Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
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Concept of sequence and time of appearance of various effects of statins is presented. Apart from hypolipidemic action due to inhibition of HMG CoA reductase activity statins exert multiple pleiotropic effects. Combination of these effects makes statins a unique instrument for solution of global tasks of prevention and treatment of atherosclerosis and its consequences (ischemic heart disease etc.). Manifestations of various pleiotropic effects of statins appear after different time intervals and in most cases are not related to suppression of cholesterol synthesis in the body. First 3-4 months (first level of the statin cascade) are characterized mainly by activity of pleiotropic properties aimed at restoration of endothelial function. These properties are responsible for enhanced eNOS expression, antiischemic, antithrombotic and antiatherogenic effects. During same period of time stabilization of unstable atheromas takes place. Manifestations of second level of the cascade of statin action appear after 2 years of treatment. They are represented by retardation of progression and even partial regression of atheromatosis of coronary and peripheral arteries. Third level is signified by achievement of strategic aims of therapy with statins (in 4-5 years) -- lowering of total and cardiac mortality, reduction of number of cardiac complications. Forth level of the cascade is represented by beneficial influences on nonatherogenic cardiological phenomena and comprise hypotensive, antiarrhythmic and cardiotonic effects. And finally some other important properties of statins constitute the fifth level of the therapeutic cascade. These properties are responsible for effects directed at noncardiac pathology (prevention of diabetes, dementia, including dementia associated with Alzheimer's disease, fractures). Immunodepression, ability to reduce saturation of bile with cholesterol belong to this group of effects.
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PMID:[Statins: therapeutic cascade of their effects]. 1547 99

Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of diabetic vasculopathy. They are both powerful independent predictors of cardiovascular risk. Advances in non-invasive methodologies have led to widespread clinical investigation of these abnormalities in diabetes mellitus, generating a wealth of new knowledge concerning the mechanisms of vascular dysfunction, risk factor associations and potential treatment targets. Endothelial dysfunction primarily reflects decreased availability of nitric oxide (NO), a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilatation of the brachial artery and plethysmography measurement of forearm blood flow responses to vasoactive agents. Arterial stiffness may be assessed using pulse wave analysis to generate measures of pulse wave velocity, arterial compliance and wave reflection. The pathogenesis of endothelial dysfunction in type 2 diabetes is multifactorial, with principal contributors being oxidative stress, dyslipidaemia and hyperglycaemia. Elevated blood glucose levels drive production of reactive oxidant species (ROS) via multiple pathways, resulting in uncoupling of mitochondrial oxidative phosphorylation and endothelial NO synthase (eNOS) activity, reducing NO availability and generating further ROS. Hyperglycaemia also contributes to accelerated arterial stiffening by increasing formation of advanced glycation end-products (AGEs), which alter vessel wall structure and function. Diabetic dyslipidaemia is characterised by accumulation of triglyceride-rich lipoproteins, small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL)-cholesterol and increased postprandial free fatty acid flux. These lipid abnormalities contribute to increasing oxidative stress and may directly inhibit eNOS activity. Although lipid-regulating agents such as HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates) and fish oils are used to treat diabetic dyslipidaemia, their impact on vascular function is less clear. Studies in type 2 diabetes have yielded inconsistent results, but this may reflect sampling variation and the potential over-riding influence of oxidative stress, dysglycaemia and insulin resistance on endothelial dysfunction. Results of positive intervention trials suggest that improvement in vascular function is mediated by both lipid and non-lipid mechanisms, including anti-inflammatory, anti-oxidative and direct effects on the arterial wall. Other treatments, such as renin-angiotensin-aldosterone system antagonists, insulin sensitisers and lifestyle-based interventions, have shown beneficial effects on vascular function in type 2 diabetes. Novel approaches, targeting eNOS and AGEs, are under development, as are new lipid-regulating therapies that more effectively lower LDL-cholesterol and raise HDL-cholesterol. Combination therapy may potentially increase therapeutic efficacy and permit use of lower doses, thereby reducing the risk of adverse drug effects and interactions. Concomitant treatments that specifically target oxidative stress may also improve endothelial dysfunction in diabetes. Vascular function studies can be used to explore the therapeutic potential and mechanisms of action of new and established interventions, and provide useful surrogate measures for cardiovascular endpoints in clinical trials.
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PMID:Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy. 1561 50

Atorvastatin (Lipitor) is an HMG-CoA reductase inhibitor with well documented lipid-lowering effects. It has recently been evaluated for the primary prevention of major cardiovascular events in patients with type 2 diabetes mellitus without elevated serum low-density lipoprotein (LDL)-cholesterol levels. Atorvastatin 10mg daily for 4 years was effective at reducing the risk of a first major cardiovascular event, including stroke, in a large, placebo-controlled, multicentre trial in patients with type 2 diabetes and at least one other coronary heart disease (CHD) risk factor, but without markedly elevated LDL-cholesterol levels. In this trial, known as CARDS (the Collaborative AtoRvastatin Diabetes Study), atorvastatin had a similar tolerability profile to that of placebo. Thus, atorvastatin has a potential role in the primary prevention of cardiovascular events in diabetic patients at risk of CHD, irrespective of pre-treatment LDL-cholesterol levels.
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PMID:Atorvastatin: a review of its use in the primary prevention of cardiovascular events in patients with type 2 diabetes mellitus. 1561 62

Cardiovascular disease is the leading cause of mortality among people with diabetes mellitus, accounting for 70% of all deaths. As the prevalence of diabetes increases significantly worldwide, greater attention must be focused on preventing cardiovascular events in this group. One contributor to this increased event rate is the characteristic pattern of dyslipidemia in diabetic patients, consisting of elevated serum triglyceride levels, decreased high-density lipoprotein levels, and an increased proportion of small, dense, low-density lipoproteins. Several pharmacologic agents have been used to treat this dyslipidemia including HMG-CoA reductase inhibitors, fibric acid derivatives, niacin (nicotinic acid), thiazolidinediones, and fish oils, as well as other non-pharmacologic measures. Currently, the most extensive data for a reduction in cardiovascular events in patients with diabetes exist for HMG-CoA reductase inhibitors. The results of these trials indicate that HMG-CoA reductase inhibitor therapy should be considered for all patients with diabetes at sufficient risk for cardiovascular events, regardless of serum low-density lipoprotein-cholesterol level. Several ongoing trials of various pharmacologic agents should help clarify the role of these agents alone and in combination with HMG-CoA reductase inhibitors in the management of diabetic dyslipidemia.
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PMID:Management of diabetic dyslipidemia: need for reappraisal of the goals. 1572 39

Morbidity and mortality in patients with type 2 diabetes mellitus is largely dominated by the occurrence of cardiovascular disease (CVD). Treatment of known risk factors of CVD has proven to be beneficial in terms of reduction in risk of major CVD events in the general population. Recent trials have provided information on the treatment of hyperglycaemia, hypertension, dyslipidaemia and platelet aggregation in the patient with type 2 diabetes. Strict glycaemic control is not associated with a significant reduction in CVD risk, although new hypoglycaemic agents may offer additional benefits. In contrast, it has been demonstrated that treatment of hypertension and dyslipidaemia significantly reduce cardiovascular risk. Meticulous control of blood pressure to a level < or =130/80 mm Hg, preferably using renin-angiotensin system-modulating agents, is of proven value. Use of HMG-CoA reductase inhibitors (statins) as low-density lipoprotein (LDL)-cholesterol-lowering therapy, initiated at a level of > or =2.60 mmol/L is firmly established. Recent trials lend support to lowering the target level for LDL-cholesterol-lowering therapy to < or =1.81 mmol/L. Mainly based on risk analogy, international guidelines advocate the use of aspirin (acetylsalicylic acid) in the primary prevention of CVD in patients with type 2 diabetes. However, there is no support from large trials that the estimated 25% risk reduction in primary prevention in a high-risk population is the same in the subgroup with diabetes. An intensified approach in order to identify and treat cardiovascular risk factors in patients with type 2 diabetes, stratified to individual patients, is necessary to reduce the excess cardiovascular burden of these patients.
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PMID:Pharmacological strategies to reduce cardiovascular risk in type 2 diabetes mellitus: an update. 1573 8

We consider clinical trials where the time to occurrence of events in the presence of competing risks is the primary endpoint for treatment evaluation. The number of events with regard to the defined primary endpoint required to ensure the specified power can be calculated according to Schoenfeld's formula like in classical survival studies. However, determination of the number of patients that have to be recruited to observe the calculated number of events requires specification of the length of the accrual period, the trial duration and assumptions about the event-specific hazard functions. Information from previous studies about expected failure rates for the reference treatment is useful and can be translated into assumptions about the appropriate model parameters. A formula for sample size computation is presented for two competing outcome states. Nomograms help to communicate different alternatives of duration and size of the trial to interdisciplinary committees whose members plan and monitor the clinical trial. The 4D trial (Die Deutsche Diabetes Dialyse Studie) designed to compare lipid lowering treatment with HMG-CoA reductase inhibitor atorvastatin with placebo in type 2 diabetic patients on hemodialysis with respect to time to the composite event "cardiovascular death or non-fatal myocardial infarction" is used as an example to outline the statistical methods.
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PMID:Sample sizes for clinical trials with time-to-event endpoints and competing risks. 1591 72

Heme oxygenase (HO) has been shown to be important for attenuating the overall production of reactive oxygen species (ROS) through its ability to degrade heme and to produce carbon monoxide (CO), biliverdin/bilirubin, and the release of free iron. Excess free heme catalyzes the formation of ROS, which may lead to endothelial cell (EC) dysfunction as seen in numerous pathological conditions including hypertension and diabetes, as well as ischemia/reperfusion injury. The upregulation of HO-1 can be achieved through the use of pharmaceutical agents, such as metalloporphyrins and some HMG-CoA reductase inhibitors. Among other agents, atrial natriretic peptide and donors of nitric oxide (NO) are important modulators of the heme-HO system, either through induction of HO-1 or the biological activity of its products. Gene therapy and gene transfer, including site- and organ-specific targeted gene transfer, have become powerful tools for studying the potential role of HO-1/HO-2 in the treatment of various cardiovascular diseases as well as diabetes. HO-1 induction by pharmacological agents or gene transfer of human HO-1 into endothelial cells (ECs) in vitro increases cell-cycle progression and attenuates Ang II, TNF-, and heme-mediated DNA damage; administration in vivo acts to correct blood pressure elevation following Ang II exposure. Moreover, site-specific delivery of HO-1 to renal structures in spontaneously hypertensive rats (SHR), specifically to the medullary thick ascending limb of the loop of Henle (mTALH), has been shown to normalize blood pressure and provide protection to the mTAL against oxidative injury. In other cardiovascular situations, delivery of human HO-1 to hyperglycemic rats significantly lowers superoxide (O(2)(-)) levels and prevents EC damage and sloughing of vascular EC into the circulation. In addition, administration of human HO-1 to rats in advance of ischemia/reperfusion injury considerably reduces tissue damage. The ability to upregulate HO-1 through pharmacological means or through the use of gene therapy may offer therapeutic strategies for cardiovascular disease in the future. This review discusses the implications of HO-1 delivery during the early stages of cardiovascular system injury or in early vascular pathology and suggests that pharmacological agents that regulate HO activity or HO-1 gene delivery itself may become powerful tools for preventing the onset or progression of certain cardiovascular pathologies.
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PMID:Heme oxygenase and the cardiovascular-renal system. 1592 76

Insulin resistance plays an important role not only in the development and progression of diabetes mellitus but also in the establishment of metabolic syndrome. Improvement of insulin resistance is thus of great importance both in improving glucose metabolism and preventing atherosclerosis. Although HMG-CoA reductase inhibitors appear to favorably affect glucose metabolism, as indicated by the results of a subanalysis in the West of Scotland Coronary Prevention Study (WOSCOPS), their effects on glucose metabolism and insulin resistance have not been thoroughly investigated in animal models. In this study, the effects of atorvastatin on the glucose metabolism and insulin resistance of KK/Ay mice, an animal model of type II diabetes, were investigated. Atorvastatin significantly decreased the non-HDL-cholesterol level in the oral glucose tolerance test, inhibited increase in the 30-min glucose level, decreased plasma insulin levels before and 30 and 60 minutes after glucose loading, and decreased the insulin resistance index, compared with corresponding values in controls, indicating that atorvastatin appeared to improve glucose metabolism by improving insulin resistance. Northern blot analysis revealed decreases in levels of mRNA of sterol regulatory element binding protein-1 (SREBP-1) and glucose-6-phosphatase (G6Pase), and it may play a role in the improvement of glucose metabolism and insulin resistance.
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PMID:Effects of atorvastatin on glucose metabolism and insulin resistance in KK/Ay mice. 1594 17

Patients with diabetes mellitus have a 2- to 4-fold increased risk of atherosclerotic cardiovascular, peripheral vascular, and cerebrovascular disease, which are the leading causes of morbidity and mortality in this population. Several epidemiological studies have shown an association between diabetic dyslipidemia, which is characterized by hypertriglyceridemia, low levels of high density lipoprotein-cholesterol, postprandial lipemia and small, dense low density lipoprotein-cholesterol (LDL-C) particles, and the occurrence of cardiovascular disease. Other studies have established the beneficial effects of lipid lowering on the reduction of major coronary events in diabetic patients. The recent National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines emphasize diabetes as a coronary heart disease risk equivalent. The NCEP ATP III states that elevated LDL-C is a major risk factor for coronary heart disease, and the primary goal of risk-reduction therapy is the reduction of LDL-C levels to 100 mg/dL. This article defines and describes diabetic dyslipidemia and its etiology and pathogenesis, as well as reviewing guidelines and recommendations for treatment of this disorder. Treatment of diabetic dyslipidemia includes 1) lifestyle modifications: physical activity and a diet low in saturated fats and cholesterol and high in complex carbohydrates and fiber; and 2) pharmacological treatment with (i) oral antihyperglycemic agents: metformin and thiazolidinediones; (ii) weight reduction drugs: orlistat and sibutramine and; (iii) lipid-lowering drugs: HMG-CoA reductase inhibitors, fibric acid derivatives, nicotinic acid, and bile acid sequestrants.
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PMID:Pathogenesis and management of diabetic dyslipidemia. 1596 59

We report a patient in whom the administration of HMG CoA reductase inhibitors (statins) might have triggered the onset and worsening of diabetes. The patient was a 48-year-old Japanese man who underwent annual medical examination but had never been told of hyperglycemia. Four months after the commencement of atorvastatin (10 mg/day) treatment, a diagnosis of diabetes mellitus was made from his typical symptoms of hyperglycemia, postprandial plasma glucose level of 29.8 mmol/l and HbA1c of 11.5%. After 2 months of insulin therapy and 3 months after the cessation of atorvastatin, almost complete resolution of diabetes was observed. During the subsequent 3 months, diet therapy alone was sufficient to control blood glucose level. Then, we prescribed pravastatin (20 mg/day). During the subsequent 3 months, HbA1c was gradually increased. However, after discontinuation of pravastatin, HbA1c was gradually decreased. In the general population, statin does not seem to have critical adverse effects on glucose tolerance, but it may uncommonly modify the natural course of the development of diabetes in certain patients.
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PMID:Acute onset and worsening of diabetes concurrent with administration of statins. 1600 32


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