Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 10, Issue 4, 2012

Given the demonstrated importance of the incretin effect on the prandial insulin response, augmentation of the incretin effect in people with type 2 diabetes is an important pharmacological approach to glycemic management. In recent years, the use of incretin-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, has increased dramatically due to their demonstrated efficacy, low risk of hypoglycemia when used as monotherapy, and reasonable tolerability. Given their effects on glycemic parameters and the likelihood of aiding in weight loss, GLP-1 receptor agonists provide a unique treatment option for people with type 2 diabetes. Increased clinical experience and study of incretin-based therapies will help answer questions about safety issues that have arisen from post-marketing reports. The potential benefit of incretin-based therapies in the treatment of people with type 2 diabetes and cardiovascular disease is currently an active area of inquiry. While the potential benefits of incretin-based therapies in the arena of cardiovascular risk reduction are promising, results from ongoing outcomes-based studies will help determine the role of these agents in this setting.

Dyslipidemia is a prominent feature of type 2 diabetes and insulin resistance that contributes to increased atherosclerosis and cardiovascular disease (CVD) risks under these conditions. Incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) have recently been developed and are approved for clinical use for treatment of type 2 diabetes. Besides improved glycemic control, other benefits are being increasingly appreciated, one of which is improved plasma lipid profile. This review aims to summarize the evidence and potential mechanism of such agents in humans in modulating fasting and postprandial lipoprotein metabolism.

The endothelium is critical for multiple processes occurring on both sides of the vascular wall including regulation of blood flow, maintenance of blood fluidity and control of inflammation. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and appears to be a critical determinant of cardiovascular events. It is frequently detected in the early stages of type 2 diabetes and even in pre-diabetes conditions. Risk factors for endothelial dysfunction are numerous and include among others fasting and postprandial hyperglycemia and hyperlipidemia, hypertension, obesity, insulin resistance and inflammation. Many of these conditions can be improved by synthetic glucagon like peptide 1 (GLP-1) mimetics or inhibitors of the main GLP-1 degrading enzyme dipeptidyl peptidase 4 (DPP-4). Acute increases in GLP-1 activity abolish endothelial dysfunction induced by high-fat meals or by hyperglycemia. In vitro and preliminary clinical studies also indicate that GLP-1 or GLP-1 agonists can improve endothelial function by direct action on endothelium. GLP-1 or GLP-1 mimetic effects appear to extend to both conduit arteries and the microvasculature, and may depend on activation of endothelial GLP-1 receptors and downstream nitric oxide production. Additional studies are necessary to confirm improvement of endothelial function after prolonged treatment with incretin based medications as well as the cardiovascular benefit of these agents.

Patients with type 2 diabetes mellitus are at high risk for developing cardiovascular diseases. Traditional medicines for type 2 diabetes, such as sulfonylureas, pioglitazone, and insulin have glucose lowering effects; however, they also increase the frequency of hypoglycemia and/or body weight and thus may cancel out the benefits of glucose lowering on the development of atherosclerosis. In contrast, the recently developed glucagon like peptide-1-based therapy using glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors has numerous beneficial effects in the management of hyperglycemia with less risk of hypoglycemia and weight gain. Glucagon-like peptide-1-based therapy also lowers blood pressure and blood lipids and thus may prevent progression of atherosclerosis. Furthermore, glucagonlike peptide-1 receptors are abundantly expressed in vascular cells such as endothelial cells, monocyte/macrophages and smooth muscle cells. Recent studies suggest that the anti-inflammatory and vasodilatory properties of glucagon-like peptide-1 signaling on endothelial cells, its anti-inflammatory effect on macrophages and anti-proliferative effects on smooth muscle cells may halt atherosclerosis. Although large clinical trials are required to confirm these beneficial effects, glucagon-like peptide-1-based therapy could provide both glucose lowering and protection against cardiovascular diseases in patients with type 2 diabetes.

Cardiovascular disease continues to be a major cause of morbidity and mortality in patients with Type 2 Diabetes Mellitus. Whilst a focus on improved glucose control and HbA1c has led to a reduction in the progression and development of microvascular complications, the potential for this strategy to reduce cardiovascular event rates is less clearly defined. Identification of the incretin axis has facilitated the development of several novel therapeutic agents which target glucagon-like peptide-1 (GLP-1) pathways. The effects on glucose homeostasis are now established, but there is also now an increasing body of evidence to support a number of pleiotropic effects on the heart that may have the potential to influence cardiovascular outcomes. In this article, we review myocardial energy metabolism with particular emphasis on the potential benefits associated with a shift towards increased glucose utilisation and present the pre-clinical and clinical evidence regarding incretin effects on the heart. In addition we discuss the potential mechanism of action and benefit of drugs that modulate GLP-1 in patients with type 2 diabetes mellitus and coronary artery disease.

Atrial fibrillation occurs in 20-50% of patients after surgical revascularization (40% have more than 1 episode), with a peak between 2nd and 3rd postoperative days. Postoperative atrial fibrillation (POAF) has been associated with an increase in adverse events, length of hospital stay and, therefore, cost of care, and late mortality. A higher risk profile in patients who develop POAF may contribute to the higher late mortality rate. The pathogenesis of PAOF is multi factorial: transient ischemia during surgical procedure, neurohormonal activation, electrolyte imbalance, fluid overload and finally an exaggerated inflammatory response have been associated with POAF. Advanced age, an history of AF or heart failure and, finally, COPD are clinically independent risk factors related to POAF. The lower incidence of POAF reported after off-pump CABG in comparison to conventional cardiopulmonary by-pass CABG techniques has not been confirmed. The administration of antiarrhythmic drugs (amiodarone, metoprolol, sotalol and recently propafenone and landiolol) before and /or after surgical procedure has been extensively investigated and most of the investigators have demonstrated a favorable effect on POAF incidence. The decreased incidence of POAF and related shorter hospital stay by PUFA administration during hospitalization needs to be confirmed. Preliminary results suggest that pre-treatment with the antianginal drug ranolazine may significantly decrease POAF incidence. Treatments directed to antagonize inflammation are presently under investigation. Recently, a randomized study with naproxen, although effective on POAF, was interrupted due to increased risk of nephrotoxicty. Despite different action mechanisms, both hydrocortisone and statins have been shown to decrease post-operative AF risk. No data at present exist on the effects of association of these drugs. Aim of the present review was to update the current practice and report the recent results of research in the prophylaxis of atrial fibrillation in patients undergoing CABG.

Anemia is a prevalent and premature comorbidity in chronic kidney disease (CKD) and associated with multiple adverse clinical consequences including increased mortality. Today Erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the cornerstones of therapy for correcting anemia in CKD patients. As no generally accepted dosing algorithms for these agents exist, current recommendations prefer a partial but not complete anemia correction thereby favoring a more conservative and individualized ESA and iron dosing. Here we discuss in detail current evidence derived from large randomized trials about the proposed hemoglobin targets to aim at in CKD and End-Stage renal disease patients and report recent data from the thriving European market of biosimilar erythropoietins. We summarize promising investigational strategies including peginesatide and prolyl hydroxylase inhibitors for stabilization of the hypoxia inducible factor and provide a clinical review of novel high dose iron formulations like ferumoxytol or iron (III)-carboxymaltose. Taking these findings together, treatment strategies for anemia of CKD have got considerably more complicated so that a careful balance between maximization of patient`s quality of life while minimizing all risks associated with anemia treatment has become a major task of current nephrology.

Inflammation is essential for atherogenesis, and many inflammatory markers have been analyzed for their association with short- and long-term outcome in patients with manifestations of coronary artery disease. C-reactive protein (CRP) plasma levels increase in patients with acute coronary syndrome (ACS). CPR is an important prognostic marker in ACS. Although CRP will remain over time a useful marker, the role and implications of increased plasma concentrations of other acute phase proteins (APPs), such as alpha-1-antitrypsin (A1AT), alpha-1 glycoprotein (A1GP), haptoglobin (HG), ceruloplasmin (CP), and C3c and C4 complement fraction, in patients with ACS are still not completely defined. Controversy is the role of statins and other drugs on inflammatory markers. This review summarizes the experimental and clinical evidence regarding the role, and the biological and clinical significance of these APPs in ACS. Furthermore, biological and clinical significance of Pentraxin 3 (PTX3), a member of the pentraxin superfamily, are discussesed.

Background. The prevention of oral mucositis (OM) in the management of hematological malignancies continues to represent an unmet clinical need. Addressing this issue has major clinical implications as OM can also greatly impair patient’s quality of life. Objectives. To review currently available measures and investigational agents to prevent OM in hematological patients. Methods: we searched for OM and related issues using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. Results/Conclusions. Many agents targeting different mechanisms of mucosal damage have been applied in order to prevent OM; most of them have failed or its efficacy has not been fully demonstrated. Palifermin is the first pharmaceutical/biological agent approved for the prevention of OM; its use is currently restricted to patients who have received radiotherapy-containing conditioning regimens prior to autologous hematopoietic stem cell transplantation. No clear benefit by this agent has been demonstrated outside of this specific setting and its application should be limited to clinical trials. Other interventions, such as other growth factors and non mitogenic measures are under investigation or in development and their application in the hematological setting is expected in the short term.