REVIEW
The endocannabinoid system: a new
therapeutic target for cardiovascular risk
factor management
NICK FINER,1 UBERTO PAGOTTO2
Abstract
E
uropean guidelines on cardiovascular disease
prevention in clinical practice have identified
obesity and smoking as primary risk factors for
cardiovascular disease, the increased prevalence of
which underlines the need for new therapeutic targets.
The endocannabinoid (EC) system is a physiological
system, comprising the cannabinoid receptors,
cannabinoid type 1 (CB1) and type 2 (CB2), and their
natural ligands, such as anandamide and
2-arachidonyl-glycerol (2-AG). The system plays a key
role in energy balance regulation, both centrally and
peripherally impacting on food intake, lipid and glucose
metabolism, and fat accumulation. The EC system is also
involved in nicotine dependence. Over activity of the EC
system, associated with obesity or chronic tobacco use,
leads to increased levels of endogenous ligands
(endocannabinoids) and disrupts the feedback
mechanism related to steady state homeostasis.
Rimonabant, the first selective CB1 receptor blocker,
normalises the EC system, reduces food intake and
body weight, improves lipid and glucose metabolism
and insulin sensitivity and reduces nicotine
self-administration. Clinical trials are ongoing to
support the therapeutic potential of rimonabant in
reducing these multiple cardiovascular risk factors.
Br J Diabetes Vasc Dis 2005;5:?-?
Key words: obesity, nicotine dependence, metabolic
syndrome, cardiovascular risk factors, endocannabinoid
system, rimonabant.
1
University of Cambridge, Wellcome Trust Clinical Research Facility,
Box 127, Level 5 ACCI, Addenbrooke's Hospital (Box 127), Hills Road,
Cambridge, CB2 2QQ, UK.
2
Endocrinology Unit and Centro di Ricerca Biomedica Applicata (C.R.B.A),
Sant’ Orsola-Malpighi Hospital, Via Massarenti 9, 40125, Bologna, Italy.
Correspondence to: Dr Nick Finer
University of Cambridge, Wellcome Trust Clinical Research Facility, Box 127,
Level 5 ACCI, Addenbrooke's Hospital (Box 127), Hills Road, Cambridge,
CB2 2QQ, UK.
Tel: +44 (0)1223 596055; Fax: +44 (0)1223 596059
E-mail: nf237@medschl.cam.ac.uk
Page no
PROOF 3
Introduction
European guidelines on CVD prevention in clinical practice have
identified obesity and smoking as primary risk factors associated
with the onset of CVD that significantly decrease life expectancy
in adulthood (table 1).1 The cumulative effects of both these risk
factors is an average 13.3 years lost life in women and 13.7 years
in men.1 The recently published INTERHEART study highlighted
abdominal obesity and smoking among the major factors pre-
dicting myocardial infarction.2 Abdominal obesity is also a central
feature of metabolic syndrome, which is linked to insulin resis-
tance, IGT, diabetes, dyslipidaemia and hypertension. These indi-
cations are all forerunners in the accelerated development of
CHD.3 CVD is more prevalent in individuals with metabolic syn-
drome, and in an Italian study with a 4.5 year follow-up, subjects
with metabolic syndrome but free of CVD, were five times more
likely to develop a cardiovascular event (19.9%) than those with-
out (3.9%).4 Smoking is recognised as a risk factor for CVD, and
is also linked to an increased risk of many types of cancer, and
insulin resistance which facilitates the chance of developing type
2 diabetes.5 The UK NSF for CHD advocates weight manage-
ment, appropriate dietary advice and smoking cessation as key
components of the care necessary to reduce the incidence of car-
diovascular risk factors such as obesity, metabolic syndrome and
nicotine dependence.6 For example, a reduction of body weight
in the order of 4–8 kg in overweight subjects with IGT can
reduce the incidence of type 2 diabetes by up to 60%.7-9
However, little impact has been made on the prevalence of
smoking, and the incidence of obesity continues to rise, under-
lining the need for new therapeutic targets to treat these two
major cardiovascular risk factors.
Overview of the EC system
The isolation of Δ9-THC, the active constituent of Cannabis sati-
va, in 1964,10 marked the discovery of the EC system, initially
characterised by high-affinity cannabinoid binding sites and first
identified in the rat brain in 1988.11 By the mid 1990s, the CB1
and CB2 receptors had been cloned,12-14 and two endogenous lig-
ands, or endocannabinoids, had been identified, anandamide
and 2-AG;15-17 three more endocannabinoids are currently being
investigated.18-20 Endocannabinoids are produced on demand and
have a transitory action, acting locally on CB1 and CB2 recep-
tors,21,22 members of the G-protein coupled receptor family locat-
ed in different areas of the body.
The EC system has been identified as a physiological system
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
 REVIEW

Abbreviations
Table 1. Years of life lost from excess weight and obesity – Framingham
Heart Study: a Life-table analysis1
2-AG 2-arachidonyl-glycerol
CB1 cannabinoid type 1
CB2 cannabinoid type 2 Overweight Obese Obese
(BMI 25–29.9 kg/m2) (BMI > 30 kg/m2) (BMI > 30 kg/m2)
CHD coronary heart disease Years of life lost Years of life lost Years of life lost
CVD cardiovascular disease (comparison to (comparison to (comparison to
Δ9-THC delta-9-tetrahydrocannabinol normal weight normal weight normal weight
non-smokers*/ non-smokers*/ non-smokers)
EC endocannabinoid
smokers†) smokers†)
GABA gamma amoni batyric acid
Women
HDL high density lipoprotein
LDL low density lipoprotein Non-smokers 3.3* 7.1* -
IGT impaired glucose tolerance Smokers 0.2† 7.2† 13.3
mRNA messenger ribonucleic acid
Men
NSF National Service Framework
Non-smokers 3.1* 5.8* -
Smokers 1.3† 6.7† 13.7

Key: BMI = body mass index; * = AUTHOR TO SUPPLY; † = AUTHOR TO SUPPLY

Acronyms
INTERHEART AUTHOR TO SUPPLY
RIO Rimonabant In Obesity
STRATUS STudies with Rimonabant And Tobacco USe
Figure 1. The central and peripheral effects of rimonabant in
modulation of the overactive endocannabinoid system

which plays a key role in the central and peripheral regulation of Obesity Chronic nicotine
use
energy balance and in glucose and lipid metabolism,23,24 and is
Overactivation of the
one of several independent orexigenic mechanisms, involving the EC system

neuropeptides, NPY and Agouti-related protein. However, dele-

Rimonabant
tion of both of these potent neuropeptides does not result in a
lean phenotype,25 whilst deletion of CB1 results in decreased Modulation of the
body weight, reduced fat mass and hypophagia, highlighting its CENTRAL EC system to
restore balance
PERIPHERAL
CB1
crucial role in balancing energy homeostasis.26 Endocannabinoid
Brain Peripheral
activity is also regulated by the adipocytokine, leptin, whose lev- tissues

els reflect the quantities of fat storage within the body. When Nucleus accumbens: Hypothalamus: CB1
motivation to appetite Adipocyte
leptin levels rise, anorexigenic neuropeptides are up-regulated, eat/smoke adiponectin

and endocannabinoid levels are decreased,27 resulting in a reduc-

tion in CB1 receptor activation and a subsequent reduction in
food intake.
Energy homeostasis is modulated through both central and
peripheral activities of the EC system, which impact upon food
intake, lipid parameters, fat accumulation and lipid and glucose
metabolism.28,29 The EC system is also involved in nicotine depen-
dence,30 via the mesolimbic system in the brain. Under normal
conditions, the EC system plays a regulatory role, acting via CB1
receptors located on peripheral tissues such as adipocytes and
centrally in the hypothalamus and mesolimbic system, by sig-
nalling a need for energy intake and fat accumulation and acti-
vating the motivation to eat.
Overactivation of the EC system as a result of
obesity/smoking
Overstimulation of the EC system leads to a disruption of feed-
back mechanisms that would normally generate steady state
energy homeostasis (figure 1). This overactivation occurs both
centrally and peripherally in obese laboratory animal models,
illustrated by elevated hypothalamic endocannabinoid levels27
and/or up-regulation of adipocyte CB1 receptors.31 Chronic nico-
Nicotine
dependance
Body weight
Metabolic utilisation
of fat stores
Fatty acid oxidation
Free fatty acid clearance
Hyperinsulinaemia Insulin sensitivity
Triglycerides HDL
Key: EC = endocannabinoid; CB1 = cannabinoid type 1; HDL = high density
lipoprotein
tine exposure also impacts upon the EC system, resulting in
enhanced endocannabinoid levels in the mesolimbic system,32
blocking the GABAergic inhibition of dopamine.30 Nicotine thus
modulates the reward pathway in the brain, increasing
dopamine levels, and leading to dependence.
Therapeutic potential of modulating the EC system
as a target for multiple cardiovascular risk factor
management
Initial studies suggesting that the blockade of CB1 receptors
results in reduced food intake and decreased nicotine depen-
dence led to the development of the first selective CB1 blocker,

VOLUME 5 ISSUE 3 . MAY/JUNE 2005 Page no

REVIEW
Key messages
● Abdominal obesity, a component of metabolic
syndrome, and nicotine dependence are primary
cardiovascular risk factors
● Overactivity of the EC system is associated with
increased food intake and fat accumulation, as well as
nicotine dependence
● By normalising the overactive EC system via selective
CB1 blockade, rimonabant presents a novel tool to
reduce cardiovascular risk factors of the metabolic
syndrome, including obesity, dyslipidaemia, type 2
diabetes, and nicotine dependence
rimonabant.33 Knockout of the CB1 gene in rodents produces a
reduction in food intake and in body weight compared to con-
trol animals.34,35 Rimonabant treatment of diet-induced obese
mice (a model which is widely used for research into human obe-
sity) reduces food intake, body weight and adiposity, corrects
insulin resistance, and lowers plasma leptin, insulin and free fatty
acid levels.28 Pair-feeding studies have shown that rimonabant-
treated animals continue to lose more weight than untreated
animals receiving the same quantity of food, indicating a meta-
bolic mechanism independent of food intake reduction.28 In vitro,
rimonabant increased adiponectin mRNA expression and protein
level in adipocytes.31 Adiponectin is a hormone involved in glu-
cose metabolism, insulin sensitivity36 and fatty acid oxidation.37
Additional preclinical study results show that rimonabant is effec-
tive in inducing weight loss, as well as reducing triglycerides,
increasing the HDL-cholesterol:LDL-cholesterol ratio, and improv-
ing glucose tolerance, which are characteristics of metabolic syn-
drome.28 Furthermore, treatment with rimonabant reduces nico-
tine self-administration in rats,30 and has also been shown to
reduce the conditioned behaviour associated with nicotine use,
one month after nicotine withdrawal.38
These preclinical results support the clinical development of
rimonabant as a therapy for the treatment of the major cardio-
vascular risk factors, obesity and related metabolic disorders, and
smoking. The CB1 receptor blocker, SLV-319 (Solvay SA), is cur-
rently undergoing Phase I trials,39 Pfizer’s compound, CP 945598
was well tolerated during Phase I,40 although their agonist, CP
55244 has been discontinued.41 Other CB1 receptor agonists are
being developed for use in multiple sclerosis, Tourette’s syndrome
and dyskinesia in Parkinson’s disease.23
Rimonabant is the most advanced of the CB1 receptor block-
ers, with two Phase III clinical development programmes, RIO
(> 6,600 overweight/obese patients) and STRATUS (> 6,500 reg-
ular cigarette smokers), currently underway. Preliminary results
from both programmes have been presented at symposia and
Page no
appear to support the theoretical expectations for CB1 block-
ade.42
Conclusions
The EC system provides a physiological link between two key fac-
tors associated with increased cardiovascular risk: obesity and
smoking. Current treatment strategies for obesity have high fail-
ure rates both in the short and long-term, and may fail to fully
address the risk factors (especially cardiovascular parameters)
associated with overweight and obesity. For these reasons, new
treatments for obesity are urgently needed to reduce the burden
of ill health to both the individual and society. The results of the
two large clinical programmes (RIO43 and STRATUS) are antici-
pated to validate the EC system as an important target in the
rapidly converging fields of metabolic and cardiovascular medi-
cine.
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