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“Residual risk”-those were the key words at this symposium examining the gaps in progress in prevention of coronary and metabolic disorders. This refers to the nontraditional risk factors that often receive little attention from clinicians after hypertension and hyperlipidemia have been treated.

Intra-abdominal Adiposity: A Key Contributor to Cardiovascular Risk

Richard Nesto, MD, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts; Chairman, Department of Cardiovascular Medicine, Lahey Clinic, Burlington, Massachusetts

Despite the progress in reducing morbidity and mortality from cardiovascular disease, most people still die from cardiovascular causes. Huge progress has been made in the prevention of myocardial infarction-in persons without diabetes. There has been little or no progress in those with diabetes. And Dr. Nesto pointed out that in New York City, as an example, the prevalence of diabetes more than doubled from 1994 to 2002, from 3.7% to 7.9%.

Why is this happening? A major problem is obesity in young persons. This may lay the substrate for atherosclerosis as persons get older. In fact, atherosclerosis in youth is linked to obesity and “early” insulin resistance. Further, obesity is independently associated with coronary endothelial dysfunction in mild coronary artery disease. In this chain leading to coronary artery disease, inflammatory mediators are elevated. Of key importance is intra-abdominal obesity, an important component of the metabolic syndrome and a contributor to a pro-inflammatory state.

Thus, cardiovascular disease prevention has a long way to go. While the strides made with agents such as statins for hyperlipidemia and antihypertensives cannot be minimized, as we continue to learn about visceral adiposity and its contribution to cardiovascular and metabolic risk, more remains to be done. While lifestyle changes such as weight loss (by any amount-even 10-15 pounds can be helpful) and exercise, improving the lipid profile, and controlling hypertension will help to decrease risk, there is room for much more.

Physiology of the Endocannabinoid System: Central and Peripheral Mediators of Adiposity and Insulin Resistance

George Kunos, MD, PhD, Scientific Director, Division of Intramural Biological and Clinical Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

Since their discovery in the early 1990s, the endocannabinoid system and endocannabinoid receptors have been studied intensely. One of the endocannabinoid receptors, CB1, has been shown to increase appetite and stimulate lipogenesis. Recent research by Dr. Kunos and others reveals that blocking the CB1 receptor improves cardiac and metabolic risk factors in mice with diet-induced obesity. To develop suitable drugs against this target, the human cannabinoid receptor was first cloned and then expressed in cells. Compounds with potential inhibitory activity against this receptor were then screened for inhibitory activity. Rimonabant emerged from this screening process as a potent CB1 receptor antagonist. The drug, which has progressed to phase III development, blocks endocannabinoid binding to neuronal CB1 receptors. It is the only endocannabinoid receptor antagonist in clinical development and thus offers a unique therapeutic approach to appetite control, weight reduction, and improvement in the overall metabolic profile, including improvement in the lipid profile.

The Effects of CB1 Blockade on Cardiovascular Risk: What Do Clinical Trials Tell Us?

Luc Van Gaal, MD, Professor of Medicine, Department of Diabetology, Metabolism, and Clinical Nutrition, University Hospital, Antwerp, Belgium

Dr. Luc Van Gaal reported on the Rimonabant in Obesity (RIO) trials in obesity, diabetes, and metabolic disorders: RIO-Europe, RIO-North America, and RIO-Lipids, which have been published; and RIO-Diabetes, which was presented at the American Diabetes Association annual meeting last year. Across all four studies, rimonabant increased high-density lipoprotein (HDL) cholesterol and decreased triglyceride levels compared with placebo. Adiponectin, measured only in the RIO-Lipids study, increased with rimonabant compared with placebo, and hemoglobin A1c (HbA1c), measured only in RIO-Diabetes, along with fasting insulin in the nondiabetic patients, were both significantly reduced with rimonabant over placebo.

The design of the RIO program includes prespecified analyses of the differences between rimonabant 20 mg and placebo treatment that could not be attributed to weight loss alone. These analyses were done using linear regression, comparing the effects on each cardiometabolic parameter in groups of patients who achieved the same weight loss from baseline to 1 year.

After adjustment for weight loss, rimonabant was found to significantly increase HDL cholesterol and adiponectin and to reduce triglycerides (Table). Significant improvements beyond those attributed to body weight loss were also seen for HbA1c in patients with type 2 diabetes and for fasting insulin in nondiabetic patients.

Table. Cardiometabolic Effects of Rimonabant Independent of Weight Loss

*Mean difference vs placebo at 1 year; P<.001 for all comparisons.

The separate weight-dependent and -independent metabolic effects of rimonabant may be explained by the physiology of the endocannabinoid system and the expression of the CB1 receptors in peripheral tissues suggested Dr. Van Gaal. So far, no specific drug interactions have been found. Rimonabant appears to be safe with statins and has a favorable adverse-effect profile.

Potential Applications for Endocannabinoid CB1 Receptor Blockade: Slowing the Progression of Atherosclerosis

Steven E. Nissen, MD, Medical Director, Cleveland Clinic Cardiovascular Coordinating Center, Cleveland Clinic Foundation, Cleveland, Ohio

One third of patients with coronary disease have total cholesterol values under 200 mg/dL, says Dr. Steven Nissen. Looking at total cholesterol and low-density lipoprotein (LDL) cholesterol only is missing the big picture. What is missing from this picture is an understanding of the metabolic effects of increased body mass index (BMI), particularly visceral adiposity. As BMI increases, the risk for diabetes and hypertension goes up steeply – independent of effects on LDL cholesterol.

Dr. Nissen, a pioneer in intravascular ultrasound, notes that what angiographers see is the “tip of the iceberg.” Residual plaque burden, not reflected by luminal size, must be addressed. Much of this is explained by endothelial inflammation. These mediators are active participants in atherogenesis. One such mediator, C-reactive protein, is becoming a major target of research

He also noted that patients in coronary care units more often than not have low HDL cholesterol. This stimulated interest in the possibility of raising HDL as a means of reducing cardiovascular risk. Dr. Nissen and colleagues conducted a study in which a recombinant form of HDL was infused into patients. This caused very large regressions in atheromatous plaque as seen on intravascular ultrasound.

These findings have further stimulated Dr. Nissen's interest in rimonabant, which raises HDL (see report by Dr. Van Gaal) and reduces C-reactive protein. Ongoing phase IIIb trial programs for rimonabant includes studies in patients with diabetes (SERENADE), dyslipidemia (ADAGIO), and cardiovascular disease (STRADIVARIUS, AUDITOR, and CRESCENDO).