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Endocannabinoid system and its implications for obesity and cardiometabolic risk

Richard W. Nesto^1,* and Ken Mackie^2,3

¹ Department of Cardiovascular Medicine, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805, USA
² Department of Anesthesiology, University of Washington School of Medicine, Box 356540, HSB BB1428, 1959 NE Pacific Street, Seattle, WA 98195-6540, USA
³ Department of Physiology and Biophysics, University of Washington School of Medicine, Box 356540, HSB BB1428, 1959 NE Pacific Street, Seattle, WA 98195-6540, USA

^* Corresponding author. Tel: +1 781 744 8962. E-mail address: richard.w.nesto{at}lahey.org

	Abstract

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
The endocannabinoid system (ECS) is an endogenous signalling system involved in maintaining energy balance. The ECS works both centrally and peripherally to promote metabolic processes that can lead to weight gain, and recent investigations suggest that obesity may be associated with ECS overactivity. Obesity, in particular, abdominal obesity, is recognized as having a role in potentiating cardiometabolic risk factors and disease progression and is often overlooked as a risk factor requiring early monitoring and management. Adipose tissue is a very metabolically active endocrine organ secreting numerous bioactive molecules, adipocytokines, which can act locally and distally. In the obese state, with the notable exception of adiponectin, these cytokines are released in excess and lead to negative metabolic sequelae, such as the potentiation of atherogenic dyslipidaemia, insulin resistance, and hypertension. Blockade of the cannabinoid type 1 (CB₁) receptor with the CB₁ receptor blocker, rimonabant, has been shown to reduce overall and abdominal obesity and improve a number of metabolic variables, including glucose tolerance, reduced plasma levels of triglycerides and insulin, and increased levels of high density lipoprotein (HDL) cholesterol and adiponectin. In addition, the pro-inflammatory and pro-atherogenic state is reduced, as evidenced by a reduction in the C-reactive protein and atherogenic ApoB lipoprotein, respectively. Thus, blockade of the CB₁ receptor may potentially reduce abdominal obesity and some other associated cardiometabolic risk factors.

Key Words: Abdominal obesity • Endocannabinoid • Global cardiometabolic risk • Rimonabant • Type 2 diabetes

	Introduction

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
The endocannabinoid system (ECS) consists of G protein-coupled, cannabinoid type 1 and type 2 (CB₁ and CB₂) receptors, their endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and degradation.¹ This signalling system, acting both centrally and peripherally, is involved in multiple physiological processes, including regulation of food intake, energy expenditure, and lipid metabolism. These endocannabinoid actions facilitate energy intake and storage.² It has been suggested that the activity of the ECS is enhanced in human obesity; thus, overactivity of the ECS may contribute to obesity and its cardiometabolic complications.^3–8

Obesity, in particular, abdominal obesity, is a major risk factor for cardiovascular disease (CVD) and type 2 diabetes, which are two of the leading causes of morbidity and mortality in the USA.^9–11 Over the past 20 years, the prevalence of obesity in US children and adolescents has increased steadily,¹² with 17% of that population being overweight in 2003–4.¹³ More recently, impaired glucose tolerance has emerged as a new major concern in this population.¹² Obesity in childhood and adolescence has been associated with a number of subclinical cardiovascular structural and functional changes that include increases in cardiac mass, accelerated atherosclerosis, and endothelial dysfunction.^14–16 Abdominal obesity, in particular, is associated with multiple risk factors which include insulin resistance, dyslipidaemia, hypertension, and a pro-atherogenic and pro-inflammatory state. Accordingly, therapeutic approaches to reduce abdominal obesity may enhance the efficacy of cardiovascular risk-reduction regimens. To that effect, recent advances in the understanding of the role of the ECS in regulating energy balance have led to a number of clinical studies assessing the effects of CB₁ receptor blockade in obesity.

Pharmacological blockade of the CB₁ receptor activity has the potential to modulate energy balance and thereby favourably impact the risk factors associated with CVD and type 2 diabetes, such as abdominal obesity, dyslipidaemia, elevated fasting plasma glucose, and insulin resistance.

This review will focus on central and peripheral components of the ECS and the biological basis for their involvement in energy balance, lipogenesis, and glucose metabolism, and the associated clinical implications for reducing cardiometabolic risk factors. The effect of rimonabant in obese patients will be examined in view of CB₁ receptor effects on multiple cardiometabolic risk factors.

	The ECS

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
High levels of CB₁ receptors are expressed in the central nervous system (CNS)¹⁷ and can also be found in many other tissues, including the liver,¹⁸ pancreas,^5,19 adipocytes,^2,7 gastrointestinal tract,²⁰ and skeletal muscle.^21,22 CB₂ receptors are primarily located in immune cells but may also be expressed in a limited fashion in the brain and other non-immune tissues,²³ including adipocytes.²⁴ The two best characterized endocannabinoids are anandamide and 2-arachidonoyl glycerol (2-AG). Anandamide is the amide of arachidonic acid and ethanolamine, whereas 2-AG is an arachidonic acid ester.^25–27 A distinguishing feature of the endocannabinoids is that, unlike classic neurotransmitters and hormones, they are not stored, but synthesized on demand from membrane-derived phospholipids.²⁸ Thus, changes in endocannabinoid synthesis have immediate consequences on endocannabinoid signalling. Following synthesis in the brain, endocannabinoids leave the post-synaptic cell and travel back across the synapse to activate CB receptors on pre-synaptic neurons, a process also referred to as retrograde signalling,²⁸ in which they inhibit calcium channels and decrease neurotransmitter release,²⁹ both processes known to occur as a consequence of inhibitory G protein activation. Termination of endocannabinoid action occurs during a two-step process. In the first step, endocannabinoids are taken up into the cell, possibly by a carrier-mediated process, common to both anandamide and 2-AG.³⁰ In the second step, endocannabinoids are hydrolyzed by specific hydrolases. For anandamide, it is fatty acid amide hydrolase (FAAH),^30,31 and for 2-AG, it is monoacylglycerol lipase.³²

Central regulation of appetite
Regulation of appetite and energy intake in the brain is thought to occur on at least two different levels. First, the ECS reinforces the motivation for seeking and consuming highly palatable food, probably through interaction with mesolimbic pathways involved in reward mechanisms.⁴ Second, the ECS in the hypothalamus becomes activated after short-term fasting, subsequently stimulating appetite.⁴ Evidence for the involvement of CB₁ receptors in regulating food intake comes from animal studies in which endocannabinoids directly administered into hypothalamic or mesolimbic brain regions dose-dependently stimulate food intake in pre-fed rats^33,34; this effect could be blocked using a CB₁ receptor blocker.³³ Moreover, in fasted rats, hypothalamic levels of endocannabinoids are elevated and decrease after food intake.^34,35

Peripheral metabolism
In addition to the central effects on food intake, CB₁ receptors in peripheral tissues suggest an involvement of the ECS in the regulation of energy balance at both the central and peripheral levels (Figure 1).²

View larger version (26K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Effects of overactivity of the endocannabinoid system at both central and peripheral levels and the effect of cannabinoid type 1 receptor blockade on endocannabinoid system actions. In animals, increased activity of the endocannabinoid system has been associated with increased food intake and weight gain; in humans, overactivity of the endocannabinoid system may contribute to obesity and its cardiometabolic complications, such as insulin resistance, dyslipidaemia, and a pro-atherogenic and pro-inflammatory state. Cannabinoid type 1 receptor blockade ameliorates many of these actions and is associated with a risk reduction for cardiovascular disease and type 2 diabetes. CB1-R, cannabinoid type 1 receptor; CVD, cardiovascular disease; ECS, endocannabinoid system; HDL, high-density lipoprotein; IL-6, interleukin 6; LPL, lipoprotein lipase; TNF-, tumour necrosis factor-; VLDL, very low density lipoprotein.

 
Evidence from several animal studies demonstrates that the effect of the ECS on energy homeostasis cannot be solely explained through its central effects on feeding behaviour and supports the concept of peripheral regulation of energy balance by the ECS.^2,36–39 Administration of a CB₁ receptor blocker in several animal models of obesity resulted in a significant and sustained weight loss that could not be solely explained by a reduction in food intake, suggesting that there was also an increase in energy expenditure.^{21,36–38,40} This observation prompted a series of studies that further established a role for CB₁ receptors in regulating energy expenditure. For example, in mice with diet-induced obesity, long-term administration of a CB₁ receptor blocker results in sustained weight loss, with only a transient reduction in food consumption.³⁸ A role for CB₁ receptors in energy balance is also suggested by the observation that CB₁ receptor knockout mice have a lean phenotype and are resistant to the development of diet-induced obesity when fed with a palatable high-fat diet.^2,39 This and other evidence stimulated the search for CB₁ receptor actions beyond simply reducing food intake outside the CNS. Various studies have demonstrated that CB₁ receptors are located in adipose tissue and intestines, as well as the liver, pancreas, and possibly skeletal muscle.^{2,18,19,21,40–43}

Effect of CB₁ receptors on adipocyte function
Evidence from cell culture and animal models supports a role for CB₁ receptors in regulating adipocyte metabolism. CB₁ receptor mRNA has been found in cultured adipocytes and epididymal fat pads, where receptor stimulation leads to activation of lipoprotein lipase and, thus, mobilization of free fatty acids (FFAs).² CB₁ receptor mRNA levels are increased in genetic models of obesity,⁴⁰ and conversely, adipocyte hypertrophy in mice with diet-induced obesity is reversed following treatment with a CB₁ receptor blocker.⁴⁴ CB₁ receptor blockade also inhibits adipocyte proliferation, at least in cell culture models.⁴⁵ Using a global analysis of adipocyte gene transcription, CB₁ receptor blockade has been shown to normalize the expression of genes altered during a high-fat diet.⁴⁴

The synthesis and secretion of the hormone adiponectin is an important autocrine function of adipocytes. In humans, adiponectin levels correlate negatively with body mass index (BMI), increased abdominal obesity (visceral and subcutaneous depots), fasting insulin and glucose concentrations, and triglyceride levels.^46–48 Conversely, adiponectin levels in these studies were positively correlated with measures of insulin sensitivity and high density lipoprotein (HDL) cholesterol levels. A decline in adiponectin levels has been implicated in the development of atherosclerosis and glucose intolerance.^46–48 Adiponectin levels are decreased in animal models of genetic and diet-induced obesity, and these changes can be reversed using a CB₁ receptor blocker, a change not seen when lean rats or mice are treated in a similar fashion.⁴⁰ Thus, CB₁ receptor blockade in adipose tissue results in lower FFA concentrations being delivered into the circulation, resulting in reduced fat storage and improved insulin sensitivity.

Effect of CB₁ receptors on intestinal motility
CB₁ receptors are also amply expressed in the intestine, where they have a role in regulating gastric emptying and peristalsis.^7,49 There is functional evidence for the presence of CB₁ receptors in human ileum longitudinal smooth muscle, where a CB₁ receptor agonist potently inhibited the electrically induced twitch response; this effect could be blocked using a CB₁ receptor blocker.⁴¹ Activation of intestinal CB₁ receptors slows peristalsis and prolongs intestinal transit times; blocking these receptors has a pro-kinetic effect.²⁰ Similar to observations in the hypothalamus, intestinal anandamide levels increase several-fold following 24 h of starvation.⁵⁰ CB₁ receptors on intestinal afferents may also play a role in the signalling of satiety. How this effect of CB₁ receptor stimulation on intestinal motility affects cardiometabolic risk remains unknown; however, delays in gastric emptying and prolonged intestinal transit times may promote weight gain.

Effect of CB₁ receptors on hepatic lipogenesis
CB₁ receptors are present in the liver, where they appear to play a role in lipogenesis.¹⁸ For example, a high-fat diet fed to mice leads to increases in hepatic anandamide, fatty acid synthesis, and CB₁ receptor expression.¹⁸ Activation of hepatic CB₁ receptors stimulates synthesis of the lipogenic transcription factor SREBP 1c and its associated lipogenic enzymes, acetyl CoA carboxylase and fatty acid synthase.¹⁸ Treatment of mice fed a high-fat diet with a CB₁ receptor blocker reduces the increases in fatty acid synthesis normally seen with this diet.¹⁸ As observed in the Rimonabant-in-Obesity (RIO) trials,^51–54 CB₁ receptor blockade in the liver may be responsible for the improvements of the dyslipidaemic profile.

Expression and function of CB₁ receptors in the pancreas
The presence of CB₁ receptors in the pancreas has been documented^19,55 and several lines of evidence suggest a role for its involvement in glucose homeostasis. Treatment with a CB₁ receptor blocker decreased insulin levels in mice with diet-induced obesity^37,39 as well as in obese Zucker rats⁴⁰; in the former group, CB₁ receptor blockade also decreased serum glucose levels.³⁷ However, the mechanism by which CB₁ receptor antagonism decreases serum insulin levels and enhances insulin sensitivity remains to be determined.

Effect of CB₁ receptors in skeletal muscle
CB₁ receptor mRNA has recently been reported in skeletal muscle of mice, with higher levels in mice with diet-induced obesity compared with lean mice.²² Administration of a CB₁ receptor blocker in ob/ob mice increased basal oxygen consumption and glucose uptake by skeletal muscle, possibly suggesting that CB₁ receptor blockade can increase energy expenditure and may improve insulin sensitivity.²¹

In summary, the ECS functions centrally to regulate appetite, and peripherally to modulate adipocyte metabolism, intestinal motility, hepatic lipogenesis, and glucose homeostasis. Furthermore, CB₁ receptor stimulation favours an anabolic state promoting fat storage/weight gain and insulin resistance, which are risk factors for CVD.

	The ECS and cardiometabolic risk

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
Adipose tissue is an active endocrine organ which produces and secretes a host of bioactive molecules, including FFAs, cytokines, plasminogen activator inhibitor 1, leptin, and adiponectin.⁵⁶ With the exception of adiponectin whose levels decrease in obesity, these adipokines are overabundant in obesity,^56,57 and when secreted in excess, can adversely affect health.⁵⁶

Thus, studies have suggested that abdominal obesity presents an important predictor of overall health risk and mortality compared with generalized overweight or obesity.⁵⁶ Abdominal obesity is a major risk factor for multiple cardiometabolic risk factors that include insulin resistance, dyslipidaemia, hypertension, and a pro-atherogenic state with elevated ApoB lipoprotein levels and a pro-inflammatory state with elevated C-reactive protein levels.⁵⁸ There is a continuum of risk towards the progression of CVD and metabolic disease; thus, early recognition and treatment of obesity is important.⁵⁹

In this regard, obesity, in particular during childhood or adolescence, is often a consistent predictor of cardiovascular and metabolic dysfunction developing at a later stage in life, including left ventricular hypertrophy (LVH),^15,16 increased carotid artery intima-media thickness,⁶⁰ coronary atherosclerosis,¹⁴ and endothelial dysfunction.⁶¹ For example, both the Bogalusa Heart Study¹⁶ and the Strong Heart Study¹⁵ demonstrated that obesity during childhood and adolescence was a significant predictor of LVH and possibly also of reduced myocardial performance in adulthood. In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, a BMI >30 kg/m² in young men (15–34 years) was associated with fatty streaks, raised lesions, and stenoses in coronary arteries, all signs of accelerated atherosclerosis.¹⁴ The Mexico City Diabetes Study, which included non-diabetic, pre-diabetic, and diabetic patients, assessed the relationship between carotid artery intima-media thickness and the onset of clinical diabetes.⁶⁰ Relative to non-diabetic individuals, pre-diabetic patients had a higher BMI, larger waist circumference (WC), higher insulin and glucose levels, and a worse lipid profile. More importantly, internal carotid artery intima-media thickness was significantly higher among the pre-diabetic individuals compared with subjects who remained free of diabetes.⁶⁰

The link between obesity and the ECS is still unresolved. In obese women, circulating anandamide and 2-AG levels are increased, whereas adipose CB₁ and FAAH (the primarily anandamide-degrading enzyme) mRNA are decreased.⁷ Moreover, in a study of >2500 subjects, a mutation in the FAAH gene was observed approximately twice as often in overweight and obese individuals when compared with normal weight individuals.⁶ It has been postulated that overactivation of the ECS, and thus CB₁ receptor activity, in obesity results in adipocyte hypertrophy⁴⁴ and markedly reduced plasma adiponectin levels, a common feature of abdominal obesity and insulin resistance.⁴⁶ Hypo-adiponectinaemia, in turn, has been implicated in a pro-atherogenic and pro-inflammatory state that includes low HDL cholesterol levels,⁴⁶ endothelial dysfunction,⁶² and elevated fasting glucose.^63,64 Moreover, an overactive ECS has also been linked to hepatic lipogenesis,¹⁸ where it may contribute to fat accumulation in the liver, leading to non-alcoholic steatohepatitis (NASH), a well-known consequence of insulin resistance, type 2 diabetes, and hyperlipidaemia.⁶⁵

Thus, the current evidence supports a role of an overactive ECS in obesity and the development of NASH, insulin resistance, and atherogenesis. Consequently, CB₁ receptor blockade is an attractive target to ameliorate multiple cardiometabolic risk factors.

	Obesity and cardiovascular risk

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
Physicians are more familiar with established risk factors for coronary heart disease, such as hypertension, dyslipidaemia, and type 2 diabetes, and have at their disposal an array of drugs to treat them. However, current therapeutic strategies for risk factor management are reactive, focusing on clinically evident risk factors in isolation. Although individual treatment goals may be met with this approach, many patients experience a significant residual cardiovascular risk. In several cardiovascular outcomes studies, up to 24% of patients still experienced cardiovascular events.^66–70

The Heart Outcomes Prevention Evaluation (HOPE) study evaluated the effects of angiotensin-converting enzyme (ACE) inhibition on cardiovascular risk reduction in more than 9000 patients with vascular disease or type 2 diabetes. Although there was a 22% risk reduction in the ACE-inhibitor-treated group after 5 years, 14% of patients in this group reached the primary endpoint of this study, myocardial infarction (MI), stroke, or death from cardiovascular cause.⁷⁰ In comparison, in the Heart Protection Study,⁶⁸ simvastatin use in more than 10 000 patients was associated with a 24% reduction in coronary mortality, MI, stroke, and revascularization procedures. Although this was impressive, over the 5-year study period, almost 900 non-fatal MIs occurred in this group, constituting a substantial 19.8% residual risk. In the Steno-2 Study,⁶⁹ both behavioural and pharmacological approaches were taken to target dyslipidaemia, hyperglycaemia, hypertension, and microalbuminuria in patients with type 2 diabetes and microalbuminuria. After almost 8 years, patients receiving intensive therapy had a 47% reduced risk of CVD compared with those receiving usual care. However, the residual risk of a cardiovascular event was still 24% in the intensively treated group. Interestingly, despite being exposed to a multifactorial intervention programme, patients in the Steno-2 study did not lose any weight, emphasizing the difficulty associated with achieving lasting weight loss.

The PROVE IT-TIMI 22 study, a state-of-the-art secondary prevention trial, assessed the risk of recurrent myocardial events and the relationship between low density lipoprotein (LDL) cholesterol and C-reactive protein levels in statin-treated patients with acute coronary syndromes. Fewer statin-treated patients with LDL cholesterol levels <70 mg/dL had recurring myocardial events (5.4%) compared with patients with higher cholesterol levels (7.4%).⁶⁷ Patients with LDL cholesterol <70 mg/dL and C-reactive protein levels <1 mg/L had the lowest event rate (3.8%). A follow-up to the PROVE IT-TIMI 22 study found that the highest C-reactive protein levels are found in patients with features of obesity and/or insulin resistance, such as a high BMI, low HDL cholesterol, high triglycerides, high fasting glucose, and hypertension.⁶⁶ This study demonstrates that despite conventional and maximal prevention drug therapy, obesity- and insulin-related risk factors may have a significant role in residual cardiovascular risk. Thus, obesity and insulin resistance should also be targets for intervention, in addition to those listed in the current secondary prevention guidelines.

	Benefits of weight loss and lifestyle management

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
Even moderate weight loss has been shown to beneficially impact multiple cardiometabolic risk factors, leading to an overall reduction of cardiovascular risk.^71–73 For example, a 5–10% loss of body weight has been associated with a decrease in circulating levels of inflammatory cytokines, improved fasting glucose and insulin levels, improved endothelial function,⁷² lower blood pressure,^74,75 and an improved lipid profile.⁷¹ In addition, weight loss has been shown to prevent type 2 diabetes in the Diabetes Prevention Program.⁷⁶ Perhaps most importantly, weight loss was associated with a significant reduction in all-cause mortality in markedly overweight men, and the data suggest that the earlier the intervention, the greater the chance of benefit.⁷⁷ However, although several large studies have demonstrated that CVD risk could theoretically be reduced by >80%⁷⁸ or even >90%⁷⁸ if individuals adhered to a healthy lifestyle that includes regular exercise, a healthy diet, abstaining from smoking, consuming small amounts of alcohol, and reducing day-to-day stress, most people were unable to do so over a long-term period. In fact, in the Nurses Health Study, only 3% of women met those criteria.⁷⁸ Because it is inherently difficult for overweight and obese individuals to lose weight and improve their cardiometabolic risk profile, effective pharmacotherapies would be beneficial.

	Therapeutic application of the CB1 receptor blocker rimonabant

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
The four RIO trials were large multicentre, multinational trials that assessed the efficacy and safety of the CB₁ receptor blocker rimonabant in reducing body weight and positively modifying multiple cardiometabolic risk factors in obese patients.^51–54 The four studies included more than 6000 overweight and obese patients, with or without co-morbidities, who received rimonabant (20 mg/day) for 1 year or longer. At the end of the studies, patients demonstrated a significant reduction of overall body weight and, more importantly, a substantial reduction of abdominal obesity, as evidenced by a reduction in WC. This loss of abdominal adipose tissue was accompanied by marked improvements in metabolic parameters, including a reduction in triglycerides, fasting glucose,⁵³ HbA1c,⁵⁴ and insulin levels.^51–54 At the same time, patients receiving rimonabant 20 mg demonstrated a significant increase in HDL cholesterol^51,53,79 and adiponectin⁵¹ levels. In addition, rimonabant therapy reduced pro-atherogenic and pro-inflammatory risk, as evidenced by a shift in the distribution of LDL-cholesterol particles towards a larger size (a 4.6% reduction of atherogenic small LDL particles) and a decrease in C-reactive protein, respectively.⁵¹

The metabolic improvements produced by rimonabant 20 mg treatment were greater than would have been expected from weight loss alone. For example, only 50% of the changes in HDL cholesterol, triglyceride levels, fasting insulin levels, and insulin resistance could be attributed to weight loss.⁵² In patients receiving rimonabant for 2 years, weight loss stabilized after 1 year; however, HDL cholesterol continued to increase.⁵² These findings suggest a weight-loss-independent effect of CB₁ receptor blockade with rimonabant on metabolic risk.

Furthermore, the percentage of patients with a diagnosis of metabolic syndrome (according to the criteria of the Adult Treatment Panel III)⁸⁰ decreased from 54% at baseline to 26% after 1 year in the rimonabant 20 mg group. This decrease was significantly greater than in the placebo group and was largely attributed to a reduction in WC and an increase in HDL cholesterol.⁵¹

Rimonabant was generally well tolerated. Treatment-related adverse events (AEs) most commonly reported with rimonabant 20 mg were similar across all four trials^51–54 and included nausea, dizziness, diarrhoea, insomnia, and anxiety. Discontinuations due to AEs over 1 year of treatment were higher in the rimonabant 20 mg group. The most common AEs leading to study discontinuation were depressed mood disorders in all treatment groups. Discontinuations due to nausea, vomiting, diarrhoea, headache, dizziness, and anxiety were more frequent in the rimonabant (20 mg/day) group than in the other groups. Although the 1-year discontinuation rate was high (33–49%), these numbers are comparable with other obesity trials and were actually slightly lower in the rimonabant group when compared with placebo. In the 2-year RIO North America study, discontinuations due to AEs in the second year were <5% in all groups and did not vary among treatment groups.⁵²

	Conclusion

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
Abdominal obesity is associated with increased risk of developing type 2 diabetes and CVD. The ECS, an endogenous signalling system implicated in the regulation of energy balance, appetite, hepatic lipogenesis, and glucose homeostasis, has been suggested to be overactive in patients with obesity, promoting a state that favours metabolic processes leading to weight gain, lipogenesis, insulin resistance, and dyslipidaemia. Treatment with the CB₁ receptor blocker rimonabant 20 mg for 1 year, reduced body weight and WC and improved multiple cardiometabolic risk factors, as evidenced by significant reductions in triglycerides, fasting insulin, HbA1c, blood pressure, and beneficial increases in HDL cholesterol and adiponectin. Therapeutic strategies targeting the ECS have the potential to delay the onset and progression of type 2 diabetes and CVD.

	Funding

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 
Funding for editorial support was provided by sanofi-aventis US.

Conflict of interest: KM has received consultancy fees from Abbott Laboratories, Bristol-Meyers Squibb, and Sanofi-Aventis.

	References

Top Abstract Introduction The ECS The ECS and cardiometabolic... Obesity and cardiovascular risk Benefits of weight loss... Therapeutic application of the... Conclusion Funding References

 

1. Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol (2006) 46:101–122.[CrossRef][Web of Science][Medline]
2. Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst ACE, Pasquali R, Lutz B, Stalla GK, Pagotto U. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest (2003) 112:423–431.[CrossRef][Web of Science][Medline]
3. Cota D, Tschop MH, Horvath TL, Levine AS. Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev (2006) 51:85–107.[CrossRef][Medline]
4. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci (2005) 8:585–589.[CrossRef][Web of Science][Medline]
5. Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V. Regulation, function and dysregulation of endocannabinoids in models of adipose and {beta}-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab (2006) 91:3171–3180.[Abstract/Free Full Text]
6. Sipe J, Waalen J, Gerber A, Beutler E. Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes Relat Metab Disord (2005) 29:755–759.[CrossRef][Medline]
7. Engeli S, Bohnke J, Feldpausch M, Gorzelniak K, Janke J, Batkai S, Pacher P, Harvey-White J, Luft FC, Sharma AM, Jordan J. Activation of the peripheral endocannabinoid system in human obesity. Diabetes (2005) 54:2838–2843.[Abstract/Free Full Text]
8. Monteleone P, Matias I, Martiadis V, De Petrocellis L, Maj M, Di Marzo V. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa. Neuropsychopharmacology (2005) 30:1216–1221.[CrossRef][Web of Science][Medline]
9. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation (2005) 112:2735–2752.[Free Full Text]
10. American Heart Association Writing Group. Heart disease and stroke statistics—2006 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Committee. Circulation (2006) Published online ahead of print January 11, 2006.
11. Gregg EW, Cadwell BL, Cheng YJ, Cowie CC, Williams DE, Geiss L, Engelgau MM, Vinicor F. Trends in the prevalence and ratio of diagnosed to undiagnosed diabetes according to obesity levels in the U.S. Diabetes Care (2004) 27:2806–2812.[Abstract/Free Full Text]
12. Goran MI, Ball GD, Cruz ML. Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. J Clin Endocrinol Metab (2003) 88:1417–1427.[Abstract/Free Full Text]
13. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA (2006) 295:1549–1555.[Abstract/Free Full Text]
14. McGill HC Jr, McMahan CA, Herderick EE, Zieske AW, Malcom GT, Tracy RE, Strong JP. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation (2002) 105:2712–2718.[Abstract/Free Full Text]
15. Chinali M, de Simone G, Roman MJ, Lee ET, Best LG, Howard BV, Devereux RB. Impact of obesity on cardiac geometry and function in a population of adolescents: the Strong Heart Study. J Am Coll Cardiol (2006) 47:2267–2273.[Abstract/Free Full Text]
16. Li X, Li S, Ulusoy E, Chen W, Srinivasan SR, Berenson GS. Childhood adiposity as a predictor of cardiac mass in adulthood: the Bogalusa Heart Study. Circulation (2004) 110:3488–3492.[Abstract/Free Full Text]
17. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev (2002) 54:161–202.[Abstract/Free Full Text]
18. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L, Kunos G. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest (2005) 115:1298–1305.[CrossRef][Web of Science][Medline]
19. Juan-Pico P, Fuentes E, Javier Bermudez-Silva F, Javier Diaz-Molina F, Ripoll C, Rodriguez de Fonseca F, Nadal A. Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium (2005) 39:155–162.[CrossRef][Web of Science]
20. Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T, Esposito G, Mascolo N, Di Marzo V, Capasso F. Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol (2001) 134:563–570.[CrossRef][Medline]
21. Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes (Lond) (2005) 29:183–187.[CrossRef][Medline]
22. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev (2006) 27:73–100.[Abstract/Free Full Text]
23. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, Le Fur G, Casellas P. Cannabinoid-receptor expression in human leukocytes. Eur J Biochem (1993) 214:173–180.[Web of Science][Medline]
24. Roche R, Hoareau L, Bes-Houtmann S, Gonthier MP, Laborde C, Baron JF, Haffaf Y, Cesari M, Festy F. Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem Cell Biol (2006) 126:177–187.[CrossRef][Medline]
25. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science (1992) 258:1946–1949.[Abstract/Free Full Text]
26. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol (1995) 50:83–90.[CrossRef][Web of Science][Medline]
27. Sugiura T, Kodaka T, Nakane S, Miyashita T, Kondo S, Suhara Y, Takayama H, Waku K, Seki C, Baba N, Ishima Y. Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure–activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J Biol Chem (1999) 274:2794–2801.[Abstract/Free Full Text]
28. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci (2003) 4:873–884.[CrossRef][Web of Science][Medline]
29. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev (2003) 83:1017–1066.[Abstract/Free Full Text]
30. McFarland MJ, Barker EL. Anandamide transport. Pharmacol Ther (2004) 104:117–135.[CrossRef][Medline]
31. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature (1996) 384:83–87.[CrossRef][Medline]
32. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA (2002) 99:10819–10824.[Abstract/Free Full Text]
33. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol (2001) 134:1151–1154.[CrossRef][Web of Science][Medline]
34. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol (2002) 136:550–557.[CrossRef][Web of Science][Medline]
35. Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature (2001) 410:822–825.[CrossRef][Medline]
36. Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci (1998) 63:PL113–PL117.[CrossRef][Web of Science][Medline]
37. Poirier B, Bidouard JP, Cadrouvele C, Marniquet X, Staels B, O’Connor SE, Janiak P, Herbert JM. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab (2005) 7:65–72.[CrossRef][Medline]
38. Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, Soubrie P. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol (2003) 284:R345–R353.[Abstract/Free Full Text]
39. Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord (2004) 28:640–648.[CrossRef][Web of Science][Medline]
40. Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol (2003) 63:908–914.[Abstract/Free Full Text]
41. Croci T, Manara L, Aureggi G, Guagnini F, Rinaldi-Carmona M, Maffrand JP, Le Fur G, Mukenge S, Ferla G. In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum. Br J Pharmacol (1998) 125:1393–1395.[CrossRef][Medline]
42. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem (1995) 232:54–61.[Web of Science][Medline]
43. Coutts AA. Cannabinoid receptor activation and the endocannabinoid system in the gastrointestinal tract. Curr Neuropharmacol (2004) 2:91–102.[CrossRef]
44. Jbilo O, Ravinet-Trillou C, Arnone M, Buisson I, Bribes E, Peleraux A, Penarier G, Soubrie P, Le Fur G, Galiegue S, Casellas P. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J (2005) 19:1567–1569.[Abstract/Free Full Text]
45. Gary-Bobo M, Elachouri G, Scatton B, Le Fur G, Oury-Donat F, Bensaid M. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol Pharmacol (2006) 69:471–478.[Abstract/Free Full Text]
46. Cote M, Mauriege P, Bergeron J, Almeras N, Tremblay A, Lemieux I, Despres JP. Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men. J Clin Endocrinol Metab (2005) 90:1434–1439.[Abstract/Free Full Text]
47. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab (2001) 86:1930–1935.[Abstract/Free Full Text]
48. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, Retzlaff BM, Knopp RH, Brunzell JD, Kahn SE. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia (2003) 46:459–469.[Web of Science][Medline]
49. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther (1997) 74:129–180.[CrossRef][Web of Science][Medline]
50. Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, Cippitelli A, Nava F, Piomelli D, Rodriguez de Fonseca F. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci (2002) 22:9612–9617.[Abstract/Free Full Text]
51. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med (2005) 353:2121–2134.[Abstract/Free Full Text]
52. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA (2006) 295:761–775.[Abstract/Free Full Text]
53. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet (2005) 365:1389–1397.[CrossRef][Web of Science][Medline]
54. Scheen AJ, Finer N, Hollander P, Jensen MD, VanGaal LF, RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet (2006) 368:1660–1672.[CrossRef][Web of Science][Medline]
55. Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V. Regulation, function and dysregulation of endocannabinoids in models of adipose and {beta}-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab (2006) 91:3171–3180.[Abstract/Free Full Text]
56. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab (2004) 89:2548–2556.[Abstract/Free Full Text]
57. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest (2002) 32(Suppl. 3):14–23.[CrossRef][Web of Science][Medline]
58. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov (2006) 5:295–309.[CrossRef][Medline]
59. Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol (2006) 47:1093–1100.[Abstract/Free Full Text]
60. Hunt KJ, Williams K, Rivera D, O’Leary DH, Haffner SM, Stern MP, Gonzalez Villalpando C. Elevated carotid artery intima-media thickness levels in individuals who subsequently develop type 2 diabetes. Arterioscler Thromb Vasc Biol (2003) 23:1845–1850.[Abstract/Free Full Text]
61. Al Suwaidi J, Higano ST, Holmes DR Jr, Lennon R, Lerman A. Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol (2001) 37:1523–1528.[Abstract/Free Full Text]
62. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation (2000) 102:1296–1301.[Abstract/Free Full Text]
63. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest (2001) 108:1875–1881.[CrossRef][Web of Science][Medline]
64. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab (2002) 13:84–89.[CrossRef][Web of Science][Medline]
65. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes (2001) 50:1844–1850.[Abstract/Free Full Text]
66. Ray KK, Cannon CP, Cairns R, Morrow DA, Rifai N, Kirtane AJ, McCabe CH, Skene AM, Gibson CM, Ridker PM, Braunwald E. Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol (2005) 46:1417–1424.[Abstract/Free Full Text]
67. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E. C-reactive protein levels and outcomes after statin therapy. N Engl J Med (2005) 352:20–28.[Abstract/Free Full Text]
68. MRC/BHF. Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet (2002) 360:7–22.[CrossRef][Web of Science][Medline]
69. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med (2003) 348:383–393.[Abstract/Free Full Text]
70. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med (2000) 342:145–153.[Abstract/Free Full Text]
71. Orzano AJ, Scott JG. Diagnosis and treatment of obesity in adults: an applied evidence-based review. J Am Board Fam Pract (2004) 17:359–369.[Medline]
72. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’Andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation (2002) 105:804–809.[Abstract/Free Full Text]
73. National Institutes of Health, National Heart, Lung, and Blood Institute, NHLBI Obesity Education Initiative, North American Association for the Study of Obesity. The practical guide: identification, evaluation, and treatment of overweight and obesity in adults. (2000) 18 September 2007. http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf.
74. Droyvold WB, Midthjell K, Nilsen TI, Holmen J. Change in body mass index and its impact on blood pressure: a prospective population study. Int J Obes (Lond) (2005) 29:650–655.[CrossRef][Medline]
75. Moore LL, Visioni AJ, Qureshi MM, Bradlee ML, Ellison RC, D’Agostino R. Weight loss in overweight adults and the long-term risk of hypertension: the Framingham study. Arch Intern Med (2005) 165:1298–1303.[Abstract/Free Full Text]
76. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med (2002) 346:393–403.[Abstract/Free Full Text]
77. Wannamethee SG, Shaper AG, Lennon L. Reasons for intentional weight loss, unintentional weight loss, and mortality in older men. Arch Intern Med (2005) 165:1035–1040.[Abstract/Free Full Text]
78. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med (2000) 343:16–22.[Abstract/Free Full Text]
79. Scheen AJ. Effects of rimonabant in patients with type 2 diabetes mellitus. Results of the RIO DIABETES trial. (2005) Paper presented at American Diabetes Association: San Diego, CA.
80. Third Report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation (2002) 106:3143–3421.[Free Full Text]

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