REVIEW

Pharmacotherapy of

Kostas Lois & Obesity is a major health problem with significant comorbidities. Its prevalence has Sudhesh Kumar† dramatically increased over the last few decades, so that it is considered an international †Author for correspondence epidemic. Large epidemiologic studies have clearly associated obesity with cardiovascular Warwickshire Institute for , Endocrinology & disease and side effects in almost every organ system, so that the need for treatment Metabolism (WISDEM), appears to be imperative. Several short- and, recently, long-term anti-obesity drugs have Clinical Sciences Research been evaluated, but so far there is no ‘magic pill’ that could permanently cure or control Institute (U of W Campus) Warwick Medical School, obesity, although a number produce significant health benefits from a medical point of University of Warwick, view. Orlistat, sibutramine and rimonabant are the most widely used anti-obesity drugs in Coventry, CV4 7AL, UK clinical practice, while new, much more promising ones will be in the market in the Tel.: +44 247 657 4869 Fax: +44 247 657 4871 following few years. E-mail: sudhesh.kumar@ warwick.ac.uk Obesity, a sign of power and wealth in the past, & obesity classification: is today the most common nutritional disorder risk status assessment and major health problem with significant Large epidemiologic studies recognize obesity as a comorbidities. Its prevalence has dramatically major risk factor for increased over the last several decades through- (CVD), while at the same time it is considered out the world, so that it is no exaggeration to causally related to increased long-term comorbid- state that it is an international epidemic. It has ity and mortality from all causes. , been estimated that approximately 315 mil- hyperlipidemia, obstructive and lion people worldwide meet the WHO criteria are only some of the obesity- of obesity. related diseases, while some types of cancer, such The WHO has defined obesity as a ‘disorder as breast, colon, prostate and endometrial cancer, of in that there is an abnor- are also more common in obese individuals. mal, absolute or relative proportion of body fat According to the National Health and Nutrition in relation to lean body mass, to the extent that Examination Survey (NHANES) III, the mor- health is impaired.’ An increase in sedentary bidity and mortality rates are closely related to lifestyle seems to be one of the principal reasons the degree of obesity, making the classification of for the dramatic increase in obesity’s preva- the weight status imperative, as this enables lence. The so-called ‘comfort eating’, rich in health practitioners to stratify individuals’ health saturated fats and sugars, causes an increase in risk and, thus, modify the level of intervention average energy intake per person, which in accordingly. BMI and waist circumference are combination with decreased physical activity, used in clinical practice for the estimation of contributes to . An individual’s weight status, while the presence of obesity- genetic background is also believed to predis- related disorders, such as hypertension and dys- pose to obesity, through the metabolic and lipidemia, further increase the overall mortality endocrine disturbances it induces. However, as risk [101]. the obesity epidemic has occurred too rapidly BMI is derived by dividing the body weight to be accounted for by changes in the genetic (kg) by the square of the height (m). It is consid- pool alone, it is clear that environmental fac- ered a relatively accurate marker of total body fat tors, in particular the fat- and sugar-rich diets mass. Generally, individuals with a BMI between and the reduction in physical activity, are the 18.5 and 24.9 kg/m2 are classified as normal Keywords: anti-obesity drugs, key to the current epidemic. weight, while those with a BMI of BMI, obesity, obesity 2 classification, orlistat, Being widely spread in all age groups and 25–29.9 kg/m are considered overweight. 2 rimonabant, sibutramine associated with several potentially life-threat- Patients with a BMI of 30–34.9 kg/m are classi- ening cardiovascular and metabolic disorders fied as obese Class I, those with a BMI of part of as well as impaired quality of life, obesity is a 35–39.9 kg/m2 are classified as obese Class II chronic disease that demands treatment. and, finally, those with a BMI of 40 kg/m2 or

10.2217/14750708.5.2.223 © 2008 Future Medicine Ltd ISSN 1475-0708 Therapy (2008) 5(2), 223–235 223 REVIEW – Lois & Kumar

over are classified as extremely obese Class III. weight is regained, health risks increase again, NHANES III suggests gradual increase in mor- suggesting obesity is a chronic disease that needs bidity and mortality rates at BMI values greater long-term or even lifelong treatment. than 25 kg/m2. The results of the Lewin study As the successful [101] are also compatible with the NHANES III requires constant effort from the patient’s side, findings, suggesting a direct correlation between their readiness and motivation to lose weight increased BMI and prevalence of comorbid con- should be assessed before deciding the weight- ditions, especially Type 2 diabetes, hypertension, loss strategy. It is very important to assess the heart disease, stroke and arthritis (Table 1). support from friends and family and the poten- The waist circumference is used in clinical tial barriers to this strategy. Achievable goals practice for the evaluation of central obesity. Of should be set, while in order to elicit their maxi- course, waist circumference measures all adipose mum effort for the requested lifestyle changes, tissue (and everything else) localized at the centre individuals’ preferences, likes and dislikes should of the body and specific ethnic and age-related be taken into account before the selection of a modifications may be necessary when inter- tailored weight-loss program. preting its values; however, it is generally consid- According to NICE guidelines, people with a ered an easy, accurate and useful measurement to BMI of less than 25 kg/m2 are not candidates for describe visceral accumulation in but rather for prevention of clinical practice. This is considered an independ- weight gain, while those with a BMI of 30 kg/m2 ent risk factor for the development of cardio- or over need treatment. Individuals with a BMI vascular and metabolic disorders [1,2] and, thus, between 25 and 29.9 kg/m2 should be treated only the distinction between visceral and peripheral if they also have obesity-related comorbidities or fat is very important. Most studies suggest that high waist circumference, since both increase the the incidence of obesity-related diseases is higher overall mortality risk. of 10% of the at waist circumference values greater than 94 cm initial body weight achieved over 6 months with a in men and 80 cm in women, while more rate of weight loss of 0.5–1 kg per week is gener- sophisticated cardiovascular risk charts, such as ally the recommended target, as greater rates of those from the Framingham study, help to iden- weight loss do not achieve better long-term results. tify individuals at increased cardiovascular risk The combination of , and behavior whose BMI is not yet significantly abnormal, but therapy remains the gold standard of the weight- whose waist circumference is. loss programs, and only if they fail should pharmacotherapy or even surgery be considered Clinical management (Table 2). It is now well determined that even a small Diets of 1000–1200 kcal/day for women and amount of steady weight loss, of approximately 1200–1600 kcal/day for men, which means a 5–10% of the initial body weight, ensues signifi- reduction of 500–1000 kcal in caloric intake per cant health benefits, as it improves metabolic day from the current level, are usually recom- and cardiovascular risk factors and prevents the mended for weight loss. Regular meals and plenty progression to Type 2 diabetes. The results of of fiber-rich foods, fruits and vegetables, in place of several studies, such as the Chinese, the Finnish foods high in fat and sugar, are strongly recom- and the US Diabetes Prevention Program, are mended by NICE [3]. Patients’ education regarding compatible with this estimation. By contrast, if caloric counting, food preparation, composition

Table 1. Increased risk of obesity-related diseases with higher BMI. Disease BMI of 25 or less BMI 25–30 BMI 30–35 BMI of 35 or more Arthritis 1.00 1.56 1.87 2.39 Heart disease 1.00 1.39 1.86 1.67 Diabetes (Type 2) 1.00 2.42 3.35 6.16 Gallstones 1.00 1.97 3.30 5.48 Hypertension 1.00 1.92 2.82 3.77 Stroke 1.00 1.53 1.59 1.75 Adapted from the American Obesity Association Centers for Disease Control Third National Health and Nutrition Examination Survey. Analysis by The Lewin Group, 1999 [101].

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Table 2. The level of intervention to discuss with the patient. Body weight – Waist circumference Comorbidities BMI (kg/m2) classification Low High* Very high* present Overweight General advice on Diet and physical Diet and physical Diet and physical (25.0–29.9 kg/m2) healthy weight and activity activity activity; consider drugs lifestyle Obesity Class I Diet and physical Diet and physical Diet and physical Diet and physical (30.0–34.9 kg/m2) activity activity activity activity; consider drugs Obesity Class II Diet and physical Diet and physical Diet and physical Diet and physical (35.0–39.9 kg/m2) activity; consider activity; consider activity; consider activity; consider drugs drugs drugs drugs; consider surgery Obesity Class III Diet and physical Diet and physical Diet and physical Diet and physical (≥40 kg/m2) activity; consider activity; consider activity; consider activity; consider drugs; consider drugs; consider drugs; consider drugs; consider surgery surgery surgery surgery *For men, waist circumference of less than 94 cm is low, 94–102 cm is high and more than 102 cm is very high. For women, waist circumference of less than 80 cm is low, 80–88 cm is high and more than 88 cm is very high. Data taken from the NICE guidelines for obesity 12/2006 [3].

and portion size make the success of the required Pharmacotherapy of obesity long-term changes more likely, and should always Although the principle of treating obesity is sim- be an integral component of the dietary therapy. ple, production of negative energy balance, the Physical activity contributes to weight loss by reality is very different. Owing to a powerful inter- increasing the total energy expenditure, but also nal biological system based on survival that tends maintains muscle mass, which decreases with to maintain and restore the fuel stores and return weight loss. It also increases the level of endor- body weight to the baseline value, any weight loss phins in the body and thus reduces psychological triggers a series of neuroendocrine effects that stress, which is usually increased in obese individ- resist any further weight loss, leading to failure of uals during periods, but most importantly most of the obesity treatments relying on lifestyle reduces the severity of obesity-associated cardio- changes alone. This is exactly the crucial moment vascular risk factors. Physical activity should be that a pharmacologic intervention can overcome gradually increased in obese patients, so that acci- any internal biopsychologic barriers, leading dents are avoided. Approximately 30–45 min of weight-loss attempts to a successful outcome. moderate physical activity as part of everyday life The use of drugs in weight management has is considered of great benefit, while the minimi- been an area of great interest for many years. Until zation of sedentary activities is the best start in recently, the recommended drugs were licensed this direction. for short-term use only, owing to their potential Obese individuals who participate in weight- for abuse or development of serious side effects. loss programs are asked to change lifelong habits Fenfluramine and its isomer dexfenfluramine are in a very short period of time, and that fact inev- the most recent anti-obesity medications to be itably restricts the likelihood of successful out- withdrawn from the market as they were causa- come of their attempt. Tailored methods and tively related to primary pulmonary hypertension behavior-change strategies that help the obese and valvular heart disease development. The patients to overcome potential barriers in their recent change in the view of obesity and its recog- compliance with dietary and physical activity nition as a serious chronic relapsing disease that instructions and which help them improve their requires long-term or even lifelong treatment led food quality, increase their physical activity level researchers to the investigation of anti-obesity and reduce their energy intake are important drugs that could meet the novel requirements. components of weight loss strategies and are part Generally, the ideal anti-obesity drug should com- of the so-called behavior therapy [3,101]. bine effectiveness and safety. Although such a If diet, exercise and behavior therapy fail to drug has not yet been developed, some progress in achieve the desired weight loss, only then this direction has already been made, as the newer should pharmacotherapy or even surgery be drugs are generally safer and appropriate for considered (Figure 1). longer use in comparison with the oldest drugs.

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Figure 1. Management pathway for the appropriate prescription of an anti-obesity drug.

Start of episode of care

Primary intervention: • Diet • Physical activity • Behavioral management

Failure to achieve 5–10% weight loss Consider drug treatment if: • BMI 30 or greater, or • BMI 27 or greater with risk factors Fulfil medical criteria for drug treatment

Drug treatment (following specific licence requirements)

Less than 5% weight loss 12 weeks 5% or greater weight loss

Drug treatment discontinued Continue drug treatment Other advice reinforced Weight regain Monthly monitoring of weight loss/ Other treatment options weight maintenance considered Duration of treatment determined by success and product licence

Reproduced with permission from [5]. Copyright © 2003 Royal College of Physicians.

The current accepted pharmacotherapy is not yet approved, as more side effects and no treatments include two main classes of weight- benefits for weight-loss management have been loss drugs: reported [3]. • Those that suppress the appetite and increase According to NICE guidelines, pharmacother- satiety, the so-called appetite suppressants; apy is indicated in patients with a BMI of 30 kg/m2 or over, as well in those with a BMI of • Those that act in the gastrointestinal tract and 27 kg/m2 or over if established obesity-related decrease the food-energy absorption (orlistat). comorbidity (CVD, Type 2 diabetes mellitus or Most of the appetite suppressants exert their sleep apnea) or three or more cardiovascular risk effect by affecting the monoamine and neuro- factors (such as smoking, hypertension, dyslipi- peptide pathways of the CNS (e.g., sibutramine demia and so on) are present. In any case, and phentermine), while rimonabant is the only pharmacotherapy should only be recommended as one in market that blocks the endocannabinoid adjunct to lifestyle modifications if they have failed system. The combined use of anti-obesity drugs to achieve the desired weight loss on their own.

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Figure 2. Weight loss (mean ± SEM) during 4 years of day. At this dose, it is estimated that approxi- treatment with orlistat plus lifestyle changes or placebo plus mately 30% of the alimentary fat is excreted lifestyle changes in obese patients (LOCF data). intact. As the typical western diet derives approxi- mately 40% of its calories from fat, orlistat may be a useful adjunct in weight-loss strategies, especially 0 in individuals with fat-rich dietary habits [4,5]. Placebo + lifestyle Orlistat was approved by the US FDA in April -3 1999 for long-term use (up to 2 years). Many p < 0.001 clinical trials that have thoroughly researched its -6 safety and efficacy over months and years, as well as its effectiveness in weight-management pro- -9 Orlistat + lifestyle grams, demonstrated that the weight loss achieved by the combination of 120 mg of orlistat three-

Change in body weight (kg) Change in body -12 times daily with hypocaloric diets is significantly 0 52 104 156 208 more than that achieved by hypocaloric diets Week alone. They also constantly demonstrated that an Reproduced with permission from [7]. individual is more likely to maintain any weight loss while on orlistat than on weight-maintenance The potential benefits and limitations of these diets only (Figure 2). medications, as well as their side effects and the In addition, it was estimated that owing to its potential impact on the life of the candidate user, method of action, orlistat reduces low-density- should be thoroughly explained and information lipoprotein (LDL) cholesterol beyond what could on services that provide advice or support on be expected from weight loss alone [6], whilst also patients should be also provided, if available. having a beneficial effect on blood pressure and Patients who are receiving pharmacotherapy HbA1c. Supporting these promising results are should be frequently assessed by the health profes- those of the prospective, double-blind, rand- sional for the success, the necessity of continua- omized, placebo-controlled, 4-year XENical in the tion and the safety of the pharmacological prevention of Diabetes in Obese Subjects (XEN- intervention. The decision in favor of one drug DOS) study [7], which demonstrated that orlistat, depends generally upon individual considerations, further to significantly increasing weight loss, also including portion sizes, snacking behavior and reduces the incidence of diabetes by 37% more dietary fat content, as well as the presence of spe- than the conventional lifestyle interventions alone. cific contraindications. If, at any time, it appears The relative reduction is even higher in the that the program is failing, a reassessment to impaired glucose tolerance patients (-45%) in determine the reasons should take place before comparison with the placebo-treated ones. It also confirmed the favorable effects of orlistat on sev- discontinuance of the treatment is decided [101]. eral cardiovascular risk factors, such as blood pres- Orlistat sure, lipids, waist circumference, fibrinogen and Orlistat (tetrahydrolipostatin) is a drug that pro- plasminogen activator inhibitor-1, providing fur- motes weight loss by preventing the digestion and ther support to the multiple metabolic benefits absorption of dietary fat from the gut. In the intes- that its administration in overweight and obese tine, there are enzymes known as lipases that break individuals may cause (Figure 3) [8]. up the dietary triglycerides into the smaller glyc- Orlistat is basically considered to be more erol and fatty acid molecules so that they can be effective in the management of those who [5]: absorbed into the body. Orlistat inhibits lipases by • Have lost at least 2.5 kg in weight prior to binding to their active serine residue in the gut. consideration of drug treatment; The unabsorbed part of the fat is later excreted in • Require longer-term behavioral change; the feces. As the drug leaves the stomach rapidly, only lipases released soon after the meal is con- •Follow a high-fat diet; sumed are inhibited, whereas fats are released by • Have elevated LDL cholesterol values; the stomach over several hours. The degree of the • Have impaired glucose tolerance or diabetes; ingested fat malabsorption is curvilinearly related • Have repeatedly lost weight in the short-term to the dose of the administered orlistat, and the and then rapidly regained it; maximum plateau value of its malabsorption-fecal • Have the ability to adhere to a low fat diet for excretion occurs at a dose of 360 mg of orlistat per the longer term.

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Figure 3. Mean percentage change from baseline low-density and vitamin deficiency, stem from its malabsorp- lipoprotein cholesterol levels in orlistat- versus tive effects. Deficiency of the lipophillic vitamins placebo-treated patients in an at-risk population with A, D, E and K may follow long-term treatment baseline levels over 130 mg/dl. with orlistat, making the usage of multivitamin supplements necessary when orlistat is used for a long time. Attention to potential interactions is Placebo + diet also needed. The manufacturer of orlistat advises Orlistat 120 mg t.i.d. + diet avoidance of its concomitant use with acarbose, owing to increased incidence of gastrointestinal 4 (n = 222) side effects, as well as its concomitant use with 2 0 amiodarone and cyclosporin, as orlistat might -2 (n = 67) reduce their absorption. By affecting vitamin K -4 absorption from the gut, orlistat may potentiate -6 (n = 203) (n = 25) the anticoagulant effect of coumarins, and close -8 (n = 133) -10 monitoring of international normalized ratio is -12 necessary in such cases [102]. -14 Change from baseline in Change from (%) LDL cholesterol (n = 118) -16 Sibutramine >10% <5% >5% to <10% The importance of the CNS monoamine and Weight-loss category neuropeptide pathways in food-intake regulation Patients had completed treatment for 2 years. has been intensively studied in recent years. The LDL: Low-density lipoprotein; t.i.d.: Three-times a day. documentation that as well as moderating mood Reproduced with permission from [14]. and various other processes in the brain, the stimu- lation of the serotonin and the noradrenergic The continuance of its therapy beyond receptors in the paraventricular nucleus (PVN) of 3 months is only recommended for individuals the hypothalamus modulates feeding and affects who have lost at least 5% of their initial body the meal quality and size by blocking the hunger weight since starting the treatment. However, as signal and enhancing the feeling of fulfilment the rates of weight loss may be slower in people from eating paved the way for the development of with Type 2 diabetes, achievable goals and less appetite suppressants. Some drugs of this category strict targets should be set in this group of affect catecholamines (e.g., dopamine and nore- patients. At the moment, its combined usage with pinephrine), and others affect monoamines other weight-loss medications is not approved by (e.g., serotonin), while others affect more than one NICE and treatment with orlistat for longer than neurotransmitter. Sibutramine was approved by 12 months is a decision that should be made, the FDA in November 1997 for body weight through negotiation between the health profes- management. It is a centrally acting appetite sup- sional and the patient, based on the potential pressant that inhibits the reuptake of norepine- benefits and limitations of such a decision. It is phrine (by 54%), serotonin (by 53%) and, to a estimated that prescriptions for orlistat have lesser extent, dopamine (by 16%). It belongs to the increased by 36-fold in recent years [9]. so-called adrenergic and serotonergic weight loss Gastrointestinal events, such as oily leakage agents and is the only drug of this class approved from rectum, flatulence, fecal urgency, liquid or for long-term use (up to 12 months). In addition oily stools, fecal incontinence, abdominal disten- to its appetite-suppressant effects, sibutramine also sion and pain, which are related to the mode of increases thermogenesis and thus the total energy action of orlistat, occur mainly in patients who do expenditure, which is considered another mecha- not comply with a low-fat diet. However, they are nism by which it contributes to weight loss. generally mild to moderately severe, and their fre- Many prospective, randomized, controlled clini- quency usually decreases after a few weeks of treat- cal trials have estimated sibutramine’s safety and ment. Administration of psyllium mucilloid once- efficacy in weight management and assessed its daily has been shown to decrease the frequency effectiveness according to the given dose. Meta- and severity of adverse effects [10]. Owing to its analysis of 29 trials [11] clearly supports the role of safety, orlistat can be used in patients requiring sibutramine in weight-loss strategies, while at the longer-term treatment. Systemic absorption of same time it emphasizes again the importance of its orlistat is very low (<1%) and thus its systemic combination with lifestyle modifications. Another side effects, such as oxalate-induced renal stones 1-year study that compared the effectiveness of 10

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Figure 4. Mean weight change (%) in sibutramine 2008, is designed to assess the effect of sibu- 10 mg versus sibutramine 15 mg versus placebo-treated tramine on the morbidity and mortality values of patients over 12 months. overweight and obese patients with high risk of CVD. The results of this study are expected to illustrate the potential benefits of sibutramine 0 treatment on cardiovascular outcomes [13]. Although it is not always possible to predict precisely which patients are going to respond to -2 this drug therapy and how much weight they Placebo (n = 76) may lose, more often, initial responders continue -4 to respond, whereas initial nonresponders do not usually respond, even with an increase in dosage [6]. Like other anti-obesity drugs, sibutramine is -6 10 mg q.d. (n = 79) indicated as adjunct to lifestyle changes in patients with a BMI of 30 kg/m2 or over, a BMI 15 mg q.d. (n = 93) of 27 kg/m2 or over and established obesity- -8 related comorbidity, or a BMI of 27 kg/m2 or Mean weight change (%) Mean weight change over and three or more cardiovascular risk factors -10 present, especially in [5]: 012 3456789101112 • Those whose appetites and eating habits are Treatment month uncontrollable •Frequent snackers q.d.: Once daily. Reproduced with permission from [14]. • Nocturnal eaters • Those who need immediate weight loss for medical reasons and 15 mg of sibutramine versus placebo in patients who were already following a hypocaloric • Patients with low HDL cholesterol values diet, suggested that in comparison with the pla- • Those with no contraindications to its use cebo-treated group, in which the weight loss was Generally, sibutramine starts working quickly, approximately 2% of the initial body weight, the with most of its users losing weight within the weight loss of the 10 mg- and 15 mg-treated first 8 weeks of treatment, and most of the groups was 6.5 and 8%, respectively (Figure 4) [1,12]. weight loss occurring within the first 6 months Although the effectiveness of sibutramine as a of therapy [14]. The suggested starting dose is weight-loss drug was supported by multiple clin- 10 mg in the morning, which is increased to ical trials, most of them demonstrated weight 15 mg daily if weight loss is less than 2 kg, fol- regain after dicontinuation of therapy. The Sibu- lowing 4 weeks of treatment with 10 mg daily. tramine Trial of Obesity Reduction and Mainte- The 5-mg dosage is only recommended for those nance (STORM) study focused exactly on the who are intolerant to the 10-mg dose. As a assessment of the long-term (2 years) effective- 3-month period is considered sufficient to iden- ness of sibutramine in weight-loss maintenance. tify the responders to sibutramine therapy, At the end of the study, it was estimated that it NICE recommends discontinuation of the treat- reduces weight regain even after many months ment if less than 5% of the pretreatment body (18 months) of discontinuation, while at the weight has been lost 3 months after the initiation same time, multiple benefits in the metabolic of the treatment. The exception to this rule are profile of the sibutramine-treated group were the Type 2 diabetics, who generally have more also maintained (reduction of triglycerides, very difficulty losing weight, and for whom lower tar- low-density lipoprotein [VLDL], insulin resist- gets should be set. ance and increase of the high-density-lipoprotein Sibutramine is generally well absorbed from the [HDL] blood levels), supporting its potential gastrointestinal tract (77%). Although it is metab- role as a metabolic risk-factor modulator, espe- olized considerably in its first pass by the cyto- cially in obese individuals with low HDL values. chrome P450 isoenzyme CYP3A4 and has a half- Finally, an ongoing multicenter, double-blind, life of only 1 h, both of its metabolites (amines, placebo-controlled trial, the Sibutramine called active metabolites 1 and 2) are active, with Cardiovascular Outcome Trial (SCOUT) study, half-lives of 14 and 16 h, respectively, prolonging which started in 2003 and will continue until its action. The most common side effects that

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have been reported by users of sibutramine in that their stimulation increases appetite raised the many clinical trials were an increase in blood pres- challenge for the development of CB1 blockers sure and, in some cases, in heart rate. The British that could lead to appetite suppression and National Formulary recommends that the blood weight loss. In 1994, researchers produced the pressure and heart rate should be monitored every first CB1-receptor-specific antagonist, rimona- 2 weeks for the first 3 months, then monthly for bant, which when administered in animals, 3 months, and then at least every 3 months there- reduced their appetite and food intake and after. The medication should be stopped if blood caused weight loss. Since then, rimonabant has pressure exceeds 145/90 mmHg or if systolic or been approved for clinical use in obese people. diastolic pressure is raised by 10 mmHg or more Data from several studies support that the or if pulse rate is raised by 10 bpm or more at two endocannabinoid system is overactivated in consecutive visits. The drug is generally contra- obese individuals, implying a causative role in indicated in patients with history of coronary the development of obesity. In addition, recep- artery disease, congestive heart failure, arrhyth- tors of this system have been identified in organs mias and stroke disease, as well as in those with with a regulatory effect on metabolism, such as hyperthyroidism and pheochromocytoma and in the adipose tissue, liver, skeletal muscle, pancreas those who are receiving treatment with monoam- and gut, which could mean involvement of the ine oxidase inhibitors or selective serotonin- endocannabinoid system in the pathogenesis of reuptake inhibitors (SSRIs). Prostatic hyper- the adverse metabolic changes presented in obes- trophy, pregnancy and lactation are also strong ity (). The Rimonabant In contraindications to sibutramine usage [102]. It is Obesity (RIO) study is a multicenter, inter- estimated that prescriptions for sibutramine have national, prospective, randomized, placebo-con- increased by fourfold in recent years. trolled study, consisting of four Phase III trials, the RIO-Diabetes, RIO-Lipids, RIO-North Rimonabant America and RIO-Europe, designed to estimate The observation that cannabis smokers often the effect of rimonabant on several metabolic experience extreme hunger pangs led scientists to risk factors, as well as its safety and efficacy as a the discovery and characterization of the endo- weight-loss drug, in different target groups. The cannabinoid system. The presence of its receptors data analysis of this study suggests that, in com- has been documented in many areas of the brain, parison with the placebo treatment, daily admin- such as those involved in pleasure, memory, istration of 20 mg rimonabant results in thought, concentration and so on [7]. However, significant weight loss (Figure 5) and improve- the identification of the CB1 cannabinoid recep- ment in a cluster of cardiovascular risk factors of tors in the hypothalamus and the documentation metabolic origin that comprise the metabolic

Figure 5. Effect of placebo or rimonabant for 52 weeks on body weight and waist circumference.

Placebo Rimonabant 5 mg Rimonabant 20 mg 2 2

0 0

-2 -2

-4 -4 p < 0.001 -6 -6 p = 0.016 p < 0.001 -8 -8 p < 0.001 Change in body weight (kg) Change in body -10 -10

0 4 81216202428323640444852 (cm) Change in waist circumference 0 4 81216202428323640444852 Week Week

Modified from [41].

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syndrome (e.g., triglycerides, HDL, insulin sen- and severe renal or hepatic impairment, while sitivity, C-reactive protein, blood pressure, waist nausea, vomiting, diarrhea, dry mouth, mood circumference), as well as a shift of the LDL changes, anxiety, irritability, nervousness and small dense molecules towards less atherogenic sleep disorders seem to be its most common side ones [15–18]. effects. However, the main area of concern is the Surprisingly, it was estimated that the improve- potential for serious depression and suicidal ide- ments in insulin resistance, HbA1c, HDL and ation, although it is uncommon. This needs to triglycerides were beyond that expected by weight be carefully monitored and the drug stopped loss alone, implying weight-independent effects early if signs of depression develop (Table 4). on the metabolic profile (Table 3) [15,18,19]. It has been suggested that the separate weight-dependent Other potential weight-loss drugs and -independent metabolic effects of rimonabant Investigational compounds for the treatment of may be explained by the physiology of the endo- obesity act via appetite regulation, appetite regula- cannabinoid system and the expression of the CB1 tion plus metabolic properties, increased energy receptors in peripheral tissues, while the direct expenditure/fat oxidation or decreased food boosting effect of rimonabant on adiponectin pro- absorption. Appetite regulation involves many duction, which increases by 57% more than could potential pathways; however, the most promising be expected from weight loss alone in rimonabant- drug-development approaches target pure CNS treated individuals, provides an additional meta- pathways or peripheral signals to the CNS. bolic pathway that could contribute to the beyond Recently, the potential use of the gut hormones weight loss metabolic effects of rimonabant, by GLP-1 and cholecystokinin (CCK) in weight-loss which it eventually reduces the incidence of CVD strategies, as agents that affect peripheral signals to and Type 2 diabetes. The beneficial cardiovascular the CNS, has been intensively investigated. and metabolic modulating role of rimonabant has Incretins (GIP and GLP-1) are hormones with been well established in overweight and obese glucoregulatory effects, produced by the endo- individuals with or without Type 2 diabetes crine cells of the intestine following ingestion of and/or dyslipidemia [15]. More importantly, food. Exenatide is an incretin mimetic with prop- according to RIO-North America and erties similar to human GLP-1 that was recently RIO-Europe trials [16,20,21], the achieved metabolic approved for the treatment of Type 2 diabetes and body weight benefits are maintained for at (marketed as Byetta®), as it enhances glucose- least 1 year after discontinuance of rimonabant. dependent insulin secretion. However, it may Rimonabant may be more useful in Type 2 also emerge as an off-label obesity-treatment diabetics, who need adjunct therapy with appe- drug, as it attains appetite-suppressant effects. tite suppressants and who are unable to take or Clinical trials have demonstrated that most peo- tolerate sibutramine. Rimonabant is licensed for ple using exenatide slowly lose weight and gener- up to 2 years use, while caution is needed when ally the greatest weight loss is achieved by people used by patients with epilepsy, mild-to-moderate who are the most overweight at the beginning of hepatic impairment, uncontrolled psychiatric ill- exenatide therapy, while the weight-reducing ness and those aged over 75 years. It is strongly effect continues at the same rate through 2 or contraindicated during pregnancy, breastfeeding more years of continued use [22–25]. Side effects of

Table 3. Summary of results for primary analysis of metabolic parameters with and without adjustment for body weight loss, mean (SEM). Cardiometabolic Overall effect* Effect beyond that of body weight Overall effect beyond that of parameter loss alone* body weight loss alone (%) HDL cholesterol (%) 8.0 3.6 45 Triglycerides (%) -14.0 -6.5 46 Fasting insulin (µIU/ml) -2.74 -1.34 49 Adiponectin (µg/ml) 1.5 (0.2) 0.85 57

HbA1c (%) -0.67 -0.37 55 *Mean difference versus placebo at 1 year; p < 0.001 for all comparisons. HDL: High-density lipoprotein. Data taken from [17].

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Table 4. Prescribing summary for orlistat, sibutramine and rimonabant. Drug Standard dose Potentially useful in Avoid in Comments Orlistat 120 mg three- , diabetes, raised LDL Malabsorption or Prescribe concurrent times daily cholesterol, hypertension, chronic gastrointestinal multivitamin pre-existing cardiovascular disease, disease patients who require long-term behavioral change Sibutramine 10–15 mg once-daily Frequent snackers, nocturnal eaters, Uncontrolled Monitor blood pressure dyslipidemia (high triglyceride/low hypertension, and heart rate HDL cholesterol) tachycardia, pre-existing cardiovascular disease Rimonabant 20 mg once-daily Dyslipidemia (high triglyceride/low History of psychiatric Monitor for mood HDL cholesterol), diabetes, illness, liver impairment disorders metabolic syndrome, hypertension HDL: High-density lipoprotein; LDL: Low-density lipoprotein.

exenatide are primarily gastrointestinal, including may become physically and psychologically nausea, vomiting and diarrhea. However, they are dependent on these medications after several mild to moderate and usually go away entirely weeks of continuous use. However, since the after a few days or weeks. It is administered change in obesity management, according to subcutaneously, twice-daily. which it is considered a chronic disease that CCK is the first gut hormone that was recog- requires long-term treatment, and since new nized to inhibit food intake in animals, over adrenergic appetite suppressants with fewer side 30 years ago [26]. The effect of CCK as an appe- effects and authorization for long-term use have tite suppressant seems to depend largely on its been developed, the older noradrenergic appe- activation of CCK-1 receptors (formerly CCK-A) tite suppressants are even less frequently used in the vagus nerve, suggesting a vagally mediated, nowadays. endocrine mechanism that is triggered by food Bupropion, a dopamine- and norepinephrine- intake and subsequent stomach distension [27]. reuptake inhibitor, which is primarily used as an Although the results of preclinical studies with antidepressant and as a smoking-cessation aid, butabindide (which protects endogenous CCK topiramate, which is anticonvulsant, and some from inactivation) [28] and GI181771X (a potent, SSRIs (fluoxetine and sertraline) have also been full CCK-1 receptor agonist) were compatible shown to suppress appetite, resulting in moderate with weight loss effects of CCK in animals, dou- weight loss in some patients following treatment ble-blind treatment with different GI181771X of 6–12 months duration. However, owing to doses or matching placebo, together with a controversial results from other studies, at present hypocaloric diet of patients with a BMI of 30 or they are not licensed as adjuncts to diet and exer- over, or 27 kg/m2 or more, did not reduce body cise in weight-loss programs [30,31]. In addition, weight and had no effect on waist circumference chitosan, a deacetylated chitin widely available as or other cardiometabolic risk markers, demon- a that claims to aid weight strating that CCK-A by itself does not have a loss, has been intensively investigated. A recent central role in long-term energy balance [29]. review that estimated its efficacy in weight loss While the gut-acting weight-loss drug (orli- concluded that it has only minimal effect on stat) and the endocannabinoid receptor blocker body weight, which is unlikely to be of any clini- (rimonabant) are relatively novel, the sympatho- cal significance [32]. Methylcellulose is the most mimetics have been in use for many years. commonly used bulk-forming laxative; however, Phentermine, diethylpropion, mazindol, ben- although it is claimed to reduce intake by pro- zphetamine and phendimetrazine are the main ducing a feeling of satiety, there is little evidence older-generation drugs of this class. They gener- to support its use in the management of obesity. ally exert their weight-loss effect by decreasing Finally, according to Misato Kobayashi et al., the appetite and increasing satiety and are recom- bile acid-binding resins, such as cholestyramine mended for short-term (up to 12 weeks) use and colestimide, which have been documented to only, as they are habit forming and individuals improve lipids and glycemic profile in animal

232 Therapy (2008) 5(2) futurefuture sciencescience groupgroup Pharmacotherapy of obesity – REVIEW

models, can also ameliorate diet-induced obesity which possesses a key role in appetite control and when given to overfeeding mice and, most energy homeostasis regulation, is currently being importantly, without reducing food intake. The intensively studied. Several agonists and antago- most probable method of action is by the reduc- nists of its receptors are assessed for their weight- tion of fat absorption from the intestine. This loss efficacy. Melanocortin-4 receptor agonists, fact could set bile acid-binding resins as novel as well as ghrelin [35], NPY, PPY [36] and melanin therapeutic agents for the treatment of obesity, concentrating hormone antagonists, are some of especially in Type 2 diabetic and dyslipidaemic them [25]. Animal data support the beneficial patients; however, they are not yet licensed for effect on weight management, by the use of such such use [33]. agonists and antagonists, but we are still a few years away from their use in clinical practice [37]. Anti-obesity drugs in development The afferent signals from the gut are a very Since the need for effective anti-obesity therapies is important part of the energy homeostasis system. currently unmet, as none of the currently used The effectiveness of exogenic pancreatic drugs seem to be the ‘magic’ solution to the obes- polypeptide (PP) as an appetite suppressant has ity epidemic, achieving quick and permanent been intensively investigated in recent years [38]. weight loss, while at the same time being cheap Administration of PP as a potential obesity treat- and safe for long-term or even lifelong use, inten- ment has the advantage that it mimics the safe sive research is still in progress for the development and natural way in which the body suppresses of novel, more effective drugs. appetite. This hypothesis is supported by the fact Leptin is considered the main long-term affer- that patients with benign PP-secreting tumors, ent signal that informs the CNS of the energy- who had elevated levels of the hormone for more stores balance, so that the necessary adjustments than 10–15 years, did not show any side effects, in feeding behavior can be made for efficient thus suggesting that PP administration may be matching between energy intake and expendi- useful for weight management. If the results of ture and the maintenance of the energy stores. this research support the effectiveness of PP in An increase in body fat mass leads to an elevation weight loss, this may lead to a treatment within in the concentration of leptin in the blood, 5–8 years, in an oral or injectable formula. inducing a negative energy balance, which tends In recent years, the role of 11-β-hydroxysteroid to return body fuel stores to the set point. Leptin dehydrogenase 1 (11β-HSD1) in the develop- binds to the ‘satiety’ center (ventral medial ment of visceral obesity has been intensively inves- nucleus) of the hypothalamus and induces the tigated. According to recent human studies, its sensation of satiety by inhibiting the activity of expression was increased twofold in central fat and NPY- and AgRP-containing hypothalamic neu- was positively correlated with waist circumference rons that induce hunger, while at the same time and insulin resistance. These results support its increasing the activity of others that induce sati- detrimental effect on the energy stores metabo- ety, such as those expressing the α-melanocyte- lism, paving the way for the development of drugs stimulating hormone (α-MSH). Administration that may target the 11β-HSD1 gene’s expression of recombinant leptin in obese individuals with a in visceral adipose tissue [39]. mutated leptin gene proved to be of great bene- The concept of adding something to food to fit, resulting in excessive weight loss, while a provide health benefits is not new. The impor- dose–response relationship with weight and fat tance of diet-induced thermogenesis in the resist- loss was observed with subcutaneous recom- ance to diet-induced obesity has been well binant leptin injections in both lean and obese documented [15,40]. Further work is needed to subjects [34], supporting a weight-reducing effect identify tissues and molecular pathways mediat- of exogenous leptin in some obese subjects who ing diet-induced thermogenesis (DIT), to already have elevated endogenous serum leptin develop foods that might cause significantly concentrations. higher thermogenesis. The determination of dif- In addition to the CB1 receptors of the endo- ferences in DIT according to a meal’s macronu- cannabinoid system, many other central recep- trient composition, as well as the role of the tors and biochemical pathways are being medium-chain triacylglycerols in thermogenesis, investigated as potential targets for future anti- irrespective of the meal components, is only the obesity drugs. The central melanocortin path- beginning of a very promising aspect of recruit- way, which includes a group of neurons located ing functional foods in weight-loss strategies in in the arcuate nucleus of the hypothalamus and the future. futurefuture sciencescience groupgroup www.futuremedicine.com 233 REVIEW – Lois & Kumar

Conclusion regarding the safety and effectiveness of current Obesity is not a recent phenomenon, but the epi- drug therapies still remain, the long-term pharma- demic of obesity is. Widely spread in modern cological approaches seem to be promising not human societies, but also in developing countries, only for weight loss, but also for maintenance of it is estimated that approximately 315 million weight loss. Orlistat, sibutramine and rimonabant people worldwide meet the WHO criteria of are currently the only anti-obesity drugs licensed obesity. Associated with several potentially life- for long-term use, while they also demonstrate threatening cardiovascular and metabolic disor- beneficial effects on several surrogate cardiovascu- ders, as well as with significant morbidity, mortal- lar markers further to weight loss; however, inter- ity and impaired quality of life, obesity is pretation is limited owing to high attrition rates considered a chronic disease that requires long- (30–40% on average) and lack of long-term term or even lifelong treatment. On the other outcome data [41]. hand, even moderate steady weight loss results in significant health benefits. Calculations made for Financial & competing interests disclosure NICE on the cost–effectiveness of current anti- The authors have no relevant affiliations or financial involve- obesity drugs suggest a figure of £15,000–30,000 ment with any organization or entity with a financial interest per quality-adjusted life year gained [5]. The com- in or financial conflict with the subject matter or materials dis- bination of diet, exercise and behavior therapy cussed in the manuscript. This includes employment, consul- remains the gold standard of weight-loss pro- tancies, honoraria, stock ownership or options, expert grams, while pharmacological intervention is rec- testimony, grants or patents received or pending or royalties. ommended in selected patients in whom lifestyle No writing assistance was utilized in the production of modifications have failed. Although uncertainty this manuscript.

Executive summary

• Obesity is major health problem with significant comorbidities.

• The use of drugs in weight management has been an area of great interest for many years.

• The research target is the development of efficient and safe drugs for long-term or even life-long usage.

• The recent years, the short-term acting drugs have been replaced by long-term acting drugs.

• Currently, the most widely used anti-obesity drugs are those that reduce the absorption of ingested fat (orlistat) and those that suppress appetite (sibutramine and rimonabant).

• Most randomized, controlled trials are compatible with significant weight loss by the use of these drugs; however, interpretation is limited owing to high attrition rates (30–40% on average).

• The gut is considered of great importance in the regulation of the energy-balance system.

• The potential role of drugs that mimic (e.g., GLP-1, PPY and so on) or antagonize gut-derived hormones (e.g., ghrelin antagonist) is being investigated.

• Other drugs that directly affect the appetite centre (e.g., melanocortin-4 receptor agonists) are only a few years away from the market.

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