Rimonabant: endocannabinoid inhibition for the metabolic syndrome

Rimonabant: endocannabinoid inhibition for the metabolicsyndrome

A. S. WIERZBICKI

Lipid Unit, St. Thomas’ Hospital, London, UK

SUMMARY

Rimonabant is the first drug to target the endocannabi-

noid (CB) pathway by inhibiting the actions of ananda-

mide and 2-archidonyl-glycerol on CB1 receptors. This

review gives an overview of rimonabant and the

CB system and how this system relates to obesity.

Rimonabant blocks the central effects of this neurotrans-

mitter pathway involved in obesity and weight control

and also blocks the direct effects of CBs on adipocyte

and hepatocyte metabolism. Blockade of CB1 receptors

leads to a decrease in appetite and also has direct

actions in adipose tissue and the liver to improve glu-

cose, fat and cholesterol metabolism so improving insu-

lin resistance, triglycerides and high-density lipoprotein

cholesterol (HDL-C) and in some patients, blood pres-

sure. The Rimonabant in Obesity (RIO) trials have

shown that rimonabant induces weight loss 15% in

30–40% of patients and 110% in 10–20% above both

a dietary run-in and long-term hypocaloric management

over a 2 year period with a low level of drug-related

side effects. Rimonabant therapy is associated with an

extra 8–10% increase in HDL-C and a 10–30% reduc-

tion in triglycerides and improvements in insulin resist-

ance, glycaemic control in patients with diabetes and

also adipokines and cytokines including C-reactive pro-

tein over hypocaloric diet therapy. In addition rimonab-

ant abolishes the weight gain associated with smoking

cessation and improves the chances of quitting smoking.

Thus rimonabant has major effects on both the meta-

bolic syndrome and cardiovascular risk factors thus has

the potential to reduce the risks of type 2 diabetes and

cardiovascular disease associated with the cardiometabol-

ic phenotype.

Keywords: Endocannabinoid; obesity; metabolic syn-

drome; cardiovascular risk; smoking; addiction; treatment

ª 2006 Blackwell Publishing Ltd

W H A T I S K N O WN A B O U T T H E S U B J E C T

• The prevalence of obesity is increasing rapidly.

• Current weight loss therapies have significant limita-

tions.

• The endocannabinoid system is involved in the regulation

of appetite and metabolism.

W H A T D O E S T H I S A R T I C L E A D D ?

• The endocannabinoid system is a new target for obesity

and metabolic syndrome therapies.

• Rimonabant is the first CB1 receptor blocker to reach

clinical practice.

• Clinical trials in man have shown that rimonabant has

consistent effects in reducing weight, abdominal obesity

in patients with obesity, obesity with dyslipidaemia and

obesity and concurrent type 2 diabetes.

R E V I E W C R I T E R I A

This review was compiled using data from PubMed identi-

fied using the search terms cannabinoid, endocannabinoid;

drug treatment added to obesity and the drug names rimo-

nabant and SR141716A. Additional data was sourced from

conference abstracts, clinical trials databases and press relea-

ses of the American Heart and Diabetes Societies.

F O R T H E C L I N I C

• Rimonabant is a new anti-obesity drug acting on the

endocannabinoid system.

• It delivers a consistent 5 kg of weight loss.

• It has a secondary beneficial effect on lipids, glucose and

neutral effects on blood pressure.

• It has a generally good tolerability profile.

Correspondence to:Dr Anthony S. Wierzbicki, St. Thomas’ Hospital, Lambeth Palace

Road, London SE1 7EH, UK

Tel.: þ 44 20 7188 1256

Fax: þ 44 20 7928 4226

Email: [email protected]

DRUG FOCUS d o i : 1 0 . 1 1 1 1 / j . 1 7 4 2 - 1 2 4 1 . 2 0 0 6 . 0 1 2 1 0 . x

ª 2006 The AuthorJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, December 2006, 60, 12, 1697–1706

I N T R O D U C T I O N

An epidemic of obesity is occurring in the developed and

developing world (1–3). As gross obesity becomes com-

moner, milder degrees of obesity remain unnoticed as they

are the norm. It is already accepted that patients recruited

for phase I drug trials in the USA should average a body

mass index (BMI) of 30 kg/m2. Yet the cardiometabolic

consequences of mild obesity are likely to be more severe.

Gross morbid obesity with its osteological and physiological

problems is associated with an increased risk of mortality

(4,5) and with a 9 years reduction in life expectancy (6–8).

Beneficial trends have been evident for 20 years in some

cardiovascular disease and diabetes risk factors including

smoking, relative saturated fat intakes and cholesterol levels.

However, these are counterbalanced and may be over-

whelmed by adverse trends in increased carbohydrate

intakes, increased food calorie densities and especially

reduced exercise resulting in obesity and rises in the preval-

ence of obesity-associated cardiometabolic risk factors (9).

T H E ME T A B O L I C S Y N D RO M E

Moderately overweight or obese individuals show increase in

abdominal circumference which are associated with other

features of the insulin resistance/metabolic syndrome

(10,11). These features as universally defined includes low

high-density lipoprotein cholesterol (HDL-C), high triglyc-

erides, systolic hypertension and hyperglycaemia. Other

abnormalities associated with the metabolic syndrome

include increased apolipoprotein B concentrations, small

dense low-density lipoprotein (LDL) particles, hyperuricae-

mia, non-alcoholic fatty liver disease/hepatic steatosis, eleva-

ted liver transaminases, gamma-glutamyl-transferase and

microalbuminuria. The more metabolic syndrome risk fac-

tors are present in any individual the higher the risk of

transition to diabetes (·20 with 14 risk factors) or cardio-

vascular disease (·3.5 with 14 risk factors) (12).

However, mild obesity and in particular central obesity

carries a large excess risk of especially diabetes and also of

cardiovascular disease (12). It is critical to treat this modifia-

ble risk factor before its complications become established.

The traditional therapy of diet and lifestyle is extremely suc-

cessful with trials such as the diabetes prevention projects

showing 40–50% reductions in new diabetes and better

results than achieved with metformin therapy (13,14).

However, the extent of lifestyle modification required is

beyond some patients. Some people cannot do 30 min of

aerobic intense exercise every day because of the osteoarthri-

tis or respiratory complications of obesity but can manage

lesser degree of exercise. Others find it difficult to adhere to

a )500 kcal/day diet as they have tried numerous diets and

exercise programmes and only shown weight cycling and

prompt regain of any lost weight and thus lost confidence

in this strategy. Agents that add to even minimal lifestyle

measures and help patients to attain realistic weight loss

goals are thus very useful. In addition as weight is lost, fea-

tures of the metabolic syndrome improve lessening the risks

of complications of obesity and some weight loss drugs may

have effects beyond weight reduction on these metabolic

risk factors.

T R E A T M E N T O F O B E S I T Y

Numerous drugs can treat various aspects of the metabolic

syndrome but few apart from weight loss agents have effects

across the whole risk profile. Yet anti-obesity drugs have a

bad reputation. They have been either been poorly effective

(15) or effective at delivering weight loss but at the cost of

addiction (amphetamines) or pulmonary fibrosis (dexfenflur-

amine). Two drugs are licensed; orlistat and sibutramine.

Orlistat delivers a 10% weight reduction in 20–30% of

patients and reduces the incidence of diabetes by 47% in

the Xenical in prEvention of New Diabetes in Obese Sub-

jects study (XENDOS) (16). Orlistat reduces triglycerides

and blood pressure but has little effect on HDL-C (16).

Unfortunately this gastric lipase inhibitor is effective only in

patients consuming excess fat (many consume excess carbo-

hydrate) and all too often is discontinued by patients

because of its gastrointestinal side effects in response to fat

consumption (15). It is a willpower aid: an ‘antabuse for

fat’. Sibutramine is a centrally acting serotonin and norad-

renaline re-uptake inhibitor (17). Sibutramine therapy

induced a 10% weight loss in 20–30% of subjects with a

9% increase in HDL-C and 35% reduction in triglycerides

in the Sibutramine Trial of Obesity Reduction and Main-

tenance (STORM) study (18). Unfortunately sibutramine

causes hypertension (þ4 mmHg in STORM) and tachycar-

dia and is contraindicated in patients with established cor-

onary heart disease. Also being a serotonin/catecholamine

re-uptake inhibitor its use is contraindicated in patients

receiving selective serotonin re-uptake inhibitors (SSRIs) or

monoamine oxidase inhibitors (MAOIs). Both SSRIs and

MAOIs are used in the treatment of depression which is

often a secondary psychological complication of weight gain

and may in themselves reduce weight (15). Thus, given the

limitations of current therapies there has been a need for a

novel approach to weight management.

T H E E N D O C A N N A B I N O I D S Y S T E M

As so often in medicine the initial breakthrough came from

clinical observation which was followed by clarification of

the underlying biochemical pathway. It had been noted for

many years that cannabis abuse was associated with weight

gain (‘the munchies’) and thirst but this was thought to be

1698 CB INHIBITION FOR THE METABOLIC SYNDROME


incidental (19,20). The complexity of the system has led to

it being called the endocannabinoid (CB) pathway (21,22)

(Figure 1). Neurochemical studies identified specific recep-

tors for D9-tetrahydrocannabinol in the brain and later the

natural ligands for these receptors (the CBs) were identified

as anandamide, mono-acyl-glycerol, 2-arachidonylglycerol

and other fatty acid ethanolamides (21). Levels of CBs are

regulated by fatty acid amide hydrolase (23). These com-

pounds are unusual as they produced postsynaptically and

act on presynaptic neurotransmitter release (Figure 1). CBs

were shown to be related to weight sensing as anandamide

concentrations were reduced when leptin was infused (24).

CB receptors, as with receptors for many other psychoactive

compounds, proved to be diverse both in terms of central

nervous location and to exist in a number of subtypes (25).

Two major CB receptor subtypes exists in man: CB1 and

CB2.

T H E C B 1 R E C E P T O R

The CB1 receptor acts through the cyclic guanosine mono-

phosphate (GMP) cascade using Gi/o and then secondarily

through voltage-gated calcium channels (L, N and P/Q sub-

types) and also induces potassium currents. These actions

extend to activation of focal adhesion and MAP kinases and

nitric oxide synthase (24). Of the receptor types CB1 recep-

tors were found in the hypothalamus, amygdala, basal gan-

glia and cerebellum (22) (Figure 1). Extensive work in

animals has led to some interesting hypotheses about what

this pathway is involved in. CB1 antagonist therapy in

rodents is associated with reductions in hedonic (reward)

behaviour (21,22,26). Thus rodents addicted to smoking

(27), sugar (28), alcohol (29,30), cocaine (31) and opiates

(32,33) show lower intakes of addictive compounds after

treatment with CB1 antagonists. Sensations of fear (34) or

pain (35) are reduced after treatment with CB1 antagonists.

CB1 receptors are also involved in suppression of seizures

and the pathogenesis of viral-induced dyskinesia in mice

(36,37). CB1 agonists have been investigated as agents likely

to reduce levodopa-induced dyskinesia (LID) in rats (38).

However in primates, in both the 1-methyl-4-phenyl-

1,2,3,6-tetrahydropyridine-induced model of Parkinson’s

disease and in LID rimonabant monotherapy did not

induce dyskinesia and indeed alleviated symptoms when

added to levodopa therapy (37) emphasising the complexity

and species-specificity of CB pathways.

The CB1 receptors are also located outside the central

nervous system (CNS) and the central and peripheral effects

of CBs can be dissociated (39). Some CB1 receptors are

located in the gut and associated with its neural tissue (40)

but others are found in adipose tissue, liver and muscle

(Figure 2). High concentrations of CB1 receptors were

found on adipocytes. In cell culture and animal models

CB1 antagonists reduced adipocyte size (41), induced cell

differentiation (42), altered cell surface receptor expression

and reduced the secretion of adipokines such as leptin, ghre-

lin (GHR) and resistin while increasing secretion of adipo-

nectin (41). Secretion of cytokines including interleukin-6

and secondarily C-reactive protein was also reduced (41,42).

CB1()/)) mice show a phenotype of thinness (orexigenic)

being 30% lighter as adults because of a 15% lower food

intake with possibly lesser effects in female mice (43). Their

CRH

CB(+)

MCH

CB(+)

NPY AgRP

GHR ORX

CB(+)

POMCCARTCB(+)

Arcuate nucleus

Effector pathways

GHR Leptin

Stomach Adipocyte

Lateral hypothalamusParaventricular nucleus

Figure 1 Neurochemical pathways

involved in the regulation of appetite.

Positive effects in open arrows; negative

effects in solid arrows. Modified after

Horvath (24). AgRP, agouti-related

protein; CART, cocaine–amphetamine

related transcript; CB[þ],

endocannabinoid synthesising cells; CRH,

corticotropin releasing hormone; GHR,

ghrelin; MCH, melanocortin; NPY,

neuropeptide Y; ORX, orexigenin;

POMC, pro-opiomelanocortin

CB INHIBITION FOR THE METABOLIC SYNDROME 1699


thermogenesis and energy expenditure were normal. These

mice also had defects in peripheral adipocyte function with

lower lipoprotein lipase activity (43). CB1 receptors are also

involved in the sterol regulatory element binding protein 1c

(SREBP-1c) pathway that is involved in regulation of

hypothalamic-driven feeding behaviour through fatty acid

synthase (FAS) (44) and the glycolytic pathway including

carnitine palmitoyltransferase-I (45–47) as well through

actions on the cocaine/amphetamine-related transcript pro-

tein system (31). CB1 receptors in the liver act to increase

production of very low-density lipoprotein via increases in

acetyl-CoA carboxylase 1 and FAS levels driven through

SREBP-1c (Figure 2). This pathway also downregulates

LDL (apoE/B100)-receptor in the liver through preprotein

convertase subtilisin kexin-9 switching triglyceride-contain-

ing lipoproteins to peripheral muscle and adipose tissue

(48). Thus CB1 antagonists were potentially useful agents

for the treatment of obesity in man as this combines psy-

chological aspects of reward with suppression of natural sati-

ety signals including responses to adiponectin, GHR and

leptin. They might also have a secondary beneficial action

other behaviours associated with eating including smoking.

C B2 A N D O T H E R R E CE P T O RS

In contrast, the CB2 system is mostly expressed in the

immune system (21) but has recently been discovered in the

brain cortex and brainstem and in haemopoetic cells (49).

As inflammation and immunity are closely related to athero-

sclerosis, the possibility exists that this CB system may also

be relevant to atherosclerosis (50). Lymphocytes and macro-

phages which stain positively for CB2 receptors have been

found in animal and human atherosclerotic plaques. As

atheromatous plaques calcify it is not surprising that CB2

receptors are involved in the control of bone mass (51). In

the apoE()/)) mouse model of atherosclerosis, low dose

tetrahydrocannabinol (below psychoactive doses) induced

atheroma regression (52). This was associated with lower

lymphocyte differentiation, lower interferon-c production

and reductions in macrophage chemoattractant protein-1

production. These effects were blocked by the CB2 antag-

onist SR144528. No studies have yet compared CB1 and

CB2 antagonists in the same mouse models as yet or inves-

tigated the effects of CB drugs on endothelial progenitor

cell release form bone marrow.

Other CB receptors including the transient receptor

potential vanilloid receptors probably contribute to the

hypotensive actions of cannabis acting via direct endothelial

effects (53) as well as adding to the effects because of car-

diac and aortic arch CB1 receptors on blood pressure in

mice and man (54). These receptors may also be involved

in modulating the effects of cannabinoids on glutamate

transmission in the hypothalamus (53).

C L I N I C A L P H A R M A C O L O G Y O F R I M O N A B A N T

The first CB1 antagonist to reach clinical use is rimonabant

(SR141716A). This acts a direct CB1 receptor antagonist in

contrast to AM-404 that interferes with anandamide trans-

port. Rimonabant is an active lipophilic compound best taken

with food with a 1000-fold selectivity for CB1 vs. CB2 recep-

tors. Rimonabant also binds to the vanilloid receptor involved

in some neuroprotective effects of this compound (55). Its

half-life varies with BMI being 6–9 days for BMI 18–28 kg/m2

High fat diet

SREBP-1c

ACC-1 & FAS FAS

Weight

SCD

CPT-1

FAAH

Leptin

Insulin Hepatic steatosis

Adiponectin Appetite

Brain Anandamide Liver

SREBP-1c

Figure 2 The role of the

endocannabinoid system in the regulation

of neural and peripheral pathways

involved in obesity. Modified after

Lichtman and Cravatt (25). ACC-1,

acetyl-CoA carboxylase-1; CPT-1,

carnitine palmitoyl transferase-1; FAAH,

fatty acid amide hydrolase; FAS, fatty

acid synthase; SCD, stearoyl-CoA-

decarboxylase; SREBP-1c, sterol

regulatory element binding protein-1c



and 16 days in BMI 1 30 kg/m2. It is metabolised by

cytochrome P450 3A4 (CYP3A4); CYP3A4 inhibitors (ketoc-

onazole) cause a 104% (40–197%) rise in rimonabant levels.

Secondary effects on rimonabant levels are also seen with

CYP2C8 inhibitors.

Rimonabant has been studied for two major indications.

The major area of investigation has been the potential of the

agent to induce weight loss as part of treatment of the meta-

bolic syndrome. The other feature that has been investigated

is the effectiveness of CB1 antagonists in smoking cessation.

R I M O N A B A N T A N D S M O K I N G CE S S A T I O N

Three STudies with Rimonabant And Tobacco USe (the

STRATUS trials) have been performed recruiting 6500

patients in the USA and Europe and investigating the

effects of rimonabant 5 mg or 20 mg against placebo on

rates of smoking cessation at 10 weeks and 50 weeks in the

context of detailed nurse counselling. STRATUS-US recrui-

ted 787 patients of average BMI 28 kg/m2 who had not

tried nay other cessation agent for 3 months. Patients were

encouraged to quit at 2 weeks and rates of smoking were

assessed at weeks 6–10 using carbon monoxide levels (56).

The quit rate was 26.7% for the 20 mg group as opposed

to 16.1% in the placebo group [RR ¼ 2.0 (1.3–3.0); p ¼0.004]. The rimonabant group lost 1.1 kg in net weight

while the placebo group gained 0.3 kg (p ¼ 0.001) with

the effects being seen in overweight or obese patients

(2.5 kg net loss; placebo )0.4 kg). STRATUS-Europe

recruited 789 patients but did not show significant differ-

ences. The combined studies remain significant (p ¼ 0.001)

for quit rates at this short end-point. STRATUS-Worldwide

recruited 5055 hardened smokers (20 cigarettes/day for

25 years and 15 previous quit attempts) and followed a

similar protocol but patients were re-randomised at week 11

to placebo, rimonabant 5 or 20 mg for a further year with

assessment of continuing cessation rates at weeks 10–32.

Loss rates from the trial were high (50%) because of proto-

col violations (20%); compliance with attending clinics

(12%) and side effects (12%). Relapse rates were signifi-

cantly decreased at 1 year in the 20 mg group and this was

associated with no weight gain (41.5% vs. 32.5%; 1.49

(1.09–2.04); p ¼ 0.005). These results though reasonable

compared with bupropion therapy and nicotine replacement

are less than those achieved the nicotinic a-4 receptor par-

tial agonist varenicline (57).

R I M O N A B A N T I N O B E S I T Y S T U D I E S

The other major trials with Rimonabant in Obesity (RIO)

series have investigated its effects in primary prevention

patients with BMI 27 kg/m2 with cardiovascular risk factors

or 130 kg/m2 without all prescribed a )600 kCal/day diet.

These trials have recruited populations in the USA and Can-

ada [RIO-North America (RIO-NA)] (58), Europe (RIO-

Eur) (59), patients with dyslipidaemia (RIO-Lipids) (60) and

type 2 diabetes (RIO-Diabetes) (61) and compared placebo,

5 mg and 20 mg for up to 2 years. RIO-NA (58) examined

the effects of 1 year’s treatment on weight loss in 3040

patients and secondarily after re-randomisation the effects of

drug withdrawal on weight regain in 1557. In the initial run-

in phase patients lost 1.9 kg in weight and their HDL-C

reduced by 5.8% and triglycerides by 1.2%. At randomisation

baseline patients weighed 105 kg had a BMI of 38 kg/m2 and

a waist circumference of 108 cm. At 1 year the 20 mg group

lost a net 4.8 kg (placebo )1.6 kg) and those continuing this

increased by a further 1.1 kg. Those receiving placebo after

rimonabant regressed to a 0.9 kg benefit over placebo

()2.3 kg). Greater than 5% weight loss was achieved in 39.7

vs. 19.7% (p ¼ 0.001) and 110% in 16.5% vs. 8.3% (p ¼0.001). RIO-Eur (59) recruited 1507 similar patients and fol-

lowed the effects of rimonabant 20 mg for 2 years. Starting at

BMI 36 kg/m2 and 108 cm waist circumference a net weight

los of 4.8 kg was achieved at 1 year against placebo

()1.8 kg). Rates of 15% weight loss were 50.9% vs. 19.2%

(p ¼ 0.001) and 110% were 27.4% vs. 7.3% (p ¼ 0.001).

Lipids changed predictably with increases in HDL-C with

diet of 12% but little change in triglycerides ()0.5%). The

extra effect of rimonabant on HDL-C was 7.8% (0.11 mmol/

l) and 11.2% on triglycerides. Regression analysis of lipid

changes against weight suggested that this accounted for only

50% of the effect of rimonabant. These differentials were

maintained at 2 years (3.3 kg net loss over 1.2 kg in the pla-

cebo group). The incidence of the metabolic syndrome fell

from 42% to 19.6%.

RIO-Lipids (60) recruited 1063 patients with a BMI

27–40 kg/m2 and dyslipidaemia defined as triglycerides

1.70–6.90 mmol/l or a total: HDL-cholesterol ratio 14.5

in women and 15 in men. During the run-in phase

patients lost 2 kg in weight and a further net 6.3 kg

(placebo 2.3 kg) with rimonabant therapy. Patients recruited

had an average BMI of 34 kg/m2, waist circumference of

105 cm, triglycerides of 2.26 mmol/l and HDL-C

1.15 mmol/l. Waist circumference fell by 5.8 cm and this

was associated a 11.2% net increase in HDL-C (placebo

12.2%), a 12.2% reduction in triglycerides (placebo

)3.6%) and a 4 nm (placebo 1 nm) increase in average

LDL particle size and a 5.2% reduction in small dense

particle number (placebo 0.4%). Blood pressure was

reduced in patients with hypertension by a net 5.9/

3.9 mmHg (placebo 7.2/2.4 mmHg). Using the National

Cholesterol Education Program adult treatment panel 3

criteria the prevalence of metabolic syndrome was reduced

from 50% to 25.8%. In parallel with these effects C-reactive

protein levels fell by a net 0.6 mg/dl while adiponectin

levels rose by a net 27% compared with a 14% rise in the



placebo group. Safety was similar to other studies with

increase in depression (2.9% vs. 0.6%), anxiety (1.7% vs.

0.6%) and nausea (1.2% vs. 0%).

RIO-Diabetes (61) recruited 1045 patients on sulphonyl-

urea (35%) or metformin therapy (65%) and BMI

27–40 kg/m2. All had hypertension with 65% having a

blood pressure 1140/80 mmHg. All were centrally obese

(waist 110 cm) with a BMI of 34 kg/m2 and moderate

glycaemic control (HbA1c 7.5%). After 1 year rimonabant

resulted in a 3.9 kg net weight loss (placebo 1.4 kg) with

16% losing more than 10% of body mass (placebo 2%).

Glycaemic control improved by a net 0.7% (placebo

þ0.1%) in all patients irrespective of hypoglycaemic therapy

43% as opposed to 23% (p 0 0.001) achieved an

HbA1c 0 6.5%. This was associated with an 8.3% net rise

in HDL-C (placebo 7.1%) and a 16.4% net reduction in

triglycerides (placebo þ7.3%). No change was seen in

LDL-C. Prevalence of the metabolic syndrome was reduced

by a net 12.3% (placebo 7.6%) (p ¼ 0.007).

T H E S A F E T Y P R O F I L E O F R I M O N A B A N T

The safety profile of rimonabant in the RIO programme

has been good. Though side effects are commonly reported

in these trials (80%) detailed analysis only reveals a few spe-

cific signals (Table 1). Nausea was seen in 12.9% vs. 3.4%;

dizziness in 8.7% vs. 4.9% and diarrhoea in 7.2% vs. 3.0%.

In patients with diabetes hypoglycaemia was reported in

5.3% vs. 1.7%. Most of these side effects were considered

mild. Only psychiatric disturbance comprising anxiety and

depression was clearly associated with rimonabant therapy

(1.5% vs. 0.3%; number need to harm ¼ 85). Among the

serious side effects reported in the pooled programme 5.6%

vs. 4.1% of patients indicated an excess of anxiety disorders.

Discontinuation rates at 1 year were doubled with rimonab-

ant therapy (13.6% vs. 7.7%) caused by depression and

anxiety (6.7% vs. 3.2%), headaches and dizziness (2.1% vs.

1.1%) and nausea (2.3% vs. 0.4%). At 2 years data were

similar with an excess of psychiatric disturbance (8.8% vs.

5.9%) and nausea (3.8% vs. 1.0%). These discontinuations

were assessed clinically as there was no change in the Hospi-

tal Anxiety and Disease Scores (62). It is too early to say

what other rare side effects may be discovered with rimo-

nabant though already there have been a case report of mul-

tiple sclerosis (63) but this may have been because of

chance. Currently the side effect profile of rimonabant fol-

lows from predictions of its mechanism of action. Thus

mood disturbance and effects on gastrointestinal motility

are predictable given the actions of CB1 receptors.

C O M P A R I S O N W I T H O T H E R A G E N T S

Rimonabant is a new agent and thus long-term safety data

applicable to rare side effects is not yet available. However, it

is possible to compare rimonabant with the other drugs used

to treat obesity (15,17) (Table 2). Orlistat is well established

as a weight loss agent and is considered pharmacologically

safe enough that in the USA it may become available over-

the-counter. However, in clinical practice a meta-analysis of

29 orlistat studies showed a 2.89 kg (2.27–3.51) weight loss

in patients with an initial BMI of 36.7 kg/m2 (15). Orlistat

therapy was associated with a 3.4-fold increase in diarrhoea,

Table 1 Reductions in cardiovascular risk factors in the Rimonabant in Obesity trial programme

TrialDose(mg)

BMI(kg/m2)

Weight(D%)

Waist(D%)

D 1 5%(%)

D 1 10%(%)

HDL-C(D%)

TG(D%)

LDL-C(D%)

Glucose(D%)

HbA1c

(%)BP(DmmHg)

North America

n ¼ 1222 20 38 7.0 5.0 40 17 þ20.4 16.5 – 0.5 – 0.4/0.5

n ¼ 607 0 2.2 2.2 19 8 þ10.2 7.5 – 0 – 0

D 5.8 3.2 21 9 þ10.2 9.0 – 0.5 – 0.4/0.5

Europe

n ¼ 599 20 36 6.6 6.0 50.9 27.4 þ20.5 29 2.6 1.7 – 1/0.9

n ¼ 305 0 1.8 2.2 19.2 7.3 þ11.8 0.0 5.4 0.0 – þ0.3/þ0.1

D 4.8 3.8 31.7 20.1 þ8.7 29 )2.8 1.7 – 1.3/1.0

Lipid

n ¼ 346 20 34 8.9 8.7 58.4 32.6 þ23.4 15.8 11.4 2.7 – 3.6/2.9

n ¼ 342 0 2.4 3.2 19.5 7.2 þ12.2 3.6 5.3 0 – 0.9/0.8

D 6.5 5.5 38.9 25.4 þ11.2 12.2 6.1 2.7 – 2.7/2.1

Diabetes

n ¼ 348 20 34 5.5 4.7 49.4 16.4 þ15.4 9.1 – – 0.6 )0.8/)1.9

n ¼ 339 0 1.5 1.7 16.4 2.0 þ7.1 þ7.3 – – þ0.1 1.6/)0.7

D 4.0 3.0 33 14.4 þ8.3 16.4 – – 0.7 2.4/1.2

Weighted change 5.4 3.6 27.7 14.7 þ9.7 15.2 0.2 1.0 – 1.3/0.8

BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides.



3.1-fold in flatulence and 1.48-fold in dyspepsia (15).

Clinical trial data from the XENDOS and other studies

shows that therapy over 2 years with % losing 15% of body

weight and % losing 110%. In parallel to these changes in

weight orlistat reduces triglycerides by 15–20% though it

has a little effect on HDL-C or blood pressure. Only 70%

of patients comply either because of poor adherence to trial

protocols, which is a common problem in obesity trials or

because of side effects. The main side effects of orlistat are

explosive diarrhoea and bloating on consumption of fat

(especially saturated fat). Thus this agent has low patient

acceptance. In addition, many obese patients especially from

ethnic minorities do not consume diets rich in saturated fat

but vast quantities of carbohydrates. In these groups orlistat

has limited efficacy.

Sibutramine has less end-point data than orlistat though

2 year studies recruiting on the basis of BMI have been per-

formed of sibutramine added to )500 kCal/day (18) and

)1200 kCal/day diets (64). In weight loss studies it induces

an average 4.45 kg (3.62–5.29) weight loss with 19–34%

achieving 15% and 12–31% achieving 110% weight loss

respectively (17). In a meta-analysis, sibutramine reduced

triglycerides by 0.04 mmol/l HbA1c by 0.3%, and raised

HDL-C by 0.05 mmol/l (17). Its blood pressure effects were

variable with long-term trials showing a 4.6/2.8 mmHg

increase. There are no data on its effectiveness in preventing

diabetes or cardiovascular disease as yet though the Sibutr-

amine Cardiovascular OUTcome study is underway (65).

The tolerability of sibutramine is 70% in obesity trials with

the majority of discontinuations being caused by poor

compliance or adrenergic side effects (headache, dry mouth,

tachycardia and tachypnoea). It has no additive effect when

combined with orlistat and seems to act as a general appetite

suppressant to reduce snacks in particular but anecdotally not

to affect meal habits or portion sizes.

The clinical trial data for rimonabant shows superior

weight loss (5.4 kg) compared with orlistat (2.85 kg) and

sibutramine (4.85 kg) in clinical trials allied with a wider

degree of benefit on cardiovascular risk factors. Compli-

ance in all the obesity trials is about 70% and side effects

are generally seen in 10–30%. The side effect profile of

rimonabant is better than that of orlistat where gastrointes-

tinal side effects occur in 20–30% and similar to sibutr-

amine where compliance and side effect rates are similar

but the drug is contraindicated in significant groups of

patients (secondary prevention and hypertension). No data

exists as yet for rimonabant in combination with other

obesity medications. Given the profoundly different mech-

anism of action of rimonabant it is a good alternative

where other anti-obesity medications have not been toler-

ated or are contraindicated. As it has beneficial action on

lipid profiles that are not seen with orlistat, it may be

superior to this agent in patients with notable dyslipi-

daemia as well as obesity and insulin resistance and also

has beneficial effects in helping increase rates of cessation

of smoking. The long-term benefits of rimonabant will be

confirmed in studies looking directly at its effects on the

progression of atherosclerosis by intravascular ultrasound

and in a cardiovascular end-point trial (the Comprehensive

Rimonabant Evaluation Study of Cardiovascular END-

points and Outcomes (66) trial) where rate of progression

to diabetes is a secondary end-point.

C O N C L U S I O N S

Rimonabant is the first drug to target the CB pathway. This

drug blocks both the central effects of this neurotransmitter

pathway involved in obesity and weight control. It also has

direct actions in adipose tissue and the liver to improve glu-

cose, fat and cholesterol metabolism so improving insulin

Table 2 Effects of different cardiovascular therapies on features of the metabolic syndrome and end-point trial evidence of effects in

prevention of diabetes and cardiovascular disease

Drug/treatment group

Component of the metabolic syndrome reduction (%)DM riskreduction (%)

CVD riskreduction (%)Weight/ waist HDL-C TG SBP Glucose

Lifestyle (4 years) (13) 6–8 þ16 34 9 3 35 25–40

Metformin (4 years) (13) 0–3 þ15 15 0–5 10 25–45 58 (UKPDS)

TZD (4 years) (67) þ4 þ9 12 5 8 51–60 16

Statin (5.5 years) (68) 0 0 to þ15 15–25 0 0 0–14 20–55

Fibrate (6 years) (69) 0–5 þ2 to þ16 15–24 0–8 0–6 0–23 10–34

Niacin (6 years) (69) 1 þ10 to þ25 15–35 2 (þ5)* ? 22–31

Orlistat (4 years)(16) 3 þ3 1 1 4 45 ?

Sibutramine (2 years) (18) 10 þ9 25 þ4 4 ? ?

Sibutramine (2 years) (64) 4.4 þ3.5 2 2 0 ? ?

Rimonabant (2 years) (58–60) 4–8 þ9 to þ11 9–29 0–2 0–3 ? ?

Bariatric surgery (10 years) (70) 13–25 þ20 to þ47 15–28 2.1 to þ4.7 1–10 29 ?

*Largest increases seen with immediate-release preparations. CVD, cardiovascular disease; DM, diabetes mellitus; HDL-C, high-density lipoprotein

cholesterol; SBP, systolic blood pressure; TG, triglycerides; TZD, thiazolidinedione. Abbreviations: United Kingdom Prospective Diabetes Study (UKPDS).



resistance, triglycerides and HDL-C and in some patients,

blood pressure. Thus this drug has the potential to have

major effects on both the metabolic syndrome and thus

reduce the risks of type 2 diabetes and cardiovascular disease

associated with the cardiometabolic phenotype.

A C K N O W L E D G E M E N T S

Dr Wierzbicki has received honoraria for lectures and advi-

sory boards as well as travel and research grants from Astra-

Zeneca, Bristol-Myers-Squibb, GlaxoSmithKline, Merck

kGA, Merck, Sharp & Dohme, Novartis, Pfizer, Sanofi-

Aventis, Schering-Plough, Solvay-Fournier and Takeda.

D I S C L O S U R E S

Dr Wierzbicki has received honoraria for lectures and advi-

sory boards as well as travel and research grants from Astra-

Zeneca, Bristol-Myers-Squibb, GlaxoSmithKline, Merck

kGA, Merck, Sharp & Dohme, Novartis, Pfizer, Sanofi-

Aventis, Schering-Plough, Solvay-Fournier and Takeda.

High relevance: advisory boards for Sanofi-Aventis on

rimonabant.

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Paper received July 2006, accepted September 2006



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Rimonabant: endocannabinoid inhibition for the metabolic syndrome