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Monumental advances in the field of lipid metabolism and its relationship to atherosclerotic cardiovascular disease have been achieved during the last half century. Epidemiologic studies have defined lipid disorders as highly significant independent risk factors for coronary heart disease, along with diabetes mellitus, hypertension and smoking. Primary and secondary prevention studies including the Coronary Primary Prevention Trial, Helsinki Heart Study, and the Coronary Drug Project have shown that lowering the atherogenic low density lipoproteins (LDL) and very low density lipoproteins (VLDL) whilst raising the high density lipoproteins (HDL) significantly decreases the risk for coronary disease. Striking evidence that aggressive therapy (to sharply lower LDL and raise HDL with newer drugs) prevents progression and induces regression of coronary narrowing has been obtained in numerous recent studies using quantitative coronary arteriography. An interesting and unexpected lesson learned from these arteriographic studies was that a highly significant reduction within months in several studies in coronary events was out of proportion to improvements in luminal narrowing. Recently, three major clinical trials to assess the effects of cholesterol reduction by the newly discovered HMG CoA reductase inhibitors (statins) have been published. Pravastatin significantly reduced coronary events in hypercholesterolemic patients [mean LDL-Chol. = 5.0 mM/L (192 mg/dl)] without a history of myocardial infarction. In a secondary prevention study, simvastatin also reduced coronary complications in hypercholesterolemic patients [mean LDL-Chol. = 4.9 mM/L (190 mg/dl)] with pre-existing coronary disease. Very recently, pravastatin treatment significantly reduced coronary events and stroke in patients with a history of myocardial infarction and average cholesterol levels [mean LDL-Chol. = 3.6 mM/L (139 mg/dl)], representing the majority of patients with coronary disease. In all these studies, reduction in cardiovascular events was approximately one-third. In subgroup analyses, men, women, elderly, smokers and hypertensives benefited from cholesterol lowering. There was no significant increase in non-cardiovascular causes of death. In the United States of America, the National Cholesterol Education Program (NCEP) Adult Treatment Panel, representing major health organizations, developed national guidelines on the detection, evaluation and treatment of high blood cholesterol in adults. In a given patient, the Panel recognizes the importance of weighing all cardiovascular disease risk factors including age (men > 45 years, postmenopausal women), family history of premature coronary disease, smoking, hypertension, diabetes and HDL-Cholesterol (< 35 mg/dl) in determining how aggressive therapy should be. The patient with manifest coronary heart disease (CHD) is given a special position as such patients are at highest risk for recurrent events. Major goals of therapy are to lower the LDL-Cholesterol to 2.6 mM/L (< 100 mg/dl) in the CHD patient. In non-CHD patients with two or more risk factors, the LDL-Cholesterol goal is 3.4 mM/L (130 mg/dl). In those with fewer risk factors, the goal is 4.2 mM/L (160 mg/dl). These guidelines should be modified as appropriate for Singapore. Patients with elevated triglycerides usually have low HDL-Cholesterol levels and often represent a heterogeneous group who may have other concurrent abnormalities including the presence of small dense LDL, insulin resistance, hypertension, obesity, overt diabetes and combined hyperlipidemia. Such patients merit individualized treatment. The prevalence of this syndrome may be more common in Singapore and requires further investigation. Current therapeutic guidelines emphasize the need for weight loss and dietary restriction of total and especially saturated fat (< 7% to 10% total calories), cholesterol (< 200 to 300 mg/day), and exercise. (ABSTRACT TRUNCATED)
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PMID:Cholesterol and atherosclerosis: a contemporary perspective. 939 24

Patients with diabetes mellitus (DM), type 1 and type 2, have an increased risk of coronary heart disease as a result of accelerated atherosclerosis. Dyslipidemia, often found in these patients, plays an important role in this process. This study investigates the efficacy and safety of lipid-lowering therapy with pravastatin, a 3-HMG-Coenzym A reductase inhibitor in hypercholesterolemic type-1 and type-2 diabetic patients. Of 49 patients (22 type-1 DM and 27 type-2 DM), 24 patients were treated with pravastatin, 20 mg/day, and 25 patients with placebo. After 24 weeks, total cholesterol (TC) was decreased by 22.2%, low-density lipoprotein (LDL) cholesterol by 25.8% and triglycerides (TG) by 13.6%. Pravastatin treatment did not induce a significant change in high-density (HDL) cholesterol levels. No differences in effects of pravastatin treatment on serum lipids and lipoproteins were found with respect to the diabetes type. No serious side effects occurred and pravastatin treatment did not cause any deterioration in glycemia control. The data suggest that pravastatin is effective and safe in the treatment of dyslipidemia in both type-1 and type-2 diabetic patients.
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PMID:Pravastatin in diabetes-associated hypercholesterolemia. 945 75

Cardiovascular disease is the leading cause of death and the leading source of healthcare expenditure in the US and most other industrialised countries. Cholesterol lowering by pharmacological means prevents atherosclerotic plaque progression and has been shown to reduce both fatal and nonfatal coronary events in patients with or without coronary artery disease (CAD). Because of their excellent efficacy and safety profiles, the introduction of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known an 'statins') in 1987 raised hopes for demonstrating the survival benefit of cholesterol reduction. In the past decade, several large-scale placebo-controlled trials with statin therapy have revisited the relationship between cholesterol reduction, cardiovascular disease and mortality. The West of Scotland Coronary Prevention Study (WOSCOPS) [pravastatin] and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [lovastatin] have shown significant cardiovascular disease reduction in primary prevention trials of patients with elevated and normal cholesterol levels, respectively. The Scandinavian Simvastatin Survival Study (4S), the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study and the Cholesterol and Recurrent Events (CARE) trial [pravastatin] have shown significant cardiovascular disease reduction in patients with a previous history of CAD with high, moderate and normal cholesterol levels, respectively. Three of these studies (4S, WOSCOPS and LIPID) have shown significant reduction in all-cause mortality, while all the statin secondary prevention trials (4S, CARE and LIPID) have demonstrated significant reduction in cerebrovascular disease/ Earlier cholesterol reduction cost-effectiveness studies with nonstatin treatments (bile acid resins, fibrates, niacin and diet) suggested that only patients at extremely high risk could be treated with lipid therapy in a cost-effective manner. More recently, rigorous outcomes evidence demonstrates that statins, particularly for simvastatin for secondary prevention and lovastatin for primary prevention, have a broadly favourable cost-effectiveness profile. Based on US medical price levels and the available clinical trial data on statins, it would be cost effective [e.g. cost less than $US50,000/year of life saved] to intervene with statin therapy in any patient with an annual CAD risk exceeding 1%. This includes all patients with pre-existing CAD or diabetes mellitus, and many more primary prevention patients than are currently contemplated by the US National Cholesterol Education Panel treatment guidelines. Achieving such a goal will require enormous changes in patient education, clinical perspective, healthcare practice and healthcare finances. But any proven opportunity for saving the lives of 25% of those dying from cardiovascular disease each year deserves to be considered with the utmost seriousness and urgency.
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PMID:Pharmacoeconomics of lipid-lowering agents for primary and secondary prevention of coronary artery disease. 1034 58

Hyperlipemia is frequent in liver transplanted patients and has been related with the existence of cholestasis, renal insufficiency, obesity, diabetes, and especially with immunosuppressant treatment. Although there are no studies that show a relationship between post-liver transplant hyperlipemia and the development of cardiovascular disease, there are data that indicate that liver transplanted patients should control their cholesterol levels to reduce the incidence of this disease. When post-transplant hyperlipemia is present, hygienic-dietary measures should be established and treatment should be carried out with the minimum dose of cyclosporine needed to maintain the graft stable. Corticoids should be discontinued as soon as possible. Treatment with some statins (Lovastatin and Pravastatin) has shown to be safe and efficacy in the liver transplanted patients with hypercholesterolemia.
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PMID:[Hyperlipidemia in liver transplanted patients]. 1050 13

Hypertriglyceridaemia is a risk factor for cardiovascular disease in patients suffering from Type II diabetes mellitus, and is due to enhanced synthesis and/or impaired clearance of triacylglycerol-rich lipoproteins. In the present study we investigated whether pseudocholinesterase (PChE) activity could serve as a marker for the rate of triacylglycerol synthesis in these patients. Patients were stratified according to their apolipoprotein E (apoE) phenotype, i.e. E3E2, E3E3 or E3E4. In study I, the relationship between PChE activity and serum triacylglycerols was investigated in 224 insulin-treated patients with Type II diabetes. In study II, which had a cross-over design, PChE activity was measured in 45 dyslipidaemic, insulin-treated patients with Type II diabetes that were treated with bezafibrate or pravastatin. In study I, PChE activity was correlated positively with serum triacylglycerol concentrations, but did not differ significantly between apoE phenotypes. The strongest relationship was found in the E3E4 group (r=0.50; P=0.001), the phenotype for which hypertriglyceridaemia is expected to be the result of increased triacylglycerol synthesis. In a stepwise multiple regression analysis, serum triacylglycerol concentrations were found to be the strongest predictor of PChE activity in the E3E4 group. In study II, PChE activity decreased as a result of bezafibrate treatment in all three apoE groups. The decrease in PChE activity with bezafibrate treatment paralleled the decrease in serum triacylglycerol concentrations in the apoE subgroups. Pravastatin treatment did not significantly affect PChE activity. Thus the present study suggests an association between PChE activity and the rate of triacylglycerol synthesis. Measurement of PChE activity may therefore be a useful tool in the choice of drug for treatment of hypertriglyceridaemia in patients with Type II diabetes.
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PMID:Is pseudocholinesterase activity related to markers of triacylglycerol synthesis in Type II diabetes mellitus? 1141 Jan 11

Pravastatin is a potent inhibitor of HMG-CoA reductase and is effective in lowering serum lipid levels. Recent studies have shown that pravastatin also reduces oxidative modification of LDL and decreases albuminuria in patients with diabetes. To determine the possible benefit of pravastatin on the diabetic kidney, we have measured the effects of pravastatin on the proliferation and the production of superoxide and fibronectin, and the expression of fibronectin mRNA of glomerular mesangial cells stimulated by oxidized-LDL and high glucose. Our results demonstrated that the [(3)H]-labeled thymidine uptake of mesangial cells decreased after oxidized-LDL stimulation (50 microg/ml, 6 h) and increased after high glucose stimulation (25 mM, 48 h). The production of superoxide and fibronectin and the expression of fibronectin mRNA of glomerular mesangial cells were all significantly increased after stimulation with either oxidized-LDL or high glucose, or the combination of oxidized-LDL and high glucose. Pravastatin (100 microM, 48 h) alone had no effect on unstimulated cells. However, pravastatin significantly reversed thymidine uptake, inhibited the production of superoxide and fibronectin, and inhibited the expression of fibronectin mRNA of glomerular mesangial cells after stimulation with either oxidized-LDL or high glucose. Our results indicate that pravastatin may effect as an antioxidant and may suppress fibronectin synthesis of glomerular mesangial cells in diabetic patients with hyperlipidemia.
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PMID:Pravastatin suppress superoxide and fibronectin production of glomerular mesangial cells induced by oxidized-LDL and high glucose. 1175 31

BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0-9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.
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PMID:A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics. 1209 48

Lipid abnormalities, which are common in type 2 diabetes, predispose to a greatly increased risk of coronary heart disease. This characteristic dyslipidaemia includes decreased concentrations of high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and a small, dense, atherogenic form of low-density lipoprotein cholesterol (LDL-C). Insulin resistance and obesity, which is commonly present in type 2 diabetes, act in concert to disrupt normal lipoprotein metabolism; reverse cholesterol transport in particular. The proatherogenic changes, which result from this process include enrichment of very-low-density lipoprotein with cholesteryl esters and enrichment of LDL with triglycerides. Results from both the Pravastatin Pooling Project and the Heart Protection Study demonstrate that, although people with diabetes obtain the same relative risk reduction with statin therapy, the absolute benefit derived is much lower than for comparable individuals without diabetes. In order to achieve improved outcomes in diabetes patients, it will be important to address other abnormalities in their lipid profiles, including elevated triglycerides and low HDL-C.
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PMID:Does statin monotherapy address the multiple lipid abnormalities in type 2 diabetes? 1604 80

Both the American Diabetes Association (ADA) and the National Cholesterol Education Program (NCEP) consider type 2 diabetes mellitus to be a coronary artery disease (CAD) risk equivalent and thus suggest that patients with either diabetes or CAD should have their plasma levels of low-density lipoprotein (LDL) cholesterol lowered to <2.59 mmol/L (<100 mg/dL). Recently the NCEP issued a white paper suggesting an even lower plasma LDL cholesterol goal of <1.81 mmol/L (<70 mg/dL) for patients at high cardiovascular risk, including patients with diabetes. This rationale was based partly on the higher risk of future cardiovascular disease seen in patients who have diabetes with or without preexisting cardiovascular disease than in nondiabetic subjects with preexisting cardiovascular disease. Additionally, as reported in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study, high-dose lipid-lowering therapy has been shown to further reduce CAD event rates compared with conventional therapy.
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PMID:Rationale for new American Diabetes Association Guidelines: are national cholesterol education program goals adequate for the patient with diabetes mellitus? 1609 41

Despite meaningful progress in the identification of risk factors and the development of highly effective clinical tools, deaths from cardiovascular disease continue to increase worldwide. Sparked by an obesity epidemic, the metabolic syndrome and the rising incidence of type 2 diabetes have led to an upsurge of cardiovascular risk. Although pharmacologic treatments with the statin class of drugs have reduced cholesterol levels and lowered mortality rates, several large controlled clinical trials, including the Scandinavian Simvastatin Survival Study, the Cholesterol and Recurrent Events trial, the Air Force/Texas Coronary Atherosclerosis Prevention studies, and Long-term Intervention with Pravastatin in Ischemic Disease study, have indicated that cardiovascular events continue to occur in two thirds of all patients. Follow-up studies, such as the Heart Protection Study and the Pravastatin or Atorvastatin Evaluation and Infection Therapy/Thrombolysis In Myocardial Infarction-22 trials, reinforced these earlier results. Although therapy with gemfibrozil, a fibric acid derivative, showed reduced occurrence of cardiovascular events in the Helsinki Heart Study and the Veterans Affairs HDL Intervention Trial, results of other studies, e.g., the Bezafibrate Intervention Program and the Diabetes Atherosclerosis Intervention study, showed less encouraging results. Although lifestyle modifications, such as improved diet and increased exercise levels, benefit general health and the metabolic syndrome and insulin resistance in particular, most people continue to resist changes in their daily routines. Thus, physicians must continue to educate their patients regarding an optimal balance of drug therapy and personal behavior.
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PMID:The forgotten majority: unfinished business in cardiovascular risk reduction. 1619 35

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