trials have demonstrated that ezetimibe lowers LDL cholesterol and raises HDL cholesterol in humans. The effect of ezetimibe on other dyslipidemias, particularly hypertriglyceridemia, is not yet known. In the present studies, we assessed the effect of ezetimibe on combined hypercholesterolemia and hypertriglyceridemia in obese hyperinsulinemic hamsters. Hamsters were fed chow, chow with cholesterol (0.12%), or the same cholesterol diet containing different dietary triglycerides (15%) in the absence or presence of 1 mg/kg ezetimibe (in diet) for up to 84 days. Body weight, serum insulin, leptin, glucose, cholesterol, and triglyceride levels were analyzed. Cholesterol and triglyceride levels were also determined in VLDL+IDL, LDL, and HDL. Hamsters maintained on high-fat diets became obese, hyperinsulinemic, hyperleptinemic, hypercholesterolemic, and hypertriglyceridemic. Ezetimibe did not affect body weight, insulin, or leptin, but ablated the combined hypercholesterolemia and hypertriglyceridemia induced by high-fat diets. Ezetimibe normalized VLDL+IDL cholesterol and triglyceride and significantly decreased LDL cholesterol to below chow-fed levels. The ratio of HDL to LDL cholesterol increased significantly with the addition of ezetimibe. Ezetimibe completely eliminated the accumulation of cholesteryl ester and free cholesterol in liver that was induced under the various dietary conditions in the absence of drug. In conclusion, ezetimibe is very effective in correcting the combined dyslipidemia in diet-induced obese hyperinsulinemic hamsters and may be an effective therapy for ameliorating combined dyslipidemia in obese insulin-resistant and/or type 2 diabetic humans.
Diabetes 2001 Jun
PMID:Ezetimibe, a potent cholesterol absorption inhibitor, normalizes combined dyslipidemia in obese hyperinsulinemic hamsters. 1137 33

Lipid-lowering agents have been shown to reduce morbidity and mortality associated with coronary artery disease (CAD) in all patients. However, these agents are more cost-effective in high-risk patients whose absolute risk of CAD is greater than that of low-risk patients. Furthermore, from preliminary data, it appears that there is greater risk reduction in those subjects achieving lower low-density lipoprotein cholesterol (LDL-C) levels (ie, lower is better). The identification and aggressive treatment of these patients should therefore be a high priority for clinicians. Guidelines from medical organizations, such as the Adult Treatment Panel (ATP) III of the US National Cholesterol Education Program (NCEP), emphasize that patients with CAD, diabetes, or global risk of CAD >20% over 10 years and LDL-C levels >130 mg/dL should receive drug therapy with a goal of reducing LDL-C levels to <100 mg/dL. The recent results of the United Kingdom's Heart Protection Study (HPS) strongly suggest that even those with CAD or who are at high risk and LDL-C levels >100 mg/dL would benefit from drug therapy. Although optimal LDL-C levels have been set at <100 mg/dL for high-risk patients, recent studies show only about 20% of such patients meet these goals. Thus, a large treatment gap remains that needs to be overcome if we are to continue to make significant inroads into preventing further morbidity and mortality in these high-risk subjects. Of therapeutic options available currently and for the near future, statins remain the most effective and well-tolerated form of lipid-lowering therapy. Other therapies include bile acid sequestrants, niacin, and plant stanols. However, none of these is, in general, sufficiently effective as an initial agent to achieve these more aggressive LDL-C goals in the high-risk patient. However, combination therapy with a statin and 1 of these other lipid-lowering agents is useful in patients who are unable to achieve lipid goals on monotherapy. A number of agents for reducing LDL-C levels currently in development may be available in the near future, including 2 new statins: pitavastatin and rosuvastatin. Rosuvastatin, which is in the later stages of the US Food and Drug Administration (FDA) approval process, has been shown to produce significantly greater reductions in LDL-C levels compared with atorvastatin, simvastatin, and pravastatin, and allows more patients to meet lipid goals. Ezetimibe, the first of an entirely new class of LDL-C-lowering agents that inhibit intestinal cholesterol absorption, also appears to offer significant therapeutic value. It is anticipated that these new options will allow clinicians to optimize the management of dyslipidemia in high-risk patients, thereby further reducing the morbidity and mortality of CAD.
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PMID:Managing dyslipidemia in the high-risk patient. 1190 Jul 20

Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk. Such observations suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L, may result in under-treatment of a significant number of patients and form the basis for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L, respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins) reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and reduced CHD event rates in primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-C reduction alone and may relate to effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as well as additional anti-inflammatory effects. With increasing focus on the benefits of intensive cholesterol reduction new, more efficacious statins are being developed. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL-C of up to 55%, with about 80% of patients reaching European LDL-C treatment targets at the 10 mg/day dosage. The Heart Protection Study (HPS) demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated with significant clinical benefit in a wide range of high-risk individuals, including patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease, irrespective of baseline cholesterol levels, with no apparent lower threshold for LDL-C with respect to risk. Various large endpoint trials, including Treating to New Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk factor and is the primary lipid abnormality in over half of CHD patients, with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and LDL-C levels below 3 mmol/L. A variety of agents are being developed, which affect both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme A-cholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60% reduction in chylomicron cholesterol content with a 10 mg/day dosage. A 1 mmol/L reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of baseline LDL-C levels. Growing evidence supports the concept that lower is better for LDL-C and that increasing HDL-C represents an important therapeutic target. Furthermore, there is growing appreciation of the role of inflammation in atherogenesis. Consequently, increasing numbers of people should receive lipid-regulating therapy with the development of newer agents offering potential mechanisms of optimising lipid profiles and thus risk reduction. In addition, the pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further risk reduction.
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PMID:Medical lipid-regulating therapy: current evidence, ongoing trials and future developments. 1516 26

Ezetimibe is a novel lipid-lowering agent that inhibits intestinal absorption of dietary and biliary cholesterol. The effects of ezetimibe on low-density lipoprotein (LDL)-cholesterol were found to generally consistent across all subgroups analyzed, including baseline lipid profile, hypertension, diabetes mellitus, and body mass index. Furthermore, recent clinical studies also revealed that co-administration of ezetimibe with on-going statins offered a well-tolerated and efficacious treatment to lower LDL-cholesterol levels in hypercholesterolemic patients with diabetes mellitus or the metabolic syndrome. Niemann-Pick C1 like 1 (NPC1L1) protein is recently found to be critical for intestinal cholesterol absorption, and is a target protein for ezetimibe. Human NPC1L1 protein is predominantly expressed in liver, whereas small intestine expression is only about 2-4% of that found in the liver. Thus, NPC1L1 does not function solely in the intestinal cholesterol absorption. Furthermore, loss of NPC1L1 expression has been shown to protect against diet-induced fatty liver. These observations let us to speculate that ezetimibe will become a new therapeutic approach for the treatment of non-alcoholic fatty liver, the hepatic manifestation of insulin resistant patients with the metabolic syndrome. In this paper, we would like to propose the possible ways of testing our hypothesis as follows. (1) Does ezetimibe treatment improve fatty liver in patients with hypercholesterolemia or the metabolic syndrome? If the answers are yes, are these beneficial effects of ezetimibe superior to those of other anti-hyperlipidemic resins with equihypolipidemic properties? (2) Does ezetimibe treatment improve insulin sensitivity in fatty liver patients with the metabolic syndrome? (3) How about the effects of ezetimibe treatment on serum levels of adiponectin, a key adipokine with insulin-sensitizing property? Large clinical trials will provide us with more definite information whether ezetimibe treatment can improve fatty liver and resultantly reduce the risk of progression of liver diseases in patients with the metabolic syndrome.
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PMID:Inhibition of intestinal cholesterol absorption by ezetimibe is a novel therapeutic target for fatty liver. 1683 21

This analysis of the Ezetimibe Add-on to Statin for Effectiveness (EASE) trial examined the effectiveness and safety of ezetimibe 10 mg added to ongoing statin therapy in patients with diabetes, metabolic syndrome without diabetes, or neither disorder who had low-density lipoprotein cholesterol (LDL-C) levels exceeding National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) goals. After six weeks of treatment, ezetimibe added to statin reduced LDL-C in patients with diabetes by 28%, metabolic syndrome by 24%, or neither by 26%, compared with a 3% reduction for placebo for each group. In each group, more patients receiving ezetimibe plus statin reached LDL-C goal (67-74%) compared with those receiving placebo plus statin (19-22%). Other parameters demonstrating greater improvement with ezetimibe included triglycerides, apolipoprotein (Apo)B/Apo A-I ratio, high-density lipoprotein cholesterol (HDL-C), and C-reactive protein. Ezetimibe plus statin was well tolerated in each group. Ezetimibe added to ongoing statin therapy offers a new treatment option that is consistently effective in improvement of lipid profiles and attainment of LDL-C goals in patients with without diabetes or metabolic syndrome.
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PMID:Ezetimibe added to ongoing statin therapy improves LDL-C goal attainment and lipid profile in patients with diabetes or metabolic syndrome. 1705 29

Although statins are effective in reducing cardiovascular risk, combination therapy may be required to meet recommended target LDL-C levels. However, the utility of current combination therapies with niacin or bile acid sequestrants is limited by side effects and compliance. Ezetimibe, as a selective cholesterol absorption inhibitor, represent a new class of pharmaceutical agents. The combination of ezetimibe with statins has shown a 16-21% increase in the percentage of patients achieving their ATP III LDL-C goal. Randomized, double-blind studies have shown that coadministration of ezetimibe with simvastatin is well tolerated, causing dose-dependent reduction in LDL-C and total cholesterol levels, with no apparent effect on high-density lipoprotein cholesterol or triglycerides. Even in diabetes mellitus type 2 patients; the addition of ezetimibe 10 mg to simvastatin 20 mg is more efficacious than doubling the dose of simvastatin in lowering lipid parameters. Similarly the coadministration of ezetimibe and rosuvastatin, has shown a mean incremental reduction in LDL-C of -16%, compared with rosuvastatin alone, while there was no apparent effect on HDL-C or triglycerides. Ezetimibe and fenofibrate co-administration has shown also improvement in the lipid/lipoprotein profile. The combination therapy with ezetimibe and statin or fibrate may be an effective therapeutic option for patients with dyslipidemia.
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PMID:Combination of a sterol absorption inhibitor and cardiovascular agents for the treatment of dyslipidemia. 1822 Oct 76

Type 2 diabetes plays a major role in the development of cardiovascular diseases. The present study was undertaken to investigate the effect of ezetimibe, a potent cholesterol absorption inhibitor, on cardiovascular injury of obese and type 2 diabetic db/db mice. Diabetic db/db mice fed a Western diet were given ezetimibe for 9 weeks, and the effects on cardiovascular injury and hepatic steatosis were examined. Ezetimibe treatment of db/db mice significantly improved vascular endothelial function, which was associated with the restoration of the decreased phospho-Akt and phospho-endothelial nitric-oxide synthase (eNOS). Moreover, ezetimibe also reduced vascular superoxide levels in db/db mice, accompanied by the attenuation of NADPH oxidase subunit gp91(phox) and Nox4 and the prevention of down-regulation of Cu/Zn-superoxide dismutase (SOD) and extracellular SOD. Thus, the improvement of vascular endothelial function by ezetimibe in diabetic mice seems to be attributed to the improvement of eNOS function and the attenuation of oxidative stress. Ezetimibe treatment also significantly attenuated cardiac interstitial fibrosis and coronary arterial thickening of diabetic mice and ameliorated cardiac macrophage infiltration. This improvement of cardiac injury was also related to the attenuation of NADPH oxidase-mediated oxidative stress. Furthermore, ezetimibe significantly prevented hepatic steatosis, inflammation, and oxidative stress in diabetic mice. Our work provides the first evidence that ezetimibe prevented cardiovascular injury and hepatic steatosis in diabetic mice. These beneficial effects were attributed to the attenuation of oxidative stress and inflammation and the improvement of eNOS function. Therefore, we propose that ezetimibe may be a promising therapeutic drug for obese and type 2 diabetes.
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PMID:Ezetimibe ameliorates cardiovascular complications and hepatic steatosis in obese and type 2 diabetic db/db mice. 2065 Oct 26

Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent with potential pleiotropic actions. Ezetimibe in combination with a statin is effective in decreasing low density lipoprotein cholesterol(LDL-C), lowering triglyceride and raising high density lipoprotein cholesterol levels. Ezetimibe plus statin achieve LDL-C targets in a greater proportion of patients than statin monotherapy. Ezetimibe also seems to improve renal function, insulin resistance and inflammatory markers. These actions are useful in patients with diabetes. Ezetimibe is a well-tolerated and effective (in terms of achieving LDL-C targets) option inpatients with hyperlipidemia with or without diabetes. This editorial will discuss several properties of ezetimibe, with special reference to diabetes.
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PMID:Ezetimibe in diabetes: more than cholesterol lowering? 2084 63

Ezetimibe is a relatively new drug that inhibits the absorption of dietary cholesterol in the small intestine. It is a low density lipoprotein-cholesterol (LDL-C) lowering medication that acts directly on the intestine by inhibiting Niemann-Pick C1 Like1 (NPC1L1). Recently, results of the ARBITER 6-HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) and the ENHANCE trial (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) showed that ezetimibe had no effect on atherosclerosis despite producing a marked decrease in LDL-C. Recent studies show a potential benefit of ezetimibe in treating insulin resistance, non-alcoholic fatty liver disease (NAFLD), gallstones and dyslipidaemia associated with chronic renal failure and organ transplantation. All of these conditions are known to be associated with an increase in risk of cardiovascular disease (CVD) and further studies are needed to assess the potential benefits of ezetimibe in these therapeutics areas.
Diabetes Obes Metab 2010 Nov
PMID:Potential therapeutic uses for ezetimibe beyond lowering LDL-c to decrease cardiovascular events. 2088 Mar 42

Patients with diabetes or metabolic syndrome frequently have higher triglycerides, lower high-density lipoprotein (HDL) cholesterol, and more particles containing apolipoprotein B (ApoB); this combination contributes significantly to their cardiovascular risk. Optimal management of dyslipidemia and increased atherosclerotic risk requires a fundamental understanding of diabetic dyslipidemia, the clinical evidence for different interventional strategies, and the potential benefit of achieving therapeutic targets. For this review, we considered guidelines, recent reviews, and clinical trial results. The features of dyslipidemia in type 2 diabetes and the metabolic syndrome are linked metabolically and are related to central adiposity and insulin resistance. Levels of ApoB and HDL cholesterol are particularly important markers of risk. Guidelines broadly agree that low-density lipoprotein (LDL) cholesterol should be reduced below population average levels. Additional or secondary strategies in patients with diabetes or the metabolic syndrome are to decrease non-HDL cholesterol, ApoB and/or LDL particle concentration, to increase HDL cholesterol, and to reduce triglycerides. Lifestyle changes and statins are the bedrock of treatment, although second-line treatment using fibrates or niacin will likely benefit many patients with residual risk. Ezetimibe, too, has a favorable effect on lipid profile and inflammatory biomarkers of risk. Dyslipidemia in type 2 diabetes and metabolic syndrome has a distinct profile, suggesting the need for a tailored therapy that targets the key features of lowered HDL cholesterol and raised triglycerides, in addition to the primary antiatherogenic strategy of lowering ApoB-containing lipoproteins, such as LDL. With the prominent failure of some recent intervention trials, new therapeutic strategies-particularly safe and effective means to raise HDL-are needed to manage dyslipidemia in this high-risk population.
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PMID:Optimal management of lipids in diabetes and metabolic syndrome. 2129 58


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