Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Canadian Cardiovascular Congress 2007

Quebec City, Quebec / October 20-24, 2007

Editorial Review:

David C.W. Lau, MD, PhD, FRCPC

Professor of Medicine/Biochemistry and Molecular Biology

Julia McFarlane Diabetes Research Centre, Chair, Diabetes and Endocrine Research Group

University of Calgary, Calgary, Alberta

The new concept of cardiometabolic risk describes a patient’s global risk for developing cardiovascular disease (CVD) and type 2 diabetes based on both traditional risk factor assessment as well as the presence of other metabolic abnormalities frequently found in the patient with abdominal obesity. In the opinion of some researchers, including Dr. Jean-Pierre Després, Director of Cardiology Research, Institut de cardiologie de Québec, and Professor, Department of Nutritional Sciences, Université Laval, Quebec City, the concept of cardiometabolic risk should not replace what was originally defined as the metabolic syndrome in our own Canadian lipid guidelines as well as those brought forward under National Cholesterol Education Program ATP III chair Dr. Scott Grundy, Director, Center for Human Nutrition, University of Texas, Dallas.

Rather, what many of us now recommend is to continue to use the Framingham risk assessment score to arrive at a patient’s 10-year CV risk, and then to consider whether a patient carries the constellation of atherothrombic and inflammatory abnormalities that define the metabolic syndrome and which increase global cardiometabolic risk.

Hypertriglyceridemic Waist

An accurate CV risk assessment is important for clinical practice. If patients are misclassified as being at low or intermediate risk for CV events, we will miss an opportunity to intervene in a timely fashion. Recent results from the European Prospective Investigation of Cancer (EPIC)-Norfolk study provide new insights into risk classification. As reported by Dr. Després, EPIC-Norfolk investigators analyzed the risk of men and women developing coronary artery disease (CAD) over an eight-year follow-up as a function of either the absence or the presence of “hypertriglyceridemic waist.” The term was coined by the Université Laval research group when they found that in middle-aged men, those with a waist circumference (WC) <90 cm and triglycerides <2.0 mmol/L had only about a 10% chance of meeting the criteria for the metabolic syndrome compared to approximately 80% of men with a WC ³90 cm and triglycerides ³2.0 mmol/L. For women, the cut points were WC <85 cm and triglycerides <1.5 mmol/L for low risk, and a WC ³85 cm and triglycerides of ³1.5 mmol/L for high risk.

Even when EPIC-Norfolk investigators adjusted individual risk based on their baseline Framingham risk score, the risk of men developing CAD over this long-term study was significantly greater if they had the hypertriglyceridemic waist. For women, its presence was an even more important predictor for CAD than it was for men. This is not to suggest that a large proportion of men and women at high risk for CAD based on their Framingham risk assessment are not also at high risk after controlling for the presence of a hypertriglyceridemic waist.

Nevertheless, researchers reclassified approximately 400 men in EPIC-Norfolk into a higher-risk category than that estimated by Framingham, based on the presence of an elevated WC and serum triglyceride levels. The CAD event rate was markedly higher among these men than it was for men who did not have a hypertriglyceridemic waist. The same held true for a significant proportion of women.

WC is now widely accepted as a better predictor for obesity-related comorbidities than body mass index (BMI). The recently published evidence-based Canadian clinical practice guidelines on the management and prevention of obesity in adults and children recommend WC measurement in all adults as a “new vital sign” to provide better assessment of health risk (Lau et al. CMAJ 2007;76(suppl 8):S1-13). Furthermore, the Canadian guidelines adopted the ethnic-specific WC cut points, which are recommended by the International Diabetes Federation as a preresquisite criterion for the classification of the metabolic syndrome. More evidence that WC and not BMI is a more potent predictor of both CV events and diabetes was provided by the recently published IDEA study (International Day for the Evaluation of Abdominal Obesity)(Balkau et al. Circulation 2007; 116:1942-51). In the IDEA study, Balkau et al. asked primary care physicians in 63 countries to measure both WC and BMI. Some 29% of over 69,000 men in IDEA had a WC in excess of 102 cm and 48% of over 98,000 women in the same study had a WC in excess of 88 cm, each factor a defining criterion for the metabolic syndrome. Abdominal obesity—as reflected by the WC—showed a graded relationship with both CVD and diabetes at all levels of BMI, even in so-called “lean” patients.

This relationship was consistent across all geographic regions and genders included in the survey, despite up to a threefold difference in the background frequency of CVD and diabetes between the different regions surveyed. In their conclusion, IDEA investigators recommended routine measurement of WC as a “convenient and inexpensive” tool for primary care physicians to better gauge individual risk for CVD and diabetes, even in patients with normal weight. Within any given range of BMI, it is important to appreciate that there can also be substantial variations in WC of up to 12 cm, according to findings from a population-based survey carried out in Quebec.

Target for Intervention

Given that abdominal obesity should clearly be targeted to reduce cardiometabolic risk, is there any evidence that we can lower that risk and with what kinds of intervention? Again, a study presented by Dr. Després suggests that considerable amounts of visceral fat can be mobilized with lifestyle intervention. In an ongoing lifestyle-modification study at Université Laval, SYNERGIE researchers demonstrated that abdominally obese men randomized to once-monthly visits with a dietitian and a kinesiologist dropped an average of 9 cm from their WC at the end of one year even though their BMIs did not necessarily change to an appreciable extent at the same end point.

More importantly, visceral fat deposits were substantially reduced, even among participants who lost less than 10% of their body weight. None of us who work with diabetic patients can emphasize strongly enough how important lifestyle modification is to help offset the high risk of CVD that diabetes confers on patients.

The same is true for patients with elevated cardiometabolic risk, for whom caloric restriction and increased physical activity are the cornerstones. At the same time, we have to admit that we are less than successful at getting patients to adopt these seemingly simple interventions. When considering pharmacological intervention, we are currently only able to target each individual metabolic abnormality that contributes to a patient’s global cardiometabolic risk.

But the discovery of the endocannabinoid system—one that some have likened in importance to the identification of the LDL cholesterol receptor—has opened up the possibility that we may be able to target a cluster of metabolic abnormalities that accompany abdominal obesity as well as abdominal obesity itself with a single intervention.

Endocannabinoid System

As Dr. Rafael Maldonado, Professor of Pharmacology, Pompeu Fabra University, Barcelona, Spain, explained, the endocannabinoid system is truly the perfect pathway to target in patients with elevated cardiometabolic risk. In essence, the endocannabinoid system selectively activates cannabinoid receptors, among them CB1 receptors, which are expressed in both the central nervous system (CNS) and peripheral tissues, including adipocytes, the liver, the skeletal muscle and the pancreas. By activating CB1 receptors in the CNS, the endocannabinoid system modulates appetite and satiety, increasing the motivation to eat and curb the sensations of fullness.

In turn, activation of CB1 receptors in adipocytes stimulates fat accumulation and blocks expression of adiponectin, the “good” cytokine that promotes fat loss and improves insulin resistance. In the liver, activation of the same receptors stimulates fatty acid synthesis while in the skeletal muscle, their activation increases insulin resistance, and hyperinsulinemia when they are activated in the pancreas.

Normally, the endocannabinoid system is turned on and off on demand and activation is only transitory. However, in the setting of obesity—especially abdominal obesity—the same system is chronically activated, as Dr. Maldonado emphasized, and which is why chronic endocannabinoid activation both perpetuates obesity and leads to type 2 diabetes. Antagonism of CB1 receptor activity reverses all of these processes and leads to a decrease in appetite; a decrease in fat accumulation in the adipocytes and an increase in adiponectin; a decrease in lipogenesis; an increase in insulin sensitivity at the level of the liver and in skeletal muscle; and a decrease in hyperinsulinemia that activation of CB1 receptor in the pancreas otherwise promotes.

CB1 receptor antagonism also leads to these metabolic effects independent of food intake, which is important in terms of reducing overall cardiometabolic risk even if patients do not lose significant amounts of weight.

Clinical Trials Program

The first CB1 receptor antagonist to have undergone extensive clinical evaluation is rimonabant in the RIO (Rimonabant in Obesity) clinical trials program. This program involved four trials of identical design but in slightly different patient populations: RIO-North America and RIO-Europe in overweight and obese subjects; RIO-Lipids in patients with dyslipidemia; and RIO-Diabetes in patients with diabetes.

As reported by Dr. Luc Van Gaal, Professor of Medicine, Antwerp University Hospital, Belgium, patients in all of the RIO trials were randomized to rimonabant 5 mg, 20 mg or placebo. They all received lifestyle intervention including regular visits to a dietitian. Some 6600 patients were involved in the overall program. After one year, patients treated with 20 mg lost a mean 8.5 cm in WC and a mean 8.6 kg in weight, suggesting that for each kilogram of weight loss with the compound, there was a 1-cm reduction in WC.

Importantly, CT measurements of visceral fat in the active treatment group confirmed that this 8.5-cm reduction in WC was roughly equivalent to a 30% to 35% reduction in visceral fat, which is an important finding in terms of cardiometabolic risk reduction. At two years, reductions in mean WC and weight in the 20-mg group remained similar at 7.5 cm and 7.2 kg, respectively. Corresponding mean reductions in WC and weight in placebo controls at two years were 3.4 cm, and 2.5 kg, respectively.

As Dr. Van Gaal reminded delegates, many of us are convinced that increasing HDL-C should help reduce overall cardiometabolic risk, as HDL-C helps promote cholesterol efflux from cells, inhibits oxidation of LDL-C particles and may limit the expression of adhesion molecules. A low HDL-C is found in many patients with elevated cardiometabolic risk. Thus, an important finding from the RIO program is that rimonabant increased HDL by approximately 20% from baseline and by 9% to 10% over and above what was observed in placebo patients.

These elevations were accompanied by a concomitant decrease in triglycerides. The same beneficial effect of the active treatment on both HDL-C and triglycerides was also seen in both the presence and absence of a statin, yet as Dr. Van Gaal emphasized, rimonabant was never intended to replace statin therapy, as it has little effect on LDL-C.

Results from one of the sister trials, RIO-Lipids, also indicated that there was a significant reduction in smaller denser more atherogenic LDL particles among patients receiving rimonabant 20 mg, suggesting that there is a shift to less atherogenic LDL particles on active therapy as well. Other beneficial metabolic changes seen in response to the higher dose was a significant 46% increase in adiponectin from baseline, as well as a significant reduction in two-hour post-glucose levels. In patients with impaired glucose tolerance at baseline, there was also a shift backwards towards more normal glucose tolerance levels in the active therapy group.

Less weight was lost in RIO-Diabetes at a mean 5.3 kg in rimonabant 20 mg patients, and there was less of a reduction in WC as well at a mean 5.2 cm at the end of the trial. Nevertheless, this could be anticipated, given that weight loss is almost always more difficult to achieve in patients with diabetes than those without. Active therapy was associated with a 0.7% reduction in hemoglobin A1c as well, which is quite impressive, given that patients in RIO-Diabetes were well controlled on study entry.

Investigators also analyzed data according to weight loss categories across the full RIO program. Based on this analysis, they concluded that CB1 antagonism has a beneficial effect on metabolic parameters that is independent of weight loss and which is likely attributable to the direct effects the molecule has at the level of the adipocyte and other tissues where it is active. Somewhat more nausea, dizziness, diarrhea, anxiety and mood disturbances were seen in the active treatment arm compared with placebo.

Summary

WC measurement is a new vital sign, and like blood pressure measurement, should be incorporated into daily clinical practice to assess health risk. We need to err on the side of caution when defining cardiometabolic risk for individual patients, firstly because there are multiple and somewhat confusing classification of that risk and secondly, because we do not as yet have hard clinical evidence that reducing CV risk improves cardiovascular outcomes. This evidence should be forthcoming when CRESCENDO (Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes) is completed and results are known in a few years’time. In the meantime, our first objective is to persuade patients to make healthy changes in eating habits and increase their level of physical activity to reduce abdominal obesity and body fat. Even a modest 5% to10% body weight loss significantly reduces the risk for type 2 diabetes. If, however, lifestyle modification fails, we can consider proven pharmacological interventions and target our truly at-risk patients accordingly.

Based on the officially recognized symposium:

“Harnessing the Endocannabinoid System to Reduce Cardiometabolic Risk.”

Accredited and co-developed as an Accredited Group Learning Activity under Section 1 of the framework of Continuing Professional Development options as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC).

Note: At the time of printing, rimonabant is not available in Canada.