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

Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and uric acid as well and it increases HDL cholesterol; in diabetics it improves glycated hemoglobin. Sibutramine has conflicting effects on blood pressure: in some studies there was a minimal decrease, in some others a modest increase. In all the studies this drug increased pulse rate. Sibutramine is not recommended in patients with uncontrolled hypertension, or in case of history of cardio- and cerebrovascular disease. Orlistat is a pancreatic lipase inhibitor that reduces fat absorption by partially blocking the hydrolysis of dietary triglycerides. A recent meta-analysis evaluated 22 studies lasting for at least 12 months, in obese patients with a mean body mass index of 36.7 kg/m2, where orlistat was associated with hypocaloric diet or behavioral interventions: the net average weight loss was 2.89 kg (confidence interval 2.27-3.51 kg). Considering the principal studies, attrition rate ranged from 33 to 57%. Orlistat significantly decreases waist circumference, blood pressure, total and LDL cholesterol, but has no effect on HDL and triglycerides. This drug significantly reduced the incidence of diabetes only in subjects with impaired glucose tolerance. The major adverse effects with orlistat are mainly gastrointestinal (fatty and oily stool, fecal urgency, oily spotting, fecal incontinence) and attenuate over time. Orlistat should be avoided in patients with chronic malabsorption and cholestasis. Rimonabant is a selective antagonist of cannabinoid type 1 receptor. This drug, by inhibiting the overactivation of the endocannabinoid system, produces anorectic stimuli at the central nervous level, but also has effects on the peripheral systems involved in metabolism control, such as liver, adipose tissue, skeletal muscles, endocrine pancreas, and gastrointestinal apparatus, influencing many processes partially unknown. An ample experimental program named RIO (Rimonabant In Obesity) involved about 6600 obese or overweight patients to identify the effects of rimonabant in weight loss and associated cardiometabolic abnormalities, over and beyond a caloric restriction of 600 kcal in the treatment and placebo arms. In the four double-blind RIO trials published (Rio-North America, RIO-Europe, RIO-Lipids, RIO-Diabetes), rimonabant 20 mg significantly (p <0.001) reduced weight by 6.3-6.9 kg in the non-diabetic groups vs placebo (-1.5-1.8 kg), whereas in the diabetic subjects enrolled in RIO-Diabetes, weight loss was 5.3 vs 1.4 kg in the placebo group. Attrition rate at 1 year ranged between 40 and 50%, similar to the studies with sibutramine or orlistat. Similarly to weight loss, also waist circumference was significantly reduced by rimonabant. As for cardiometabolic parameters, rimonabant induced a significant increase in HDL cholesterol and a significant decrease in triglycerides. Even if no significant LDL reduction was achieved, the RIO-Lipids study showed a significant decrease in small dense LDL particles, more atherogenic, in rimonabant-treated subjects. Non-diabetic treated patients improved basal insulin and indirect indexes of insulin resistance, while in the RIO-Diabetes study, the only one including diabetics, glycated hemoglobin improved by 0.7% in the active treatment arm vs placebo. The effects on HDL cholesterol and glycated hemoglobin seem in a large percentage unrelated to weight loss. These effects have been confirmed by another trial, named SERENADE, evaluating the treatment in naive diabetic patients. Rimonabant is not recommended in patients with a history of depressive disorders or suicidal ideation and with uncontrolled psychiatric illness, and is contraindicated in patients with ongoing major depression or ongoing antidepressive treatment. In conclusion, despite an enormous advancement in basic research to understand the pathogenetic mechanisms at the base of obesity, the pharmacological research did not reach the therapeutic opportunities available for other chronic conditions, like hypertension and dyslipidemia. However, the few molecules available for clinical practice (sibutramine, orlistat, rimonabant) have shown, when properly used, to contribute to reduce body weight and undoubtedly improve cardiometabolic risk factors. With this preamble, according to current guidelines and pharmacoeconomic studies, patients who might benefit from antiobesity treatment are those with a body mass index > or =30 or 27-29.9 kg/m2 with major obesity-related comorbidities such as hypertension, diabetes, dyslipidemia, obstructive sleep apnea, and metabolic syndrome.
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PMID:[Pharmacological therapy of obesity]. 1877 55

Although low-density lipoprotein (LDL) cholesterol is often normal in patients with type 2 diabetes mellitus, there is evidence for a reduced fractional catabolic rate and consequently an increased mean residence time (MRT), which can increase atherogenic risk. The dyslipidemia and insulin resistance of type 2 diabetes mellitus can be improved by aerobic exercise, but effects on LDL kinetics are unknown. The effect of 6-month supervised exercise on LDL apolipoprotein B kinetics was studied in a group of 17 patients with type 2 diabetes mellitus (mean age, 56.8 years; range, 38-68 years). Patients were randomized into a supervised group, who had a weekly training session, and an unsupervised group. LDL kinetics were measured with an infusion of 1-(13)C leucine at baseline in all groups and after 6 months of exercise in the patients. Eight body mass index-matched nondiabetic controls (mean age, 50.3 years; range, 40-67 years) were also studied at baseline only. At baseline, LDL MRT was significantly longer in the diabetic patients, whereas LDL production rate and fractional clearance rates were significantly lower than in controls. Percentage of glycated hemoglobin A(1c), body mass index, insulin sensitivity measured by the homeostasis model assessment, and very low-density lipoprotein triglyceride decreased (P < .02) in the supervised group, with no change in the unsupervised group. After 6 months, LDL cholesterol did not change in either the supervised or unsupervised group; but there was a significant change in LDL MRT between groups (P < .05) that correlated positively with very low-density lipoprotein triglyceride (r = 0.51, P < .04) and negatively with maximal oxygen uptake, a measure of fitness (r = -0.51, P = .035), in all patients. The LDL production and clearance rates did not change in either group. This study suggests that a supervised exercise program can reduce deleterious changes in LDL MRT.
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PMID:Effect of 6-month supervised exercise on low-density lipoprotein apolipoprotein B kinetics in patients with type 2 diabetes mellitus. 1894 Apr 1

The etiology and pathogenesis of type 2 diabetes mellitus (T2DM) are not completely understood although it is often associated with other conditions such as obesity, hypertension, and dyslipidemia. Lipoprotein lipase (LPL) is a key enzyme in human lipid metabolism that facilitates the removal of triglyceride-rich lipoproteins from the bloodstream. LPL hydrolyzes the core of triglyceride-rich lipoproteins (chylomicrons and very low density lipoprotein) into free fatty acids and monoacylglycerol. To gain insight into the possible role of LPL in T2DM, nine single nucleotide polymorphisms (SNPs) of LPL were analyzed for the association with T2DM using 944 unrelated Koreans, including 474 T2DM subjects and 470 normal healthy controls. Of the nine LPL SNPs we analyzed, a significant association with multiple tests by the false discovery rate (FDR) was observed between T2DM and SNP rs343 (+13836C>A in intron 3). SNP rs343 was also marginally associated with some of T2DM-related phenotypes including total cholesterol, high density lipoprotein cholesterol (HDLc), and log transformed glycosylated hemoglobin in 470 normal controls, although no significant association was detected by multiple tests. In total, our results suggest that the control of lipid level by LPL in the bloodstream might be an important factor in T2DM pathogenesis in the Korean population.
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PMID:Association of lipoprotein lipase (LPL) single nucleotide polymorphisms with type 2 diabetes mellitus. 1898 10

Data from the Centers for Disease Control and Prevention indicate that the prevalence of diabetes is increasing steadily and is coupled with a rise in obesity. Studies such as the Nurses' Health Study show that even slight glucose abnormalities, namely insulin resistance, increase the risk of myocardial infarctions, strokes, other cardiovascular disease, and mortality. Insulin resistance was found to accelerate atherosclerosis, inflammation, the onset of diabetes, cardiovascular disease, obesity, hypertension, chronic kidney disease, and dyslipidemia. Adiponectin was found to have potent antiinflammatory and antiatherosclerotic effects. Similarly, studies indicate that peroxisome proliferators-activated receptor agonists have the potential to treat obesity, diabetes, and atherosclerosis. From a preventive standpoint, it was shown that intensive glucose control reduces long-term cardiovascular risk. This intensive control approach included the use of thiazolidinediones (TZDs; troglitazone, pioglitazone, and rosiglitazone), which were demonstrated to have vascular and nonglycemic effects beyond glucose-lowering. A drawback of using TZDs is peripheral fluid retention. The DREAM study showed that participants with impaired fasting glucose or impaired glucose tolerance who are free from cardiovascular disease benefited significantly from taking 8 mg rosiglitazone per day. The ADOPT study provided evidence that rosiglitazone is more efficient at controlling glycemic loss and maintaining low glycosylated hemoglobin levels than metformin and glyburide. Data from the CHICAGO study indicate that the progression of carotid artery intima-media thickness, a marker of atherosclerosis and a surrogate end point for cardiovascular disease, was slowed more with pioglitazone than glimepiride in a racially diverse population of men and women with diabetes mellitus type 2. Overall, investigators have shifted from a focus on hyperglycemia to a multifactorial approach to risk management in diabetes. This multifactorial approach includes intensive glycemic control, lifestyle intervention, and intensive management of comorbid (dyslipidemia, hypertension, early renal disease) conditions. The implementation of a regular, rigorous exercise and diet program greatly decreased insulin resistance and allowed far more patients to reach their glycosylated hemoglobin goals. Studies with atrovastatin show significant improvement in cardiovascular risk factors in patients with diabetes and hypertension. Short-term studies provide support for the administration of a combination of TZD + sulfonylureas in patients with diabetes mellitus type 2. Likewise, studies have shown that a combination of TZDs + metformin reduced the risk of myocardial infarction. Finally, dipeptidyl peptidase-IV inhibitors and glycolipoprotein-1 analogs show potential for helping prevent the deterioration of glucose metabolism in early diabetes mellitus type 2.
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PMID:Cardiovascular manifestations of insulin resistance. 1911 74

Evidence-based guidelines for the treatment of type 2 diabetes mellitus focus on three areas: intensive lifestyle intervention that includes at least 150 minutes per week of physical activity, weight loss with an initial goal of 7 percent of baseline weight, and a low-fat, reduced-calorie diet; aggressive management of cardiovascular risk factors (i.e., hypertension, dyslipidemia, and microalbuminuria) with the use of aspirin, statins, and angiotensin-converting enzyme inhibitors; and normalization of blood glucose levels (hemoglobin A1C level less than 7 percent). Insulin resistance, decreased insulin secretion, and increased hepatic glucose output are the hallmarks of type 2 diabetes, and each class of medication targets one or more of these defects. Metformin, which decreases hepatic glucose output and sensitizes peripheral tissues to insulin, has been shown to decrease mortality rates in patients with type 2 diabetes and is considered a first-line agent. Other medications include sulfonylureas and nonsulfonylurea secretagogues, alpha glucosidase inhibitors, and thiazolidinediones. Insulin can be used acutely in patients newly diagnosed with type 2 diabetes to normalize blood glucose, or it can be added to a regimen of oral medication to improve glycemic control. Except in patients taking multiple insulin injections, home monitoring of blood glucose levels has questionable utility, especially in relatively well-controlled patients. Its use should be tailored to the needs of the individual patient.
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PMID:Management of blood glucose in type 2 diabetes mellitus. 2064 60

Elderly patients are at a higher risk for complications after percutaneous coronary intervention (PCI) when performed through the femoral approach. The impact of age on complications in patients treated using the transradial approach is not known. The bleeding and ischemic outcomes at 30 days, 6 months, 1 year, and 3 years after transradial PCI and maximal antiplatelet therapy were compared in 1,348 patients aged <70 or > or =70 years with acute coronary syndromes. All patients received aspirin and clopidogrel before catheterization, followed by abciximab at the time of PCI. Patients aged > or =70 years (n = 259 [19%]) had more hypertension, dyslipidemia, family histories, and previous coronary artery bypass grafting. Older patients had lower baseline hemoglobin, platelet, and creatinine clearance values, and they also more often had 2- or 3-vessel syndrome (p = 0.001), as well as longer procedure durations (p = 0.024). At 30 days, the rates of major adverse cardiac events and major bleeding were similar in older and younger patients. Only the incidence of gastrointestinal bleeding (p = 0.021) and mild to moderate access-site hematoma were higher in older patients (p = 0.036). The rates of major adverse cardiac events were also similar in the 2 age groups at 6 months (6% vs 9%, p = 0.08), 1 year (10% vs 13%, p = 0.22), and 3 years (19% vs 20%, p = 0.73), but mortality was significantly higher at 3 years in patients aged > or =70 years (p = 0.0031). In conclusion, age per se is not a predictor of major adverse cardiac events or major bleeding after transradial PCI with maximal antiplatelet therapy. However, older patients remain more prone to gastrointestinal bleeding and local hematoma compared to younger patients, and preventive measures need to be further investigated.
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PMID:Comparison of outcomes in patients > or =70 years versus <70 years after transradial coronary stenting with maximal antiplatelet therapy for acute coronary syndrome. 1969 34

Subclinical atherosclerosis in young beta-thalassemia major (beta-TM) patients and its risk factors including dyslipidemia compared to type 1 diabetic patients were assessed. Ninety subjects were included and divided into three groups: group I comprised 30 beta-TM patients with a mean age of 18.4 +/- 6.18 years; group II comprised of 30 type 1 diabetic patients with a mean age of 19.23 +/- 4.25 years, and 30 healthy subjects served as controls in group III. Fasting lipid profiles, hemoglobin (Hb) electrophoresis, serum ferritin and high resolution ultrasound for the measurement of carotid artery intima media thickness (CIMT) were done. Serum triglycerides, total cholesterol, apoprotein A (ApoA), and CIMT were significantly elevated, while high density lipoproteins (HDL) were significantly lowered in thalassemic and diabetic patients compared to controls. In thalassemic patients, CIMT was positively correlated with age, Hb F, ferritin and cholesterol levels. Atherogenic lipid profiles in young thalassemic patients with increased CIMT highlights their importance as prognostic factors for vascular risk stratification.
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PMID:Subclinical atherosclerosis in young beta-thalassemia major patients. 1995 91

The aim of this study was to assess whether body mass index (BMI) was associated with abnormal results of other tests related to metabolic disorders in the periodic health checkup, and determine whether changes in BMI were associated with changes in these other tests. We surveyed 2,392 Japanese male workers, aged 19-59 who have received regular health checkups in 2003 and 2004. During the mandatory workplace health checkup, the following are tested: BMI, systolic and diastolic blood pressure, and the levels of total cholesterol, triglyceride, high density lipoprotein cholesterol, hemoglobin A(1C), aspartate aminotransferase, alanine aminotransferase, and gammaglutamyl transpeptidase. These parameters were measured in 2003 and 2004. The receiver operating characteristic (ROC) curve was used to determine the efficacy of BMI in screening for abnormal results in 2003. The areas under the ROC curves for hypertension, dyslipidemia, diabetes, and liver dysfunction were 0.68-0.89, 0.65-0.67, and 0.51-0.67 for 19-39, 40-49, and 50-59 yr olds, respectively. Multiple regression analysis revealed that changes in BMI were significantly associated with changes in the respective items in one year. The BMI predicts metabolic disorders to a certain extent, especially in younger workers, and BMI monitoring may be a useful indicator of change in other annual health checkup items.
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PMID:Body mass index as an indicator of metabolic disorders in annual health checkups among Japanese male workers. 1999 36

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

Chronic kidney disease (CKD) is a strong risk factor for cardiovascular events and death. Hypertension, dyslipidemia, anemia, vascular calcification, and secondary hyperparathyroidism have all been implicated in the pathogenesis of cardiovascular disease associated with CKD. Numerous trials have been performed assessing the effects of modifying these risk factors on cardiovascular events and on the progression to end-stage renal disease. Many guidelines have been issued. In this article we review the guidelines and the strength of evidence supporting them. Specifically, we discuss blood pressure goals for patients with CKD, the role of renin-angiotensin system blocking agents for blood pressure control and proteinuria reduction, and the evidence for treatment recommendations of dyslipidemia. We review the trials addressing risks and benefits of different hemoglobin targets for treatment of anemia with erythropoietin. The use of phosphate-binding drugs to prevent and treat secondary hyperparathyroidism is likely beneficial, but few data support the use of vitamin D compounds. Supplementation with sodium bicarbonate may be an inexpensive treatment to retard progression to end-stage renal disease. The article concludes with a discussion of the case vignette presented in the previous article.
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PMID:Management of chronic kidney disease: what is the evidence? 2013 75


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