UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
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Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulfonylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women.Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on beta cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety.In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.
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PMID:New drugs for type 2 diabetes mellitus: what is their place in therapy? 1884 4

Diabetes mellitus and heart failure (HF) commonly coexist, and together these conditions are associated with increased morbidity and mortality compared with either condition alone. Although the optimal treatment strategy to achieve glucose control in HF patients with type 2 diabetes has not been well studied, given the common coexistence of these conditions and the need to adequately treat hyperglycemia to prevent microvascular complications, it is important for clinicians to understand the potential implications of diabetic therapy in patients with established HF. Until recently, metformin was contraindicated in patients with HF because of the potential risk of lactic acidosis; however, recent retrospective studies of metformin use in HF patients have shown that this medication may be used safely and indeed may be beneficial in patients with stable HF. The association between thiazolidinediones (TZDs) and HF remains controversial, but recent prospective randomized trials of TZD use in HF patients suggest that worsening volume retention associated with these agents may lead to worsening of HF symptoms. The recently developed incretin-based therapies, such as exenatide and sitagliptin, also have not been extensively studied in HF populations; however, small pilot studies of glucagon-like peptide-1 have shown potential promise in the treatment of diabetic patients with HF. Although they may be difficult to perform, future randomized controlled trials are needed to establish optimal treatment goals and strategies in this population.
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PMID:Management of type 2 diabetes in patients with heart failure. 1902 77

Glucagon-like peptide-1 (GLP-1) is an incretin secreted in response to nutrient ingestion. Understanding the incretin effect on diabetes pathophysiology has led to development of a new class of agents termed incretin mimetics. Exenatide is the first GLP-1 agonist approved to treat type 2 diabetes mellitus (T2DM). Clinical studies have demonstrated exenatide's efficacy in improving glycemic control, often coupled with weight loss. Studies are investigating the potential cardiovascular benefits of GLP-1 agonists. Blood pressure, cholesterol levels, C-reactive protein, and insulin resistance may improve in patients treated with exenatide. The direct effect of GLP-1 on cardiac myocytes and vascular smooth muscle has been an active area of investigation. Infusions of GLP-1 in animal models and human subjects with heart failure have demonstrated significantly improved cardia parameters. In patients with T2DM, GLP-1 infusion has been shown to improve endothelial function, irrespective of changes in insulin sensitivity. These pilot studies provide a foundation for developing therapies aimed at modulating incretin physiology for the additional benefit on the cardiovascular system in patients with T2DM and heart disease.
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PMID:The role of incretins in cardiovascular control. 1914 96

Metabolic modulation has been an attractive therapeutic approach to heart failure as scientific evidence for an altered metabolic state in the failing heart has been demonstrated for decades. However, the ability to safely alter the substrate metabolism in the myocardium without adverse effects while at the same time be able to provide long-term benefits have not been widely investigated. Meanwhile, the ability to alter long-term molecular, cellular, and hormonal changes as a result of progressive cardiac dysfunction has been directly associated with improvement in clinical outcomes. Among the drugs that have been studied, glucagon-like peptide-1 (GLP-1) analogs and trimetazidine have demonstrated promise in this area. Data on GLP-1, although promising, remain to show short-term improvements. In contrast, trimetazidine has extensive long-term experience with favorable effects on reverse remodeling. However, the appropriate candidate to receive such therapies and the appropriate targets of therapy remain unclear, which may warrant further investigations.
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PMID:The metabolic approach in patients with heart failure: effects on left ventricle remodeling. 1927 49

Pharmacologic intervention for the failing heart has traditionally targeted neurohormonal activation and ventricular remodeling associated with cardiac dysfunction. Despite the multitude of agents available for the treatment of heart failure, it remains a highly prevalent clinical syndrome with substantial morbidity and mortality, necessitating alternative strategies of targeted management. One such area of interest is the ability to modulate myocardial glucose uptake and its impact on cardioprotection. Glucose-insulin-potassium (GIK) infusions have been studied for decades, with conflicting results regarding benefit in acute myocardial infarction. Based on the same concepts, glucagon-like peptide-1-[7-36] amide (GLP-1) has recently been demonstrated to be a more effective alternative in left ventricular (LV) systolic dysfunction. This paper provides a review on the current evidence supporting the use of GLP-1 in both animal models and humans with ischemic and nonischemic cardiomyopathy.
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PMID:Glucagon-like peptide-1 and myocardial protection: more than glycemic control. 1945 89

Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
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PMID:A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. 1961 27

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.
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PMID:Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control? 1968 66

The hypothesis proposed is that heart failure (HF) is associated with a reactive hyperadrenergic state that increases circulating plasma free fatty acids (FFAs), which leads to impaired glucose metabolism and insulin resistance. We propose that increased FFA-induced mitochondrial uncoupling and substantial oxygen wastage is closely associated with the generation of reactive oxygen species, inflammatory markers, and the development of insulin resistance. The therapeutic aims of metabolic therapy are as follows: 1) to decrease hyperadrenergic drive; 2) to inhibit lipotoxicity and glucotoxicity; and 3) to increase glucose uptake by muscle. These aims are achieved, respectively, by the following: 1) the use of beta-adrenergic blockade and all measures that relieve the mechanical load on the heart; 2) the use of drugs that inhibit fatty acid oxidation (trimetazidine, perhexiline), although without clinical evidence that the heart is their major site of action in HF; and 3) increase of the transport of glucose into the cells by exercise and metformin. Of these measures, only data concerning the reduction of mortality as the result of exercise are available. Of all the other measures, there are substantial positive data on the use of trimetazidine that demonstrate metabolic and clinical benefit with almost no side effects, but data from a large outcome trial are lacking. Our data suggest a major extracardiac site of trimetazidine action. Ranolazine, which inhibits the late sodium inward current, requires testing in human HF. Insulin to reduce hyperglycemia and FFAs is untested in HF, with incretins such as glucagon-like peptide-1 on the horizon. Other future therapies may include malonyl-coenzyme A regulators to inhibit fatty acid oxidation, fish oil omega-3, and activators of protein kinase C-epsilon.
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PMID:The adrenergic-fatty acid load in heart failure. 1985 Feb 4

The incretin hormone glucagon-like peptide-1 (GLP-1) and its analogs are currently emerging as antidiabetic medications. GLP-1 improves left ventricular ejection fraction (LVEF) in dogs with heart failure (HF) and in patients with acute myocardial infarction. We studied metabolic and cardiovascular effects of 48-h GLP-1 infusions in patients with congestive HF. In a randomized, double-blind crossover design, 20 patients without diabetes and with HF with ischemic heart disease, EF of 30 +/- 2%, New York Heart Association II and III (n = 14 and 6) received 48-h GLP-1 (0.7 pmol.kg(-1).min(-1)) and placebo infusion. At 0 and 48 h, LVEF, diastolic function, tissue Doppler regional myocardial function, exercise testing, noninvasive cardiac output, and brain natriuretic peptide (BNP) were measured. Blood pressure, heart rate, and metabolic parameters were recorded. Fifteen patients completed the protocol. GLP-1 increased insulin (90 +/- 17 pmol/l vs. 69 +/- 12 pmol/l; P = 0.025) and lowered glucose levels (5.2 +/- 0.1 mmol/l vs. 5.6 +/- 0.1 mmol/l; P < 0.01). Heart rate (67 +/- 2 beats/min vs. 65 +/- 2 beats/min; P = 0.016) and diastolic blood pressure (71 +/- 2 mmHg vs. 68 +/- 2 mmHg; P = 0.008) increased during GLP-1 treatment. Cardiac index (1.5 +/- 0.1 l.min(-1).m(-2) vs. 1.7 +/- 0.2 l.min(-1).m(-2); P = 0.54) and LVEF (30 +/- 2% vs. 30 +/- 2%; P = 0.93), tissue Doppler indexes, body weight, and BNP remained unchanged. Hypoglycemic events related to GLP-1 treatment were observed in eight patients. GLP-1 infusion increased circulating insulin levels and reduced plasma glucose concentration but had no major cardiovascular effects in patients without diabetes but with compensated HF. The impact of minor increases in heart rate and diastolic blood pressure during GLP-1 infusion requires further studies. Hypoglycemia was frequent and calls for caution in patients without diabetes but with HF.
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PMID:Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure. 2008 Nov 9

Gastrointestinal peptides play important roles regulating feeding and energy homeostasis. Most gastrointestinal peptides including glucagon like peptide-1, peptide YY, amylin, and oxytomodulin are anorectic, and only ghrelin is an orexigenic peptide. Ghrelin increases appetite, modulates energy balance, suppresses inflammation, and enhances growth hormone secretion. Given its diversity of functions, ghrelin is expected be an effective therapy for lean patients with cachexia caused by chronic heart failure, chronic respiratory disease, anorexia nervosa, functional dyspepsia, and cancer. Clinical trials have demonstrated that ghrelin effectively increases lean body mass and activity in cachectic patients. Ghrelin interrupts the vicious cycle of the cachectic paradigm through its orexigenic, anabolic, and anti-inflammatory effects, and ghrelin administration may improve the quality of life of cachectic patients. We discuss the significant roles of ghrelin in the pathophysiology of cachectic diseases and the possible clinical applications of ghrelin.
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PMID:Translational research of ghrelin. 2063 40

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