Obesity - The growing epidemic The Indian scenario
Obesity identified as a nutritional disorder, thirty years ago, still continues to be one of the most important, yet preventable health hazards. Obesity has now become an important health problem in developing countries particularly in India, which is currently experiencing a rapid epidemiological transition.
Central obesity in the elderly population of India is a major public health problem. Obesity is considered to be the link between insulin resistance and metabolic abnormalities inclusive of diabetes, hypertension and dyslipldaemia, all of which are risk factors for coronary artery disease.
Obesity is associated with significant increase in morbidity and mortality. Projections indicate that by the year 2020 there will be 470 million people aged 65 and above in developing countries which will be more than double the number of developed world. The prevalence of obesity in different countries varies from 10%- 40%. The body mass index (BMI) associated with the lowest mortality falls within the range of 18.5 to 24.9 in men & women between the ages of 30 & 74. It was found that BMI of 26 or more is a significant risk factor for diabetes & BMI more than 30 was significantly associated with arthritis & hypertension.1 Studies from different states of India regarding the health threat due to this problem suggest that the prevalence ranged from 10 to 50 per cent.
Indicators of obesity
Body mass index
Body mass index (BMI) or Quetelet Index is a statistical measure of the weight of a person scaled according to height. BMI is promulgated to be the most useful measure of obesity. BMI is defined as the individual's body weight divided by the square of their height.
It is nevertheless a crude index that does not take into account the distribution of body fat, resulting in variability in different individuals and populations.
Waist circumference
Waist circumference has also been recommended as a simple and practical measure for identifying overweight and obese patients. Waist circumference is measured around the narrowest point between ribs and hips when viewed from the front after exhaling. Hip circumference is measured at the point where the buttocks extended the maximum, when viewed from the side. Two consecutive recordings are made for each site to the nearest 1 cm using a metal tape on a horizontal plane without compression of skin. The mean of two sets of values is used. Waist measurement alone may be relevant when assessing severely obese subjects whose hip measurements are difficult and unreliable. Waist circumference has become the preferred measure for abdominal obesity and is the best surrogate measure for visceral fat mass.
Waist-hip ratio
Waist-hip ratio may be a better predictor of cardiovascular risk than waist circumference, as it is less dependent on body size and height. Furthermore, hip circumference is an index of muscle mass and may reflect exercise status and insulin sensitivity. Waist-hip ratio may prove also to be a more appropriate and universal indicator of risk for ethnically diverse populations, including small-framed Asian and Indian groups. Waist-hip ratio appears superior to blood pressure and lipid levels in predicting cardiovascular endpoints.
BMI is not considered to be a good estimate of obesity in Asian Indians as they have a characteristic obesity phenotype, with relatively lower BMI but with central obesity. Fat distributed in the abdominal region, particularly visceral fat is more metabolically important than other fat depots. Abdominal adiposity assessed using waist
Disease risk associated with obesity by BMI and waist circumference
Weight category BMI (kg/mz) Waist circumference Men ^102 cm (< 40 in) Women <. 89 cm (^35 in) Waist circumference Men > 102 cm (> 40 in) Women > 89 cm (> 35 in)
Underweight <18.5 Low (but risk of other clinical problems may be increased) -
Normal 18.5 to 24.9 - ¥
Overweight 25.0 to 29.9 Increased High
Obesity class 1 30.0 to 34.9 High Very high
Obesity class II 35.0 to 39.9 Very high Very high
Obesity class III >40 Extremely high Extremely high
BMI = body mass index. *--Disease risk for type 2 diabetes, hypertension and cardiovascular disease. ¥-lncreased waist circumference can also be a marker for increased risk even in persons of normal weight
circumference is considered to be more appropriate to predict metabolic disorders than generalized adiposity assessed by BMI. For any given BMI, Indians tend to have increased waist circumference. Further, Indians also tend to have excess body fat, abdominal and truncal adiposity. For any given waist circumference, they have increased body fat accumulation and for any given body fat, they have increased insulin resistance. These features have been referred to as the "Asian Indian Phenotype or Paradox". The World Health Organization has revised the BMI cut-off for Asian Indians and suggested a BMI of 25 kg/m2 to define obesity against the 30 kg/m2 recommended for Europeans. Several studies from India have attempted to modify the threshold for obesity and abdominal obesity using various metabolic abnormalities as gold standard. These studies have suggested cutoffs for BMI ranging from 19-22 kg/m2 while that of waist circumference ranges from 72-85 cm in men and 65.5 - 80 cm in women.23 (Table 2)
Unmet needs in obesity and the metabolic syndrome
Obesity, metabolic syndrome, and diabetes have reached epidemic proportions
Increased prevalence of these conditions is projected to have a major impact on CV disease and associated costs of care
Even modest weight loss (5%-10%) can reduce cardiometabolic risk factors Current behavioral and dietary approaches to weight loss have limited success New approaches to weight loss are urgently needed
The Endocannabinoid System (EC System)
The recent discovery of cannabinoid receptors and their natural ligands, the endocannabinoids, has provoked an accelerated program of research to uncover the physiological roles of these systems. The Endocannabinoid System (EC System) is a physiological system of cannabinoid receptors and corresponding chemical messengers that is believed to play an important role in regulating body weight and glucose and lipid metabolism. The EC System also plays a role in tobacco dependence.5
The chemical messengers of the EC System are endocannabinoids (ECBs), which bind to and activate the cannabinoid (CB 1) receptors. CB 1 receptors are found in the brain as well as in some peripheral tissues of the body such as adipocytes (or "fat cells"), which are associated with lipid and glucose metabolism.
Through both this central and peripheral activity, the EC System helps to regulate food intake and energy expenditure. It is also involved in the body's response to tobacco use.
Physiologically, the EC System is activated in response to stressful stimuli to help reestablish the normal steady state of the affected cells or tissues. Therefore, the effects of EC System activation are short lasting, confined to those cells or tissues that have been subjected to stress or damage, and normally end once the organism has recovered from a transient "unbalanced" condition.
Central activity
In the central nervous system, CB 1 -receptors are necessary to kick-start food intake after a short period of food deprivation and, when activated, they also preferentially stimulate the ingestion of palatable food. Studies using a variety of behavioural paradigms indicate that ECBs may play a very specific role in appetite control. This is achieved by modulating the expression and release of appetite suppressing and appetite stimulating chemical messengers in the hypothalamus region of the brain.5
CB 1 receptor activation is also apparent in an area of the brain called the nucleus accumbens shell, a small subcortical area, which is believed to be important in motivational processes that mediate the incentive value of food, and which is also important in the process by which tobacco dependence is acquired and maintained.5
The EC System functions in many levels of the energy balance system including the gastro intestinal tract and adipocyte. At the peripheral level the activation of the CB 1 receptor has been shown to stimulate lipogenesis in adipocytes, which results in fat accumulation and modulation of the expression of adiponectin, a hormone that regulates the metabolism of lipids and glucose. Through its effects on the multiple components of the energy balance system, the EC System helps regulate the physiological need to eat and the energy storage state.
Over-activation of the EC System in obesity and metabolic disorders
In the obesity setting6, the EC System is operating out of
its normal range and receives aberrant signals from the malfunctioning weight control system. Its activity is up regulated and it is converted from a system that is intermittently transiently activated, to one that is chronically overactivated. This overactivity not only promotes fat storage in the adipocytes, but can also be associated with insulin resistance, glucose intolerance, elevated triglycerides and low HDL cholesterol levels, all of which are risk factors for cardiovascular disease. Therefore, regulating the EC System is important in the control of food/energy storage and release in the body. CB 1 receptor blockade modulates overactivity of the EC System resulting in the restoration of balance. Blocking the CB1 receptor eliminates the part of obesity that is controlled by the EC System such as increased appetite, excessive hunger and food intake.7 It also increases adiponectin levels, which is thought to result in increased fat metabolism and an improvement in glucose metabolism.8 This may result in reducing cardiovascular risk factors through weight loss and an improvement in metabolic risk factor profile.
Targeting the EC System
The EC System exerts significant influence on a number of risk factors for cardiovascular disease. Overeating and increased fat storage due to dysregulation of endocannabinoid signalling can contribute to obesity and other
hallmarks of the metabolic syndrome, such as dyslipidemia and type 2 diabetes. In addition, dysregulated endocannabinoid signalling can reinforce tobacco dependence. Thus, using a selective CB 1 blocker to regulate endocannabinoid signalling represents a potential therapeutic strategy in managing cardiovascular risk factors.
Therapeutic approaches to treatment of obesity
The agents that have been used for the treatment of obesity include Dexfenfluramine, Phentermine, Sibutramine and Orlistat.
The growing prevalence of obesity has stimulated the search for drugs to treat this condition.
Phentermine
Phentermine is PDA-indicated for use in combination with a hypocaloric diet, exercise, and behavior modification to treat obesity. It is only approved for short-term management and should be reserved for patients with a BMI > 30 kg/m2 or those with a BMI > 27 kg/m2 with existing cardiovascular comorbidities (e.g., diabetes, dyslipidemia). Phentermine inhibits the reuptake of norepinephrine and dopamine in nerve terminals in the hypothalamic feeding center, which results in appetite suppression. The most common adverse effects associated with Phentermine are overstimulation, dizziness, euphoria, dysphoria, xerostomia, and constipation.9
Sibutramine
Sibutramine is PDA-approved for weight loss and maintenance of weight loss in conjunction with a reduced-calorie diet, exercise, and behavior modification for patients who have obesity (BMI >30 kg/m2) or those with a BMI > 27 kg/m2 and at least one cardiac risk factor. Sibutramine inhibits the reuptake of norepinephrine, serotonin, and to a much lesser extent, dopamine in the centra! nervous system (CMS). The active metabolites of Sibutramine also cause norepinephrine and serotonin reuptake inhibition. This neurotransmitter increase in the CNS results in satiety and decreased caloric intake. Pxtension of therapy for up to 2 years is associated with an average regain of approximately half of the weight lost initially. In most patients, the major adverse effects of Sibutramine relate to its adrenergic properties. Approximately 10% to 15% of patients experience new-onset hypertension that can be managed by antihypertensive therapy; fewer than 3% of patients need to discontinue this drug because of uncontrolled hypertension. Dry mouth, constipation, headache, insomnia, and rhinitis are the most common adverse effects of Sibutramine affecting greater than 10% of patients. Tachycardia and nervousness also occur in approximately 5% of Sibutramine users. Hypertension has been a concern of researchers during Sibutramine trials. Studies have shown systolic and diastolic blood pressure increases significantly by 1 to 6 mm Hg and heart rate increases by 4 to 5 beats per minute for subjects taking Sibutramine.
Oriistat
Oriistat is PDA-approved for use as adjunct therapy with a reduced calorie diet, exercise, and behavior modification to reduce weight for patients with a BMI > 30 kg/m2 or for those with an additional cardiovascular risk factor and a BMI > 27 kg/m2. The medication is also indicated for long-term maintenance therapy to help prevent weight regain. Orlistat's mechanism of action is different compared with Phentermine and Sibutramine. Gastric, carboxylester, lipoprotein, and pancreatic lipases in the gastrointestinal (Gl) tract are reversibly inhibited by Oriistat. The drug forms a covalent bond with the active sites of these lipases, inactivating them. At the time the lipases become inactive, they are unable to hydrolyze dietary fat into absorbable triglycerides. Less systemic fat absorption leads to decreased caloric intake and weight loss. Extension of Oriistat therapy to 2 years is associated with a regain of approximately one-third of the weight initially lost, versus regain of two-thirds of the initial loss in those who took placebo during the second year. Gl effects, such as oily stools, flatulence, increased defecation, and fecal incontinence are the most common adverse effects associated with Oriistat use.
Rimonabant - A multi facet anti obesity drug
A new drug, Rimonabant, is now available to treat obesity, diabetes, and metabolic syndrome. In addition, it promises to aid smoking cessation. Rimonabant is the first of a new class of pharmaceuticals: selective CB1 blockers. To date, results of phase III studies indicate that Rimonabant helps overweight/obese patients lose weight while improving their metabolic profiles. Data also show that patients with diabetes were able to lower their HbA]c in one year of therapy and that smokers had a higher quitting success rate in 10 weeks without the usual post - cessation weight gain.10
Chemistry
Rimonabant (SR141716) is a neurokinin-3 antagonist and selective cannabinoid (CB1) receptor antagonist currently being researched and developed. The chemical name is N-piperino5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3 carboxamide.
Mechanism of action
Rimonabant is the first in a new class of agents that act by selectively blocking the cannabinoid-1 receptors with resultant central and metabolic peripheral effects,
thereby decreasing food intake and increases energy expenditure. CB1 receptors are present both in the CNS as well as in certain peripheral tissues like adipocytes, gastrointestinal tract and liver. Rimonabant is reported to possess a 1000-fold higher affinity for the CB1 receptor than CB2 receptor. It shows high affinity for the centrally located cannabinoid receptor, while displaying low affinity for the peripherally located receptor. Additionally, it has little or no affinity for non-cannabinoid receptors.
Action of Rimonabant on
Peripheral tissue (Adipocytes) CB1 receptors
· Decreased Insulin resistance
· Decreased Triglycerides
· Increased Glucose tolerance
· Increased HDL-cholesterol
· Increased Adiponectin
Pharmacokinetics
• Rimonabant has demonstrated a long duration of action (8 hours) and good oral bioavailability.12
• Rimonabant is able to antagonise the pharmacologic effects induced by cannabinoid receptor agonists.13
• It powerfully reduces food intake and increases energy expenditure.
• It modulates the rewarding properties of food by inhibiting the action of endogenous cannabinoids at specific mesolimbic areas.
• It alters the variety of signals of peripheral origin (leptin, ghrelin and adiponectin), which modulate the neurochemical activation of hypothalamic neurons and the state of relative energy balance.
• Rimonabant also inhibits the enzymes involved in lipogenesis.14
Adverse effects
• Rimonabant treatment showed an excellent tolerance among patients, except for some mild gastrointestinal adverse effects at the highest dose administered.
.• Safety data from the preliminary results of the RIO-Lipids, RIO-Europe and RIO-North America - trials revealed that Rimonabant is well tolerated among patients.
• The most frequently reported adverse effects are nausea, dizziness and upper respiratory infections.
• Diarrhoea was seen most commonly in the RIO-Europe trial (2.3%, 5.8% and 7% for placebo, Rimonabant 5 mg/day and 20 mg/day, respectively).
Indications
Rimonabant is approved by the U.S. Food and Drug Administration (PDA) in February 2006:
• As an adjunct to diet and exercise for the treatment of obese patients (BMI =30kg/m2)
• Overweight patients (BMI>27kg/m2) with associated risk factors, such as type 2 diabetes or dyslipidaemia.
Advantages
Rimonabant increases adiponectin
• Rimonabant has pleiotropic effects other than weight loss
• In the liver, lipogenic enzymes and fatty acid synthesis are upregulated by endocannabinoids, and in adipose tissue, antagonism of CB 1 receptors increases secretion of adiponectin
Rimonabant reduces food intake, increases energy expenditure and thermogenesis
• Antagonism of CB 1 receptors acutely reduces food intake
• Rimonabant produces a sustained decrease in body weight on a background of a transient reduction in food intake
• An increase in energy expenditure has been implicated, possibly mediated via the peripheral endocannabinoid system
• The long-term effects on weight reduction and metabolic regulation appear to be mediated by stimulation of energy expenditure and by peripheral effects related to liver, skeletal muscle, adipose tissue, and pancreas physiology
• There was a profound increase in thermogenesis, particularly during the dark phase of each circadian cycle of interscapular brown adipose tissue (IBAT) temperature throughout the treatment period
• The Rimonabant -induced elevation in IBAT temperature and decrease in body weight were significantly attenuated following denervation, indicating an involvement of the CNS
• The long-term weight loss associated with Rimonabant treatment is likely due to an elevation in thermogenesis mediated primarily by the central endocannabinoid system
• Rimonabant reduces the overactivity of the endocannabinoid system, improving lipid and glucose metabolism and regulating food intake and energy balance
Rimonabant produces improvement in HBA1c and may be helpful in diabetes
• Rimonabant 20 mg once daily significantly improved HbAlc in overweight / obese patients with type 2 diabetes uncontrolled with metformin or sulfonylurea
• Over 50% of the improvements in HbAlc are independent of the weight loss achieved, suggesting a direct effect of Rimonabant on these parameters
• Rimonabant is able to reduce blood sugar levels in a patient population where further control or lowering is often difficult to attain. This is very important because for every 1% reduction in HbA]c there is an associated reduction of risk of 21% for any endpoint related to diabetes
Rimonabant improves lipid profile
• Rimonabant treatment significantly reduced elevations in leptin, insulin and glucose
• Rimonabant significantly reduced triglycerides and low-density lipoprotein cholesterol and increased the HDL-C/LDL-C ratio
• Chronic Rimonabant treatment improves serum biochemical and lipid profiles and demonstrates a weight-independent effect
Rimonabant also prevents weight gain in persons quitting smoking
• Gaining weight is a serious obstacle for many people who would like to quit smoking
• Rimonabant allows them to focus on quitting without being distracted by worries of weight gain
• Rimonabant nearly doubles a person's chances of successful smoking abstinence while avoiding post-cessation weight gain
Rimonabant improves cardiovascular risk factors and metabolic syndrome
• Endocannabinoid system, (CB1 and CB2 subtypes) and their endogenous agonistic ligands (endocannabinoids) play an important role in the central and peripheral regulation of food intake, fat accumulation, and lipid and glucose metabolism
• Alterations of these functions are associated with endocannabinoid system hyperactivity
• The cannabinoid receptor CB1 antagonist Rimonabant normalizes the over activated endocannabinoid system which contributes to the regulation of energy homeostasis, and improves lipid and glucose metabolism-decreases body weight, waist circumference, intra-abdominal obesity and triglycerides, increases HDL-C, improves insulin sensitivity according to HOMA index
• Rimonabant shows antiatherogenic effects (increased adiponectin, decreased marker of inflammation CRP and improvement of LDL profile) as well as decreased percentage of subjects with NCEP/ATPIII defined metabolic syndrome
• Thus Rimonabant is suggested to be a prospective drug decreasing cardiometabolic risk factors
Clinical efficacy of Rimonabant Preclinical trials
A number of preclinical trials have been conducted on the effects of Rimonabant in rodent models. The trials demonstrated that Rimonabant treatment was associated with a reduction in intake of highly palatable as well as normal foods in rats. Wiley ef a/ demonstrated that CB1 antagonist Rimonabant dependency decreased food consumption at doses, which did not affect motor activity in mice.15 Rimonabant may affect the actions of endogenous cannabinoids in regulating appetite, or it may directly affect feeding behaviour. In another study, rodents were put on a high fat diet to develop obesity, increase energy intake and insulin resistance. During a five- week treatment period, Rimonabant resulted in 48% reduction of food and 20% reduction in body weight. In addition, it helped in correcting insulin resistance.16
Clinical trials
crossover study assessed the effect of Rimonabant on hunger, satiety, food consumption and body weight in obese humans and showed a reduction in their food intake and body weight.17 The results of phase III studies called RIO (Rimonabant in obesity) Europe, RIO-North America and RIO-Lipids, comparing Rimonabant 5, 20 mg and placebo, have indicated significantly more weight loss with Rimonabant. The RIO-Lipids and RIO Europe studies showed that the Some phase l/ll clinical trials have been completed with Rimonabant. A randomised, double blind, placebo controlled average loss of weight at 12 months was 6.9 and 8.6 kg, respectively, with Rimonabant 20 mg/day; 3.1 and 4.8 kg, respectively, with Rimonabant 5 mg/ day.17'18 The RIO-North America trial was a two-year study that enrolled 3040 obese people throughout USA and Canada. The investigators found that those who received the highest dose of Rimonabant (20 mg) lost >5% of their body weight, while one-third of them lost >10% of their body weight.19 The results also showed an increase in HDL-C levels with a decrease in atherogenic LDL-C levels. The incidence of metabolic syndrome decreased by nearly one-third and insulin sensitivity was reported as greatly improved.
Rimonabant: More than an anti-obesity drug
• Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease.
• First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful.
• The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity.
• Rimonabant is the first of a new class of selective cannabinoid (CB) receptor-1 blockers.
• Rimonabant blocks the central effects of this neurotransmitter 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 glucose, fat and cholesterol metabolism so improving insulin resistance, triglycerides and high-density lipoprotein cholesterol (HDL-C) and in some patients, blood pressure.
• RIO (Rimonabant In Obesity and related disorders) is a large phase III programme (>6600 patients) evaluating the efficacy and safety of Rimonabant (5 or 20 mg/day), a CBI receptor antagonist of endocannabinoid system, in obese or overweight patients with or without comorbidities (RIO-Europe and RIO-North America), with untreated dyslipidaemia (RIO-Lipids) or with type 2 diabetes treated with metformin or sulfonylurea (RIO-Diabetes).
• RIO-NA: Daily 20-mg Rimonabant treatment significantly lowered weight, reduced abdominal circumference, and reduced cardiovascular risk factors. Of subjects taking 20 mg of Rimonabant daily for two years, 62.5% lost more than 5% of their initial body weight, whereas 36.7% and 33.2% of subjects experienced the same loss when taking 5 mg of Rimonabant and placebo, respectively.
• RIO-Europe: Subjects taking 20 mg achieved major reductions in body weight and waist circumference and also displayed improved lipid and glycemic profiles, compared to those taking 5 mg of Rimonabant and placebo.
RIO - Diabetes: Patients taking 20 mg of Rimonabant for the duration of the study achieved significant weight reductions. HDL levels rose and triglyceride levels fell much more in patients taking 20 mg of Rimonabant than in those taking placebo. They also decreased their HbAlc by 0.6%, compared to a 0.1% increase with placebo.
RIO - Lipids: Subjects taking 20 mg of Rimonabant lost more weight than those taking either 5 mg daily or placebo, and their lipid profiles improved significantly. There was a 57.7% increase in adiponectin versus a 13.6% increase in placebo. C-reactive protein was decreased by 27% in subjects taking 20 mg of Rimonabant daily, and insulin sensitivity improved.
Compared to placebo, Rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome.
Almost half of the metabolic effects, including adiponectin increase, occur beyond weight loss, suggesting a direct peripheral effect of Rimonabant.
The Rimonabant in Obesity (RIO) trials have shown that Rimonabant induces weight loss > 5% in 30-40% of patients and > 10% 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% reduction in triglycerides and improvements in insulin resistance, glycaemic control in patients with diabetes and also adipokines and cytokines including C-reactive protein over hypocaloric diet therapy.
In addition Rimonabant abolishes the weight gain associated with smoking cessation and improves the chances of quitting smoking.
Rimonabant has major effects on both the metabolic syndrome and cardiovascular risk factors thus has the potential to reduce the risks of type 2 diabetes and cardiovascular disease associated with the cardiometabolic phenotype.