June 9, 2006

The answer to the question posed in the title is that each component of cardiovascular (CV) and metabolic risk can affect others. A clustering of risk factors-overweight, smoking, hypertension, hyperlipidemia, insulin resistance, glucose intolerance-increases risk geometrically. Tantalizing recent data suggest that treatment of global CV risk, and particularly hypertension, can diminish the risk of cognitive function. The link: angiotensin II, which causes potent vasoconstriction, aldosterone secretion and sympathetic activation. All of these actions contribute to the development of hypertension and cerebral insufficiency. Agents that reduce the actions of angiotensin II therefore appear to be a useful component of decreasing CV risk and cognitive disorders.

FOXO in the Brain

Domenico Accili, MD

Insulin signaling can be viewed as a three-tiered system, in which a metabolic response requires initially tyrosine phosphorylation, then phosphoinositol generation, and ultimately serine/threonine phosphorylation. At each step, “checkpoints” prevent the system from going astray. Thus, tyrosine phosphatases, inositol phosphatases, and serine/threonine kinases dampen insulin signaling. Each of these checkpoints may be a therapeutic target in reversing insulin resistance.

June 10, 2006

Metabolic syndrome—characterized by a clustering of risk factors for heart disease and diabetes—has been described as a modern epidemic but has been defined by medical organizations in a variety of ways, with some even questioning its existence as a syndrome. Physicians are receiving conflicting guidance about what is gained—or lost—by diagnosing the metabolic syndrome.

Does diagnosing the syndrome make it easier to identify those at risk for heart disease or diabetes? In this symposium, the speakers view the metabolic syndrome from epidemiologic, research, and definitional perspectives.

Strategies to Define Syndrome Trait Clustering—Or, 10 Pitfalls of Epidemiology

John S. Yudkin, MD

Dr. Yudkin viewed the metabolic syndrome from an epidemiologic standpoint because it has been defined largely on the basis of epidemiologic data. From a medical perspective, he defined the steps in the epidemiologic method: 1) select a population, 2) take individual anthropometric measures, 3) take venous blood samples, usually in the fasting state, 4) measure markers of disease (as determined by procedures such as electrocardiogram and intimal media thickness, and 5) perform statistical analyses. But, he observed, epidemiology has its pitfalls. Additional methods are necessary to apply causation, and causation has not been established with certainty in the metabolic syndrome—which he referred to as syndrome X.

Samuel Klein, MD

The precise relationship between individual abdominal fat depots and insulin resistance is not clear. Studies of the role of increased visceral fat as a cause of insulin resistance have yielded variable results. Imprecision in the measurement of body fat depots and real biologic variation in lipolytic activity of fat depots may both play a role. Visceral fat appears to have a very small role in the oversupply of free fatty acids to extrahepatic tissues in insulin-resistant states. Subcutaneous fat, especially in the upper body, is the major contributor to this mediator of insulin resistance.

Several outcomes studies have examined whether pharmacologic interventions in combination, early in the disease process, can prevent progression from impaired glucose tolerance or impaired fasting glucose to type 2 diabetes. Other outcomes studies examining monotherapy failure in the newly diagnosed patient with type 2 diabetes and the relationship between macrovascular events and glucose control are under way. A recent Veterans Administration study examines whether expensive new therapies for diabetes are cost-effective. This program discussed the impact of these studies, with a focus on three: DREAM, ADOPT, and VADT.

Alan J. Garber, MD, PhD

Dr. Garber discussed a variety of completed trials with varied results, but all showing that early intervention can improve some outcomes in some patients at high risk for development of diabetes. In the TRoglitazone In the Prevention Of Diabetes (TRIPOD) study, troglitazone reduced the incidence of diabetes by 55% in Hispanic women with a history of gestational diabetes. Women who were protected during the trial remained protected 8 months later and had stable β-cell function over 54 months. The Pioglitazone In Prevention Of Diabetes (PIPOD) was an open-label study of pioglitazone, 45 mg/d, given to women who completed TRIPOD. The risk of diabetes was lowest in women with the largest reduction in total intravenous glucose tolerance test insulin area after 1 year of treatment. Comparison of changes in β-cell compensation for insulin resistance across the TRIPOD and PIPOD studies revealed that pioglitazone stopped the decline in β-cell function that occurred during placebo treatment in the TRIPOD study and maintained the stability of β-cell function that had occurred during troglitazone treatment in the TRIPOD study. These data support a class effect of thiazolidinedione drugs to enhance insulin sensitivity, reduce insulin secretory demands, and preserve pancreatic β-cell function, all in association with a relatively low rate of type 2 diabetes, in Hispanic women with prior gestational diabetes.

Since the discovery of the first endocannabinoids, anandamide and 2-arachidonyl glycerol, other endocannabinoids have been discovered and the pathway to their biosynthesis and degradation has been determined, and, as a result, the role of endocannabinoids in the brain has been elucidated. Progress has been made in understanding the implications of endocannabinoids in the brain and the periphery, using, first, knockout mouse models. This basic research has led to the development of novel therapies in medicine. Among these are treatment of obesity, and, in particular, metabolic syndrome and visceral adiposity.

This symposium examined the molecular and physiologic mechanisms of endocannabinoids, their metabolic actions, and the use of the endocannabinoid antagonist rimonabant in the management of cardiometabolic disorders.

Stephen C. Woods, PhD

Dr. Woods set the stage with an overview of key appetite-regulating systems. These systems serve both the sensations of satiety and hunger. Satiety is regulated by an interplay of hormones and neurotransmitters signaling between the gut and the brain. The "satiety hormones" include cholecystokinin (CCK), bombesin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). There is considerable evidence for the satiating effects of CCK; not only does endogenous CCK clearly contribute to a sense of fullness, but inhibition of CCK action, such as by a CCK-A receptor antagonist (loxiglumide), increases caloric intake in humans and can lead to obesity. Furthermore, the effects of CCK release from the duodenum in response to ingesting a meal are integrated with the effects of stretching of the stomach, through vagal afferents signaling to the brainstem.

June 11, 2006

Common cardiovascular and metabolic (cardiometabolic) risk factors in high-risk patients include lipid abnormalities (dyslipidemia), insulin resistance, hypertension, and abdominal adiposity. Abdominal adiposity is an important underlying risk factor for clinical atherosclerotic disease and, along with the other cardiometabolic risk factors, requires early identification and management. Overstimulation of the endocannabinoid system, a newly identified physiologic system involved in lipid and glucose metabolism, is associated with the development of various cardiometabolic risk factors. Cannabinoid receptors, specifically CB1 receptors, found in the brain and in various peripheral organs, play a pivotal role in regulating energy balance and body weight. Blockade of CB1 receptors improves various cardiometabolic risk factors in obese or overweight patients and even in patients with pre-existing diabetes and dyslipidemia. This symposium examined how to improve outcomes in high-risk patients through targeted risk-reduction strategies aimed at each patient’s individual cardiometabolic risk-factor profile.

Cardiovascular and Metabolic Risk Factors: How Can We Improve Outcomes in the High-Risk Patients?

Scott M. Grundy, MD, PhD

Patients at risk for cardiovascular disease can be divided into those at high short-term risk (<10 years) and those at high long-term risk (>10 years). Patients at high short-term risk include those at high risk (10-year risk for hard coronary heart disease (CHD) <20%) and those at moderately high risk (10-year risk 10%–20%). The absolute risk for all cardiovascular events, including stroke, is approximately twice the risk for CHD. High-risk patients include those with established CHD (history of myocardial infarction, unstable angina, stable angina pectoris, coronary artery procedures, and documented myocardial ischemia). Other high-risk patients are those without established CHD but with a 10-year risk >20%. These patients are called CHD risk equivalents. They include those with other forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease); diabetes mellitus; and 10-year risk >20% by Framingham risk scoring. Patients at moderately high risk are those with 2+ CHD risk factors and one of the following: a) 10-year risk 10%–20% by Framingham scoring and b) metabolic syndrome. All patients at high risk should be treated according to the guidelines outlined for secondary prevention by the American Heart Association. Slight adjustments of the AHA algorithm are required for some patients with CHD risk equivalents. For patients at moderately high risk, similar therapies are employed, but therapies need not be as intensive.

June 12, 2006

Minimizing the Risks for Cardiovascular Disease

Steven M. Haffner, MD

Dr. Haffner acknowledged the recent debate about the metabolic syndrome: whether it exists, what causes the clustering of metabolic disorders not likely to occur by chance alone, and the pathogenesis of the syndrome.

Insulin resistance is widely considered the foundation of the metabolic syndrome. Visceral fat is more often associated with insulin resistance than lower body obesity and subcutaneous fat. It is associated with higher plasma levels of fatty acids, which allow accumulation of triglycerides in muscle, cause hepatic fat accumulation, and produce pro-inflammatory adipokines, thus resulting in increased insulin resistance. Insulin resistance is also associated with atherogenic dyslipidemia, hypertension, glucose intolerance, impaired fibrinolysis, inflammation, polycystic ovary syndrome, and nonalcoholic fatty liver disease.

Introduction

Does the metabolic syndrome really exist as a clinical entity? If it does, how should we best define it, and what are the implications, if any, for treatment of patients who have it? In particular, should we focus on treating the individual components of the syndrome or is there a way to treat the global syndrome of metabolic abnormalities? The long-term goal would seem to be to reduce the risk of long-term complications of disease, both macrovascular and microvascular, particularly of cardiovascular disease. But does naming this disease actually change treatment? These were some of the issues discussed in this debate