Print Version

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.

Abdominal Adiposity and Cardiometabolic Risk: Do We Have All the Answers?

Steven M. Haffner, MD

INTERHEART was the first large, international study to establish that obesity is a cardiovascular disease risk factor that is statistically significant in basically all of the world's populations. Subsequent prespecified analyses of the INTERHEART results have further determined that a simple measure of waist circumference is a more powerful predictor of obesity-associated cardiovascular disease risk level than any other single measure of obesity (eg, BMI) or constellation of measures (eg, metabolic syndrome).

Dr. Haffner reported on a second large trial, the International Day for the Evaluation of Abdominal Obesity (IDEA) study, which showed that waist circumference is a stronger predictor of cardiovascular disease outcomes than BMI. First results of this large international study in over 170,000 people indicate that waist circumference is associated with cardiovascular disease independently of the relationship that BMI has with cardiovascular disease risk and regardless of age or geography. This finding confirms the importance of measuring waist circumference, alongside current measures such as BMI, blood pressure, blood glucose, and lipid levels, in identifying patients in a primary care setting who are at increased cardiometabolic risk.

The IDEA study involved 6407 primary care physicians in 63 countries (the United States declined to participate). An unselected population made up of 177,345 patients aged 18-80 years who consulted their primary care physicians for any reason on 2 prespecified half-days were enrolled in the study between May and July 2005. In addition to measurements of waist circumference, height, and body weight, demographic data were collected on gender, age, and highest level of education. The presence or absence of classic cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia, and smoking status) and existing cardiovascular disease (CHD, stroke, or prior revascularization) were also recorded.

Both waist circumference and BMI were independently associated with the presence of cardiovascular disease. Each increase in waist circumference of 14 cm for men and 14.9 cm for women increased the likelihood of a person having cardiovascular disease between 21% and 40%. When adjusted for BMI, waist circumference was an even stronger predictor of cardiovascular disease, particularly in men.

Understanding Metabolic Homeostasis and Imbalance: What is the Role of the Endocannabinoid System?

George Kunos, MD, PhD

Dr. Kunos reviewed the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in his laboratory showed that endocannabinoids, acting via CB₁ receptors, are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain, and amygdala. CB₁ receptor knockout mice are lean and are resistant to diet-induced obesity despite similar energy intake to wild-type mice with diet-induced obesity, suggesting that CB₁ receptor regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB₁ expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB₁ receptors are present in the liver and are increased in diet-induced obesity. CB₁ receptor stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids.

What is the Potential Role of CB₁ Receptor Blockade in Glucose and Lipid Management?

Michael D. Jensen, MD

The endocannabinoid system comprises two cannabinoid receptor subtypes, CB₁ and CB₂, their endogenous ligands [the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG)], and enzymes for ligand biosynthesis and degradation. Knowledge of this signaling system has stimulated development of a drug for the treatment of obesity: rimonabant, a selective CB₁ receptor antagonist. Blockade of CB₁ receptors causes reduction of food intake in food-deprived lean animals, and in obese animals fed ad libitum.

Hypothalamic endocannabinoids are subject to negative regulation by leptin and are permanently elevated in genetically obese rodents, where they contribute to hyperphagia. However, it is also clear that the persistent weight loss that follows chronic blockade of CB₁ receptors is largely independent from its transient inhibition of food-intake. CB₁-deficient mice exhibit significantly less fat mass than wild-type mice, and are not susceptible to develop obesity following a high-fat diet, even when they consume as much food as wild-type mice. These findings suggest that the endocannabinoid system contributes to obesity via peripheral mechanisms, possibly by being permanently upregulated, as recently shown in the liver of mice with diet-induced obesity.

Chronic blockade of CB₁ receptors in obese animals and humans also reduces the signs of the metabolic syndrome. It is not clear whether these additional beneficial effects are merely the consequence of weight loss or also the result of peripheral actions of CB₁ receptor blockers exerted directly on cells involved in lipogenesis and insulin production, (white adipocytes and pancreatic islet β-cells). White adipocytes do express functional CB₁ receptors, whose levels are higher in obese rats and whose blockade leads to increased levels of adiponectin, an adipokine that enhances insulin sensitivity and glucose and lipid metabolism.