The Evolving Role of the Cardiologist in the Management of Type 2 Diabetes.

PURPOSE OF REVIEW: To evaluate the treatment of type 2 diabetes from a cardiologist's view. RECENT FINDINGS: A new era in the treatment of type 2 diabetes began for the cardiologist in 2015 with the publication of the EMPA-REG outcome trial finding a significant reduction in CV death with empagliflozin (oral sodium-glucose co-transporter-2 [SGLT2] inhibitor) in patients with type 2 diabetes at increased cardiovascular risk. Shortly thereafter, the injectable glucagon-like peptide agonists (GLP-1) liraglutide and semaglutide found a significant reduction in composite major cardiovascular events (CV death, non-fatal MI, or stroke). Both classes have demonstrated significant renal protection when added to usual care. Moreover, there may be some exciting new benefits of SGLT2 inhibitors for patients with heart failure. These research studies are underway. These two new classes of cardiovascular drugs for type 2 diabetes usher in a new era for the cardiologist who sees greater than 50% of patients with diabetes. The off-target effect of these agents is different as with all new cardiovascular compounds. While safety profiles in these populations are consistent with the known effects of these classes, new off-target effects have been seen with some agents in this class. Ongoing collaboration between cardiologists and other care providers remains important in the implementation of the evidence and care of patients with type 2 diabetes.

Importancia del líquido sinovial en la articulación temporomandibular y sus implicancias en la patología articular / Value of synovial fluid in the temporomandibular joint and its implications in articular pathology

RESUMEN: El objetivo de este estudio fue realizar una revisión de la literatura respecto de la importancia del líquido sinovial en la articulación temporomandibular y sus implicancias en la patología articular. El líquido sinovial corresponde a un fluido viscoso y filante de color amarillento claro, compuesto principalmente por proteínas plasmáticas, componentes celulares, moléculas lubricantes, citoquinas, factores de crecimiento y enzimas. Es producido por la membrana sinovial y se encuentra en relación directa con las superficies articulares y la membrana sinovial, mediando las interacciones entre los tejidos de las articulaciones sinoviales. En la articulación temporomandibular desempeña un papel fundamental en el mantenimiento y regulación de la fisiología, a través de funciones lubricantes, reguladoras y metabólicas, disminuyendo el roce de las superficies articulares durante todos sus movimientos. En los trastornos temporomandibulares, la composición y función del líquido sinovial se puede ver alterada por cambios en los tejido de la articulación temporomandibular, estos cambios pueden resultar en una disminución en la capacidad de lubricar las superficies articulares y generar un ambiente catabólico en el interior de la articulación, contribuyendo conjuntamente al deterioro de éstas.

SUMMARY: The aim of this study was to conduct a review of the literature on the value of synovial fluid in the temporomandibular joint and its implications in joint pathology. The synovial fluid is a viscous and filamentous fluid of a light yellow color, composed mainly of plasma proteins, cellular components, lubricating molecules, cytokines, growth factors and enzymes. It is produced by the synovial membrane and is in direct relation with the joint surfaces and the synovial membrane, mediating the interactions between the tissues of the synovial joints. In the temporomandibular joint it plays a fundamental role in the maintenance and regulation of physiology, through lubricating, regulating and metabolic functions, decreasing the friction of the joint surfaces during all its movements. In temporomandibular disorders, synovial fluid function can be altered by changes in the tissues of the temporomandibular joint, these changes can result in a decrease in the ability to lubricate the joint surfaces and generate a catabolic environment inside the joint, contributing together to the deterioration of these.

Aortic stiffness: pathophysiology, clinical implications, and approach to treatment.

Aortic stiffness is a hallmark of aging, and classic cardiovascular risk factors play a role in accelerating this process. Current changes in medicine, which focus on preventive care, have led to a growing interest in noninvasive evaluation of aortic stiffness. Aortic stiffness has emerged as a good tool for further risk stratification because it has been linked to increased risk of atherosclerotic heart disease, myocardial infarction, heart failure, and stroke. This has led to the invention and validation of multiple methods to measure aortic stiffness. Pulse wave velocity is emerging as the gold standard for evaluation of aortic stiffness. This review focuses on the pathophysiology involved in aortic stiffness, methods available for evaluation of aortic stiffness, the importance of central pressure as a predictor of future cardiovascular events, and therapies that affect aortic stiffness.

Hypoglycemia from a cardiologist's perspective.

Hypoglycemia in people with diabetes mellitus (DM) has been potentially linked to cardiovascular morbidity and mortality. Pathophysiologically, hypoglycemia triggers activation of the sympathoadrenal system, leading to an increase in counter-regulatory hormones and, consequently, increased myocardial workload and oxygen demand. Additionally, hypoglycemia triggers proinflammatory and hematologic changes that provide the substrate for possible myocardial ischemia in the already-diseased diabetic cardiovascular system. Hypoglycemia creates electrophysiologic alterations causing P-R-interval shortening, ST-segment depression, T-wave flattening, reduction of T-wave area, and QTc-interval prolongation. Patients who experience hypoglycemia are at an increased risk of silent ischemia as well as QTc prolongation and consequent arrhythmias. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed an increase in all-cause mortality with intensive glycemic control, whereas the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study and Veteran's Affairs Diabetes Trial (VADT) showed no benefit with aggressive glycemic control. Women, elderly patients, and those with renal insufficiency are more vulnerable to hypoglycemic events. In fact, hypoglycemia is the most common metabolic complication experienced by older patients with DM in the United States. The concurrent use of medications like ß-blockers warrants caution in DM because they can mask warning signs of hypoglycemia. Here we aim to elucidate the pathophysiology, review the electrocardiographic changes, analyze the current clinical literature, and consider the safety considerations of hypoglycemia as it relates to the cardiovascular system. In conclusion, in the current era of DM and its vascular ramifications, hypoglycemia from a cardiologist's perspective deserves due attention.

Glucose Control and Cardiovascular Outcomes in Clinical Trials of Sodium Glucose Co-transporter 2 Inhibitor Treatments in Type 2 Diabetes.

Currently available medications for the treatment of type 2 diabetes have limitations, and many patients do not achieve glycaemic control. Recently, a new approach has emerged using sodium glucose co-transporter 2 (SGLT2) inhibitors that decrease glucose reabsorption in the kidneys, increasing urinary glucose excretion. These agents offer the potential to improve glycaemic control independently of insulin pathways while avoiding hypoglycaemia. Two drugs of this class, canagliflozin and dapagliflozin, have been approved by the US Food and Drug Administration (FDA); another, empagliflozin, has been filed for regulatory approval and several others are in advanced development. These drugs have been shown to effectively reduce blood glucose, fasting plasma glucose and glycated haemoglobin (HbA1C) levels in phase III clinical trials when used as monotherapy and as add-on therapy to other diabetes medications, including insulin. Another advantage of the SGLT2 inhibitors over existing treatments is the improvement in cardiovascular risk factors, particularly in terms of reductions in blood pressure and body weight. SGLT2 inhibitors have been generally well tolerated. While more long-term safety data are required to elucidate the benefit-risk profile of SGLT2 inhibitors, the rationale for their use in type 2 diabetes therapy is strong.

Acute coronary syndrome in patients with diabetes mellitus: perspectives of an interventional cardiologist.

Diabetes mellitus (DM) is well known to be a coronary artery disease risk equivalent but the cellular mechanism is not completely understood. Recently, virtual histology intravascular ultrasound has demonstrated that patients with DM tend to have a higher occurrence of vulnerable plaques as compared with patients without DM. Insulin-sensitizing agents, such as metformin, have been shown to have limited cardioprotective effects, whereas thiazolidinediones, such as rosiglitazone, have been reported to have possible deleterious effects on cardiovascular mortality in a meta-analysis; however, limited data exist. In contrast, pioglitazone has been reported to have a significant benefit in patients with type 2 DM with acute coronary syndrome (ACS). Animal and human studies have demonstrated the myocardial protective effects of incretins and hold promise in reducing the incidence of major adverse cardiac events in patients with DM. Moreover, in addition to aspirin, the early use of potent antiplatelet agents, such as prasugrel and intravenous glycoprotein IIb-IIIa inhibitors, in patients with DM presenting with ACS is crucial for reducing cardiovascular events in most patients. Thus, patients with DM deserve special attention in global risk factor reduction and development of newer therapeutic agents to improve glycemic control while minimizing or reducing cardiovascular events. This article focuses on ACS in patients with DM, the pathophysiology of "vulnerable blood" in patients with DM, and newer treatment strategies to improve outcomes in this high-risk patient population.

Implementing cardiovascular risk reduction in patients with cardiovascular disease and diabetes mellitus.

The role of cardiovascular risk reduction in patients with diabetes mellitus is significant as several factors have been found to promote accelerated atherosclerosis in persons with diabetes including hyperglycemia-induced endothelial dysfunction, impaired fibrinolysis, increased platelet aggregation, plaque instability, dysfunctional arterial remodeling, and fibrotic and calcified coronary arteries. Recent attention has focused on identifying a cardiovascular biomarker that would propose a better noninvasive way to detect or visualize subclinical cardiovascular disease and prevent cardiovascular events. This article reviews the use of commonly used cardiovascular risk assessment tools and emerging biomarkers including coronary artery calcium scanning, metabolomics, genomics, and the role of optimal revascularization and risk reduction strategies and their impact on reducing risk in patients with cardiovascular disease and diabetes.

Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies.

The global epidemic of diabetes mellitus (~95% type 2 diabetes) has been fueled by a parallel increase in obesity and overweight. Together, these metabolic disease epidemics have contributed to the increasing incidence and prevalence of cardiovascular disease. The accumulation of metabolic and cardiovascular risk factors in patients with type 2 diabetes--risk factors that may exacerbate one another--complicates treatment. Inadequate treatment, treatment that fails to achieve goals, increases the risk for cardiovascular morbidity and mortality. From a clinical perspective, type 2 diabetes is a cardiovascular disease, an observation that is supported by a range of epidemiologic, postmortem, and cardiovascular imaging studies. Vascular wall dysfunction, and particularly endothelial dysfunction, has been posited as a "common soil" linking dysglycemic and cardiovascular diseases. Vascular wall dysfunction promoted by environmental triggers (e.g., sedentary lifestyle) and metabolic triggers (chronic hyperglycemia, obesity) has been associated with the upregulation of reactive oxygen species and chronic inflammatory and hypercoagulable states, and as such with the pathogenesis of type 2 diabetes, atherosclerosis, and cardiovascular disease. Glucagon-like peptide-1 (GLP)-1, an incretin hormone, and synthetic GLP-1 receptor agonists represent promising new areas of research and therapeutics in the struggle not only against type 2 diabetes but also against the cardiovascular morbidity and mortality associated with type 2 diabetes. In a number of small trials in humans, as well as in preclinical and in vitro studies, both native GLP-1 and GLP-1 receptor agonists have demonstrated positive effects on a range of cardiovascular disease pathologies and clinical targets, including such markers of vascular inflammation as high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, and brain natriuretic peptide. Reductions in markers of dyslipidemia such as elevated levels of triglycerides and free fatty acids have also been observed, as have cardioprotective functions. Larger trials of longer duration will be required to confirm preliminary findings. In large human trials, GLP-1 receptor agonists have been associated with significant reductions in both blood pressure and weight.

A cardiologist's view of hypoglycemia.

Recent studies have failed to show an improvement in cardiovascular mortality with intensive glycemic control and aggressive glycated hemoglobin (A(1c)) targets less than 7.0%. Excessive hypoglycemic episodes with intensive glucose-lowering therapy are thought to be a major factor in the failure to show cardiovascular benefit in these trials. In this article, we review the physiology of glucose metabolism, the cardiovascular pathophysiology of hypoglycemia, and the trials with an intensive glucose-lowering strategy that have studied microvascular and macrovascular complications. We also review the current non-insulin drugs available for the treatment of diabetes and their potential hypoglycemic and cardiovascular impacts.

Effect of glitazones on the progression of coronary artery disease in type 2 diabetes patients.

The effect of thiazolidinediones (TZDs) on the progression of atherosclerosis in diabetes patients remains unclear. There has been heightened interest in recent years in this class of diabetes medications due to the non-glycemic lowering effects, such as altering lipids, inflammation and hematologic profiles. There have been several exciting studies over the past few years focused on the mechanism of action of the TZDs with respect to alteration in the cardio-metabolic profile in diabetes patients. New tools such as intravascular ultrasound have been used to follow plaques characteristics over time on a much more sensitive scale than has ever been possible in the past by coronary angiograms. These advances have enabled researchers to follow closely the macrovascular effects of different anti-atherosclerotic medications such as statins and TZDs. This article reviews the pathophysiology of atherosclerosis in diabetes, the role that TZDs play in this process and the imaging trials looking at the progression or regression of atherosclerosis in patients treated with TZDs.

Impaired fasting glucose as a treatment target in diabetes management.

Impaired fasting glucose (IFG) contributes to microvascular and macrovascular complications and increased cardiovascular disease risk. Although type 2 diabetes is largely considered to occur as a result of IFG, understanding of physiologic and associated management targets is uniformly lacking among health care professionals. Once definitions are standardized, diagnostic criteria and screening tools may help to identify individuals at risk sooner, thereby minimizing the rapid deterioration that often results. To counter the rising pandemic of obesity and diabetes, it is important to understand the vascular risk of IFG and impaired glucose tolerance in patients at risk.

GLP-1 agonist-based therapies: an emerging new class of antidiabetic drug with potential cardioprotective effects.

Cardiovascular disease is a leading cause of death in the United States and across the world, and better therapies are constantly being sought to improve patient outcomes. Recent studies have brought our attention to the mechanisms of glucagon-like peptide 1 (GLP-1). Not only does it demonstrate beneficial effects in regard to cardiovascular risk factors (i.e., diabetes, lipid management, and weight control), but it also has been shown in animal studies to have positive cardiac effects irrespective of its effects on glucose control and weight loss. This review discusses the biology of GLP-1 and its effects on cardiovascular risk factors, and it also elaborates on the positive direct cardiovascular outcomes of GLP-1 in animal studies.