Journal of Clinical Lipidology (2007) 1, 575582

Cardiovascular disease in obesity: A review of related risk factors and risk-reduction strategies
Louis J. Aronne, MD,* W. Virgil Brown, MD, Kathy Keenan Isoldi, MS, RD, CDE
Weill-Cornell Medical College of Cornell University, New York, NY (Dr. Aronne); The Comprehensive Weight Control Program, 1165 York Avenue, New York, NY 10028 (Dr. Aronne and Ms. Isoldi); Emory University School of Medicine, Atlanta Veterans Affairs Medical Center, Atlanta, GA (Dr. Brown) KEYWORDS:
Adiponectin; Bariatric surgery; Cardiovascular disease; Leptin; Metabolic syndrome; Obesity; Orlistat; Rimonabant; Risk factors; Sibutramine Abstract. Cardiovascular disease (CVD) is the number one cause of mortality in men and women. Currently, two thirds of US adults are overweight or obese. CVD and obesity are closely linked and together take a substantial toll on the health of individuals and the community. It is creating a growing burden on public health and nancial difculties in both personal and institutional funding of health care. A review of recent scientic literature reveals that modest weight loss of 5% to 10% ameliorates cardiometabolic risk factors and improves health outcomes. To date, successful weight-loss interventions have been elusive. The choice of weight-loss medications is limited, and the risks of surgical intervention demand that this option be reserved for those patients with extreme obesity. Research has elucidated an improved understanding of the mechanisms leading to obesity and disease. The potential role of hormones, such as leptin and adiponectin, in altering metabolism and vascular disease is better understood. The endocannabinoid system is now recognized as a potentially viable pathway to modulate appetite and energy, lipid, and glucose metabolism. 2007 National Lipid Association. All rights reserved.

Cardiovascular disease (CVD) is the number one cause of mortality in the United States, and has been every year since 1900, with the exception of 1918 when a u epidemic caused a high mortality toll. It is estimated that one in three adults in this country suffers from one or more types of CVD. Prevalence of CVD in the United States is expected to create an annual nancial burden of more than $430 billion in 2007, due to both direct and indirect health-care costs.1 Prevalence of overweight and obesity has skyrocketed during the past few decades, and this is contributing to the overall cost of health care. The economic burden due to overweight and obesity in this country for direct costs, expressed in 2002 dollars, is estimated at $92.6 billion.2 An

* Corresponding author. E-mail address: ljaronne@med.cornell.edu Submitted October 10, 2007; Accepted for publication October 12, 2007.

increase in worksite injuries in obese employees has contributed to the indirect nancial burden incurred from excessive body weight gain. Using data from the Duke Health and Safety Surveillance System, researchers report a clear linear relationship between body mass index (BMI; calculated as kg/m2) and rates of workers compensation claims, resulting in loss of productivity and increased absenteeism.3 The nancial concern is only a small part of the total burden of overweight and obesity created by excessive weight gain. Obese individuals are at greater risk of developing heart disease, hypertension, cerebrovascular disease, type 2 diabetes mellitus, osteoarthritis, many forms of cancer, gallstones, nonalcoholic fatty liver disease, sleep apnea, and asthma.4,5 Additionally, obese individuals are often stigmatized, experience depression, are targets of discrimination, and have lower scores on health-related quality-of-life surveys.4 6 Recent data estimate that two thirds of the adult US population are overweight, with a BMI 25 kg/m2; 32%

1933-2874/$ -see front matter 2007 National Lipid Association. All rights reserved. doi:10.1016/j.jacl.2007.10.005

576 of adults meet the criteria for obesity, with a BMI 30 kg/m2; and 4.8% are in the extreme obesity category, dened as a BMI 40 kg/m2.3 Unfortunately, the rise in obesity prevalence has not been conned to adults. Obesity has been on the rise in toddlers, children, adolescents, and teens, promoting the onset of risk factors for chronic disease in our youth. In the 1970s, obesity prevalence in children aged 2 to 19 years remained steady, at approximately 5%.7 However, since 1980, there has been more than a threefold increase in obesity in the population under 20 years of age, with current estimates reporting a prevalence of 17.1%.3 Increases in incidence of insulin resistance, the metabolic syndrome, type 2 diabetes mellitus, nonalcoholic fatty liver disease, dyslipidemia, hypertension, left ventricular hypertrophy, atherosclerosis, bowed legs, asthma, and obstructive sleep apnea have been reported, coinciding with rising childhood obesity rates.8 The belief that development of CVD begins in childhood has been supported by recent data. Precursors to CVD have been identied in youth and young adults. Researchers have reported the appearance of fatty streaks and brous plaqueprecursors to atherosclerosisin the aorta and coronary arteries of adolescents and young adults during autopsies performed after accidental death.9 Experts predict that the health detriment imposed on children by excess body fat can result in todays youth being the rst generation in more than 2 centuries to experience a reduction in life expectancy.10,11 Data reported by Fontaine and colleagues12 highlight the inuence of excess body weight on the life expectancy of young adults. They reported that young white men aged 20 years with a BMI 45 kg/m2are estimated to cut their life expectancy by 13 years, and white women in the same weight category are expected to lose 8 years of life. Young black men and women aged 20 years with severe obesity are estimated to reduce their life expectancy by 20 years and 5 years, respectively.12 The need to curb obesity and prevent the nancial and health burdens carried at both the individual and the community levels is apparent. This dire need for action has prompted the Robert Wood Johnson Foundation to commit to a $500 million initiative over the next 5 years to support research aimed at nding superior obesity prevention and treatment interventions to reverse the obesity epidemic in children.11 A large part of the increase in disease risk attributable to obesity, including CVD, is the effect of excessive fat mass on cardiometabolic risk factors, stemming from inammatory processes. This article will review the connection between obesity, inammation, increased cardiometabolic risk factors, and development of CVD. Current recommendations and realistic options for obesity treatment and CVD prevention will be discussed.

Journal of Clinical Lipidology, Vol 1, No 6, December 2007 CVD risk. Elevated concentrations of total cholesterol and low-density lipoprotein cholesterol (LDL-C), as well as low concentrations of high-density lipoprotein cholesterol (HDL-C), are associated with risk for coronary heart disease (CHD). Prevalence rates of hypercholesterolemia ( 200 mg/dL), elevated LDL-C ( 130 mg/dL), and low HDL-C ( 40 mg/dL) are estimated at 48.4%, 32.5%, and 16.7%, respectively, in US adults.1 Several studies have found that elevations in LDL-C particle number are strongly associated with CHD and that the LDL particles are often small and more dense with reduced cholesterol content (measurements 25.5 nm), causing an underestimation of the number of LDL and underestimating their power as an independent risk factor.13 In addition, hypertension is quite common in US adults and contributes to development of CVD. It is estimated that one in three US adults has high blood pressure.1 Prehypertension, dened as an untreated systolic blood pressure (BP) of 120 to 139 mm Hg, or an untreated diastolic BP of 80 to 89 mm Hg, affects an estimated 37% of the US adult population.1 As part of the Framingham Heart Study, Wilson and colleagues14 investigated the long-term outcomes of overweight and obesity in risk factor development for CVD, as well as disease outcomes in 5000 men and women. Researchers prospectively followed participants aged 35 to 75 years for up to 44 years. Strong correlations were found between overweight and obesity and development of hypertension, angina pectoris, total CHD, and total CVD (Table 1).14 Recent evidence supports that atherosclerosis results from mechanisms other than dyslipidemia and lipid storage and is, in fact, initiated and promoted by an inammatory process as well. It was observed decades ago that white blood cells adhere to the intact endothelium of early-stage atherosclerotic lesions. In animal studies, just 1 week after starting an atherogenic diet, proinammatory cytokines and oxidized lipoproteins induced the release of vascular cell adhesion molecule-1; this adhesion molecule promotes adhesion of monocytes and lymphocytes to the intimal surface of the endothelium. Chemokine release promotes penetration of leukocytes into the vessel wall.15

Inammatory mediators of disease

There is a strong association between fat-mass accumulation and disease promotion. Fat mass functions as an endocrine organ, secreting adipokines and free fatty acids (FFAs) that inuence lipid metabolism, insulin sensitivity, vascular homeostasis, BP regulation, metabolism, inammation, angiogenesis, and regulation of energy balance.16 Metabolic and immune pathways are interconnected. Preadipocytes have been found to act as macrophages, therefore, fat mass inuences innate immune function.17,18 Obesity overactivates the immune system, creating a state of chronic low-grade inammation.16

CVD risk factors

Dyslipidemia, hypertension, insulin resistance, and inammatory markers are well-recognized as predictors of

Aronne et al Cardiovascular disease in obesity

Table 1

Relative risk and population attributable risk percentage for risk factor development and vascular disease outcomes in overweight and obese men and women Overweight men, RR (95% CI) Obese men, RR (95% CI) 2.23 (1.752.84) 1.06 (0.841.33) 1.85 (1.312.61) 1.81 1.17 1.45 1.58 1.61 1.38 0.98 (1.282.55) (0.821.67) (1.042.01) (1.242.03) (0.982.67) (1.121.69) (0.591.63) Composite (BMI 25 kg/m2) population attributable risk (%) 26 10 21 26 14 20 23 20 15 2 Overweight women, RR (95% CI) 1.70 (1.481.94) 1.29 (1.141.45) 0.91 (0.721.15) 1.42 0.91 0.98 1.22 1.10 1.13 0.77 (1.081.86) (0.611.36) (0.691.41) (0.991.52) (0.771.56) (0.961.33) (0.501.18) Obese women, RR (95% CI) 2.63 (2.203.15) 1.04 (0.881.23) 1.36 (1.031.78) 1.63 1.46 1.30 1.54 1.02 1.38 1.56 (1.182.25) (0.942.28) (0.851.98) (1.191.98) (0.651.59) (1.141.68) (1.002.43) Composite (BMI 25 kg/m2) population attributable risk (%) 28 9 3 22 5 4 15 4 10 1

Risk factor Hypertension* Hypercholesterolemia Diabetes mellitus Outcomes Angina pectoris Myocardial infarction Hard CHD Total CHD Cerebrovascular disease Total CVD CVD death

1.48 (1.241.75) 1.21 (1.051.39) 1.27 (1.081.44) 1.47 1.26 1.37 1.43 1.28 1.24 1.05 (1.121.92) (0.981.61) (1.081.74) (1.191.73) (0.861.91) (1.071.44) (0.741.48)

BMI, body mass index; CHD, coronary heart disease; CI, condence interval; CVD, cardiovascular disease; RR, relative risk. *Multivariable adjustment for age, smoking, diabetes, and hypercholesterolemia. Multivariable adjustment for age, smoking, diabetes, and hypertension. Multivariable adjustment for age, smoking, hypertension, and hypercholesterolemia. Multivariable adjustment for age, smoking, diabetes, hypertension, and hypercholesterolemia. Adapted from Wilson et al,14 with permission of the American Medical Association.

577

578 Leptin is a hormone secreted from fat cells that inuences body weight regulation.19 Adiponectin is also secreted by fat cells and serves as an anti-inammatory adipokine that favorably inuences insulin sensitivity and endothelial integrity. Adiponectin levels are reduced in obese individuals.20 Other secretions from adipocytes, such as interleukin-6, tumor necrosis factor- , plasminogen activator inhibitor-1, angiotensinogen, C-reactive protein, and resistin, promote inammation and a prothrombotic state.18,21 In addition to the detrimental effect of proinammatory adipokines on health, increased levels of serum FFAs are associated with disease initiation and progression. FFA levels in the blood result from a balance between release from intravascular lipolysis of triglyceride-rich lipoproteins and lipolysis of adipose tissue triglyceride stores, and uptake in adipose tissue and the liver.22 In obese individuals, FFA concentrations are usually elevated.23 High circulating FFA levels create negative feedback on insulin secretion and action, increase hepatic glucose production,23 and stimulate production of very low density lipoprotein (VLDL) triglyceride by hepatocytes.22 This cycle contributes to development of insulin resistance and disease progression. Insulin resistance reduces the action of lipoprotein lipase, an enzyme that degrades VLDL particles, resulting in elevated triglyceride concentrations. Elevated circulating VLDL particle concentrations also result in the increased production of small, dense LDL particles and enhanced clearance of HDL-C particles.24

Journal of Clinical Lipidology, Vol 1, No 6, December 2007

Table 2 Criteria Waist circumference Men Women Blood pressure Systolic Diastolic Serum HDL-C Men Women Serum triglycerides Serum fasting glucose Criteria for the Metabolic Syndrome* Measurement 102 cm ( 40 in) 88 cm ( 35 in) 130 mm Hg 85 mm Hg 1.03 mmol/L ( 1.3 mmol/L ( 1.7 mmol/L ( 5.6 mmol/L ( 40 mg/dL) 50 mg/dL) 150 mg/dL) 100 mg/dL)

HDL-C, high-density lipoprotein cholesterol. *According to the National Cholesterol Education Program Adult Treatment Panel II with minor modications by the American Heart Association and the National Heart, Lung, and Blood Institute. Satisfying any three of the following characteristics will meet the criteria for diagnosis of the metabolic syndrome. Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III),26 with permission of Lippincott, Williams & Wilkins.

The metabolic syndrome and obesity

The metabolic dysfunction created by excess fat mass inuences multiple factors of disease risk. A clustering of factors, including abdominal adiposity, dyslipidemia, hyperglycemia, and hypertension, has been referred to as the metabolic syndrome, and the presence of this syndrome has been found to increase risk of cardiovascular morbidity and mortality by two- to threefold.24 More recently, elevations in serum glucose, triglycerides, BP, and waist circumference; and reductions in serum HDL-C measurements, have been referred to as cardiometabolic risk factors25 and, when clustered, are referred to as the metabolic syndrome.26 The National Cholesterol Education Program Adult Treatment Panel III, the International Diabetes Federation, and the World Health Organization have each developed guidelines for diagnosing the metabolic syndrome, with some variation in criteria.27 There has recently been disagreement among experts as to whether identifying individuals with the syndrome is useful, and questions remain regarding which set of criteria is most accurate in the diagnostic process. However, the American Diabetes Association and the American Heart Association jointly reported that identifying the core set of risk factors for cardiometa-

bolic risk was essential for clinicians to conduct an accurate patient assessment.25 Table 2 provides an outline of the National Cholesterol Education Program Adult Treatment Panel III criteria for diagnosing the metabolic syndrome.26,28 When these criteria are met, several large studies indicate that risk of a major cardiovascular event is essentially doubled. Diagnosis of the metabolic syndrome using the National Cholesterol Education Program criteria provides for inclusion of persons whose individual risk factors may not exceed thresholds that call for specic treatment, but when clustered confer signicant risk and call for more aggressive treatment. Elevated BMI readings are associated with increased risk for CVD development. However, abdominal adiposity, identied through waist circumference measurement, has been found to be a strong, independent predictor of insulin resistance and of cardiovascular risk factors.29 In 1956, Vague rst described the difference in disease risk based on fat distribution in the upper body (android) versus lower body (gynoid).29 More than half a century has passed and researchers continue to support the hypotheses put forth by Vague. Fat that accumulates in the abdominal area, sometimes referred to as visceral or intra-abdominal fat, carries an increased risk for disease development. Abdominal obesity is strongly associated with insulin resistance, dyslipidemia, glucose intolerance, atherosclerosis, and CHD.29 In the United States, waist measurements 102 cm in men and 88 cm in women are associated with increased risk of disease. Recommended waist measurement cutoffs are lower for Asian and Pacic populations, with the cutoff for men and women of 90 and 80 cm, respectively.29

Aronne et al

Cardiovascular disease in obesity

Paresthesia, taste aversion, constipation, CNS effects33 Fatigue, small but signicant increase in serum creatinine34 Gastrointestinal35

579

Obesity treatment: Lifestyle and medication

Effectively preventing and treating excess weight gain is essential to halting the rise in obesity prevalence and averting devastating CVD outcomes. The fundamental basis for any weight-loss intervention, as well as the obvious rst defensive action, is lifestyle modication aimed at increasing calories expended during physical activity and decreasing calories consumed from food. The history of success in weight-loss interventions targeting diet and exercise has been modest and usually temporary. However, even stabilization of weight can be considered a helpful intervention in many. Furthermore, even a reduction of just 5% to 10% of body weight is considered successful, as it has been shown to improve lipid prole, insulin sensitivity, and endothelial function, and to reduce thrombosis and inammatory markers.30 The National Heart, Lung, and Blood Institute of the National Institutes of Health recommends considering the addition of appetite suppressants to the treatment plan for individuals who fail lifestyle interventions and have a BMI 30 kg/m2, or a BMI 27 kg/m2 in the presence of comorbidity.31 Surgical intervention for obesity is reserved for those with extreme obesity, who have a BMI 40 kg/m2, or a BMI 35 kg/m2 in the presence of co-morbidity.31 Pharmacologic treatment of obesity has thus far revealed less than encouraging results.32 Phentermine, a sympathomimetic amine, was approved by the US Food and Drug Administration in 1959 for short-term treatment of obesity. To date, there are only two US Food and Drug Administrationapproved weight-loss medications for long-term use in obesity. Sibutramine, a combined norepinephrine and serotonin reuptake inhibitor, and orlistat, a lipase inhibitor, received US Food and Drug Administration approval in 1998 and 1999, respectively. Topiramate, zonisamide, bupropion, and metformin have been found to reduce body weight but are approved only for treatment of other illnesses. Placebo-corrected weight-loss totals from these medications reveal modest weight reductions.33 Table 3 reviews pooled medication-induced weightloss data.3335 Although medication alone results in small amounts of weight loss, Wadden and colleagues36 reported a 59% increase in weight loss in their group of obese study participants, when sibutramine was combined with intensive lifestyle and behavior modication, compared with the medication only group. These data shed light on the potential outcomes when treatment modalities are combined.
Palpitations, tachycardia, elevated BP, gastrointestinal effects33 Diarrhea, atulence, bloating33 Increased BP, increased pulse, dry mouth, insomnia, constipation34 Dry mouth, diarrhea, constipation, insomnia33

Length of treatment (wk)

Common side effects

Surgical treatment of obesity

Bariatric surgery is reserved for the most severe cases of obesity. The National Heart, Lung, and Blood Institute guidelines state that those individuals with a BMI 40 kg/m2 or those with weight-related co-morbidity who have a BMI 35 kg/m2 may be considered for surgical treatment of obesity.31 Bariatric surgery involves surgical alteration of

Phentermine

Zonisamide*

Orlistat Sibutramine

Table 3

Metformin

Topiramate

Medication

Bupropion

BP, blood pressure; CNS, central nervous system; FDA, Food and Drug Administration. *Data obtained from one trial. Data obtained from the Diabetes Prevention Program Research Group Trial. Individuals with impaired fasting glucose were treated with drug.

5233 5233

2433

1633 Weight-loss mechanism unknown34 2000/seizure disorder33 5.0%33

Weight-loss pooled data (placebo-corrected)

245233

224

Lipase inhibitor33 Combined norepinephrine and serotonin reuptake inhibitor33 Weight loss may be due to inhibition of norepinephrine and dopamine uptake34 Weight-loss mechanism unknown34

Efcacy and safety of weight-loss medications

FDA approval (y)/intended use

33

Sympathomimetic amine

1999/long-term weight loss33 1998/long-term weight loss33

1985/antidepressant, smoking cessation34

Mid-1990s/seizure disorder33

1959/short-term weight loss

1990s/type 2 diabetes

Insulin sensitizer; suppresses hepatic glucose production

Action

33

2.0 kg34,35

2.75 kg33 4.45 kg33

2.77 kg33

33

6.5%33

3.6 kg

14634

33

580 the anatomy of the gastrointestinal tract. The surgical procedures produce malabsorption of nutrients bypassing portions of the small intestineand/or restrict gastric capacity. Restrictive procedures include gastric stapling, adjustable gastric banding, and vertical (sleeve) gastrectomy. Adjustable gastric banding is a relatively new procedure and involves placement of a subcutaneous reservoir that allows the physician to adjust gastric restriction through saline injections. The vertical restrictive gastrectomy is a procedure in which resection of the gastric body leaves a narrow tube of stomach.37 The Roux-en-Y bypass surgery involves a combination of restriction and reduction of intestinal length available for absorption. The stomach is stapled to create a small upper gastric pouch with a 30.0-mL capacity. The small intestine is divided at the mid-jejunum, and the distal portion, or Roux limb, is anastomosed to the gastric pouch. Food comes into contact with pancreatic enzymes and biliary secretions only below the anastomosis, creating an environment of malabsorption.37 A more extensive bariatric surgical procedure, once again combining restriction and malabsorption, is the biliopancreatic diversion, referred to as the duodenal switch. This procedure is often performed in stages beginning with the restrictive procedure, i.e., the vertical (sleeve) gastrectomy. Once the patient has lost enough weight to reduce surgical risks, intestinal bypass surgery is performed, reducing nutrient absorption.37 Weight-loss results from bariatric surgical procedures are impressive, with typical losses reported in the range of 20 to 50 kg.37 These data help explain the recent interest and subsequent rise in the total number of bariatric surgical procedures. However, there are many surgical risks, postoperative complications, and long-term potential adverse effects from this invasive treatment modality for obesity, which must be considered. The mortality rate associated with bariatric surgery is reported to range from 0.1% to 2.0%. Perioperative complications include venous thromboembolism, anastomotic leaks, wound infections, bleeding, incidental splenectomy, incisional and internal hernias, and early small bowel obstruction. Postoperative complications include nausea, vomiting, and the dumping syndrome. The malabsorptive procedures, i.e., Roux-en-Y and duodenal switch, can induce nutrient deciencies of iron, calcium, copper, folate, vitamin B-12, protein, and vitamins A, D, E, and K.37 Nutrient deciencies can be avoided by continued monitoring and care from qualied physicians, nurses, and registered dietitians knowledgeable about the needs of bariatric surgical patients.

Journal of Clinical Lipidology, Vol 1, No 6, December 2007 appetite and energy metabolism.32 The endocannabinoid system has recently been identied as an interesting pathway that inuences body weight and glucose and lipid regulation.38 Endogenous cannabinoids activate the endocannabinoid system by coupling to specic receptors. Cannabinoid receptors types 1 and 2 have been identied and cloned. Cannabinoid type 1 receptors are found in the central nervous system and peripherally in adipocytes, hepatocytes, gastric mucosa, endothelial tissue, and skeletal muscles.38 Obese individuals exhibit an overactivation of the endocannabinoid system.39 Animal research has revealed weight-loss benets and improved lipid and glucose metabolism when cannabinoid type 1 receptors are blocked.40 Promising animal research on the endocannabinoid system has led to development of a selective cannabinoid type 1receptor blocker, rimonabant. Rimonabant-in-Obesity (RIO) trials have investigated the efcacy and safety of rimonabant in 6600 overweight and obese men and women.41 44 Four RIO trialsRIO-North America, RIOEurope, RIO-Lipids, and RIO-Diabetes have been conducted at multiple sites in North America, South America, and Europe. Participants were randomized to placebo, and 5- or 20-mg rimonabant groups and treated for 1 year. The primary study endpoint was weight loss, with waist circumference, lipid, glucose, and other measurements of cardiometabolic risk factors reported as secondary endpoints. RIO-North America continued for 2 years, investigating maintenance of weight loss and reduced cardiometabolic risk factors in the second year of the trial. All participants were instructed on a 600-caloriereduced diet and were counseled to increase physical activity. Statistically signicant reductions in weight, waist measurements, triglyceride levels, and incidence of the metabolic syndrome, as well as increases in HDL-C levels were reported in the 20-mg rimonabant group vs the placebo group in the RIO-North America, RIO-Europe, RIO-Lipids, and RIO-Diabetes trials.41 44 Additionally, the RIO-Lipids trial reported signicantly reduced levels of C-reactive protein and the number of small, dense LDL particles, and increased levels of adiponectin in the group of untreated hyperlipidemic participants in the 20-mg rimonabant group vs the placebo group.43 The RIO-Diabetes trial reported statistically signicant reductions in levels of C-reactive protein and hemoglobin A1c in the participants with diabetes in the 20-mg rimonabant group versus the placebo group.44 Table 4 reviews placebo-corrected outcome measurements of the RIO trials. In year 2 of RIO-North America, participants who continued taking rimonabant 20 mg maintained lost weight and reduced cardiometabolic risk factors, whereas the participants switched to placebo in year 2 regained most of their lost weight.41 Rimonabant was reported in the RIO trials to be generally well-tolerated, with dizziness, headache, anxiety, depressed mood, and nausea as the most common reasons for study discontinuation in the 20-mg rimonabant group.41 44 Incidence of depression of approximately 4%

New treatments on the horizon

During the past decade, great strides in improving our understanding of the many varied pathways that inuence body weight regulation have been made. Researchers are investigating many new systems and targets to modulate

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Cardiovascular disease in obesity

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Table 4 Placebo-corrected changes in outcome measurements in the Rimonabant in Obesity trials for patients treated with rimonabant 20 mg* Outcome measurements Weight loss (kg) Waist circumference (cm) Change in triglycerides (%) Change in HDL-C (%) Change in small dense LDL (%) Change in HbA1c (%) Change in adiponectin ( g/mL) Change in CRP (mg/L) Reduction in the MetS (%) RIO-North America41 4.7 3.6 13.2 7.2 31 RIO-Europe42 4.8 4.1 13.1 8.7 32 RIO-Lipids43 5.4 4.7 12.4 8.1 4.7 1.5 0.5# 28 RIO-Diabetes44 3.9 3.3 16.4 8.3 0.7 1.4# 8#

CRP, C-reactive protein; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; MetS, metabolic syndrome; RIO, Rimonabant in Obesity. *Intent-to-treat population data. All results statistically signicant at P 0.001 vs placebo, except where noted. Values based on modied intent-to-treat data (all randomized participants who received at least one dose of study drug and had at least one postbaseline assessment). P 0.0001 vs placebo. P 0.002 vs placebo. Data collected on a subgroup of participants. #P 0.02 vs placebo.

was statistically higher than the incidence of approximately 2% reported in the placebo group. Studies are underway to determine if this is predictable and preventable in patients who are candidates for this drug therapy. Rimonabant is available in several countries in Europe; however, it is not currently available for use in the United States, presumably awaiting further data on the relationship to depression.

Financial disclosures
Grants or research support to L.J.A. were received from Amylin Pharmaceuticals, Inc., GlaxoSmithKline, Medtronic, Inc., Merck & Co., Inc, Obecure Ltd., Orexigen Therapeutics, Inc., Pzer, Inc., sano-aventis Pharmaceuticals, Inc. W.V.B. was a consultant for grants or research support, or received honoraria for speaking engagements from Abbott Laboratories, AstraZeneca, Bayer AG, Atherogenics, Inc., GlaxoSmithKline, Eli Lilly and Company, LipoScience, Merck & Co., Inc., Merck/Schering-Plough Corporation, Pzer Inc, Reliant Pharmaceuticals, Inc., sano-aventis, Takeda Pharmaceutical Co. W.V.B owns no equities or warrants in any of these pharmaceutical companies.

Conclusions
Obesity is a strong, independent factor promoting development of cardiometabolic risk factors and CVD. We have yet to provide a universally accepted treatment option that provides long-term weight-loss success for the majority of overweight and obese individuals in this country. Although surgical procedures have been shown to produce sustained weight loss, these are reserved for patients with severe obesity or severe co-morbidities because of the risk. Lifestyle modications and medications remain the treatments of choice for obese and overweight individuals with comorbidities. Combining treatment modalities appears to offer improved outcomes; however, medication options for the treatment of obesity are limited. Many new pathways are under investigation to target body weight regulation. The endocannabinoid system is a novel pathway that shows promise in promoting modest but signicant weight loss and reductions in cardiometabolic risk factors. Research conrms that aiding patients in achieving and maintaining a loss of 5% to 10% of body weight will greatly reduce several major risk factors for CVD. This targeted range should be our current therapeutic goal in obese patients.

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