DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW Diabetes Metab Res Rev 2012; 28(Suppl 2): 820.

Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2349

ARTICLE

Do we need anti-obesity drugs?

ch Hainer1 Vojte Irena Aldhoon Hainerova 2

1

Summary
The increasing global prevalence of obesity urgently requires an implementation of efcient preventive and therapeutic measures. Weight loss and its maintenance should be considered one of the most important strategies to reduce the incidence of obesity-related co-morbidities such as diabetes and cardiovascular diseases. Lifestyle modication focused on diet and physical activity represents the essential component of any kind of weight management. However, only an intensive lifestyle intervention can be efcient in terms of long-term weight loss. Anti-obesity drugs affect different targets in the central nervous system or peripheral tissues and improve regulatory and metabolic disturbances that contribute to the development of obesity. Antiobesity medications provide modest additional fat loss to that achieved by lifestyle modication alone, reduce visceral fat stores, improve programme adherence, weight loss maintenance, diminish obesity-related health risks and improve a quality of life. Anti-obesity drugs do play a role in weight management. Their replacement with placebo is followed by weight regain. Due to adverse events, several anti-obesity drugs were withdrawn from the market over the past few years and currently only orlistat remains available for long-term obesity management. Drug withdrawals, failure of clinical trials with several new anti-obesity compounds as well as inappropriate demands of drug regulating agencies concerning the study protocol led to scepticism about the perspectives in the pharmacotherapy of obesity. However, recently developed anti-obesity medications such as gut hormone analogues and drug combinations provided encouraging results in terms of weight loss, safety and improvement of cardio-metabolic health risks.

Institute of Endocrinology, Prague, Czech Republic Department of Paediatrics and Centre for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic *Correspondence to: ch Hainer, MD, PhD, Institute Vojte of Endocrinology, Na rodn 8, 116 94 Prague 1, Czech Republic E-mail: vhainer@endo.cz

Keywords obesity treatment; lifestyle modication; anti-obesity drugs; efcacy; safety; novel compounds

Introduction
Obesity has become a serious and worldwide public health problem [13]. According to the World Health Organization (WHO) and International Obesity Task Force (IOTF) report 2000, it is expected that globally in the year 2015, 700 million adults will be obese and 2.3 billion adults will be considered overweight [4]. Obesity is related to several health risks such as type 2 diabetes, hypertension, cardiovascular diseases, dyslipidaemia, arthritis and certain cancers. Obesity signicantly decreases quality of life and reduces life expectancy. It has been shown that even a moderate weight loss of 510% leads to a reduction in health risks of obesity [5]. Management strategies for weight reduction in obese individuals should be based on lifestyle modication that includes the reduction of caloric intake, increased physical activity and cognitive behavioural therapy. According to the international guidelines, lifestyle modication should be the rst and essential part of weight

Received: 14 October 2011 Revised: 8 March 2012 Accepted: 19 March 2012

Copyright 2012 John Wiley & Sons, Ltd.

Do we need anti-obesity drugs?

management [4,5]. Long-term effects of diet and exercise on weight though are often disappointing [6]. Further strategies are represented by pharmacological treatment and bariatric surgery. These strategies should be used in combination with lifestyle modication in order to achieve greater efcacy [7]. Bariatric surgery is the most effective treatment in terms of long-term weight loss, improvement in cardiometabolic risks and quality of life and decline in overall mortality in patients with morbid obesity [5]. However, the so-called metabolic surgery has been recommended even for patients with body mass index <35 kg m2 as recently reviewed experiences with surgery in these patients revealed resolution of laboratory and clinical manifestations of type 2 diabetes together with appropriate weight loss [8]. Obesity treatment should be individually tailored, taking into account the gender, age, degree of obesity, health risks, psychobehavioural characteristics and the outcome of previous weight loss attempts [9]. Only an intensive lifestyle intervention is an efcient tool in terms of weight loss and reduction of health risks. Can we afford it? A recently published systemic review of reviews on the effectiveness of dietary and physical activity interventions reported weight loss of 35 kg after lifestyle intervention in duration of 12 months and 23 kg after 36 months [10]. Lifestyle modication has proved to be effective in preventing the development of type 2 diabetes mellitus, especially in high-risk groups [11]. However, several randomized studies in both obese adults and children demonstrated that the effect of lifestyle intervention on body weight is very limited and decreases with time [12].

It has been shown that only intensive lifestyle intervention is an efcient tool for weight management. Results of the LOOK AHEAD study clearly demonstrated that 1-year intensive lifestyle intervention can induce a signicant weight loss in obese diabetics [13]. The mean weight loss in the intervention group was )8.6% versus )0.7% of the group receiving conventional diabetes support and education [13]. One may wonder if such an intensive lifestyle intervention can be considered as a realistic goal due to several facts that must be taken into account. An efcient intensive lifestyle intervention often requires frequent face-to-face contacts and high dropout rates are observed. There are also high time and cost demands. This type of intervention is more efcient when combined with other therapeutic approaches, e.g. meal replacement [13]. Placebo groups in trials with anti-obesity drugs exhibited only modest weight loss, although supervised lifestyle intervention was usually an integral part of the treatment protocol (Table 1). Long-term weight management by drug treatment alone does not seem realistic at present. The combination of medication and lifestyle modication induces greater weight loss than either medication or lifestyle intervention alone [14,15]. In clinical trials with antiobesity drugs, weight loss ranged from 4.1 to 14.2 kg (Table 1) [16].

Targets for anti-obesity drugs

Anti-obesity drugs play a role in weight management affecting several mechanisms either in the central

Table 1. Mean weight loss in clinical trials with anti-obesity drugs Mean weight loss (kg) Drug Phentermine [30] Diethylpropion [30] Diethylpropion [37] Mazindol [30] Fenuramine [30] Dexfenuramine [30] Orlistat [32] Sibutramine [32] Rimonabant [32] Lorcaserin [114] Lorcaserin [58] Cetilistat [56] Liraglutide [76] Pramlintide [81] Tesofensine [60] Phentermine + fenuramine [95] Phentermine CR + topiramate CR [100] Pramlintide + phentermine [104] Pramlintide + sibutramine [104] Pramlintide + metreleptin [103] Naltrexone SR + bupropion SR [98] Naltrexone SR + bupropion SR [99] *The trial was not placebo-controlled.
Copyright 2012 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2012; 28(Suppl 2): 820. DOI: 10.1002/dmrr.2349

Number of studies 6 9 1 22 14 14 15 10 4 1 1 1 1 1 1 1 1 1 1 1 1 1

Mean study duration 13 weeks 18 weeks 6 months 11 weeks 10 weeks 30 weeks 1 year 1 year 1 year 1 year 1 year 12 weeks 1 year 1 year 24 weeks 34 weeks 56 weeks 24 weeks 24 weeks 24 weeks 56 weeks 56 weeks

Placebo )2.8 )3.5 )3.1 )3.0 )2.4 )3.8 )2.4 )2.2 )1.6 )2.2 )2.9 )2.2 )2.0 )0.8 )2.2 )4.6 )1.4 )2.2 )2.2 )* )1.9 )5.2

Drug minus placebo )3.6 )3.0 )6.2 )2.7 )2.4 )5.1 )2.9 )4.2 )4.7 )3.6 )2.9 )1.9 )5.8 )7.2 )9.1 )9.6 )8.8 )9.1 )8.9 )* )6.1 )4.1

Drug )6.4 )6.5 )9.3 )5.7 )4.8 )8.9 )5.3 )6.4 )6.3 )5.8 )5.8 )4.1 )7.8 )8.0 )11.3 )14.2 )10.2 )11.3 )11.1 )11.5 )8.0 )9.3

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nervous system (CNS) or in the peripheral tissues (muscle, fat, kidney or gastrointestinal tract) [17]. Substantial research activity has been done with several molecular targets and strategies being investigated. Antiobesity drugs may: (i) reduce appetite or induce satiety via their action on serotoninergic, noradrenergic, dopaminergic, opioid, cannabinoid or specic hormonal receptor systems in the brain; (ii) increase energy expenditure and fat oxidation, mainly through the activation of catecholaminergic mechanisms in the CNS and or peripheral tissues; (iii) reduce fat absorption by lipase inhibition in the gastrointestinal tract; and (iv) induce depletion of nutrients, e.g. by inducing glucose depletion in the kidney.

Goals of treatment with anti-obesity drugs

Anti-obesity drugs should reduce body fat stores by normalizing regulatory or metabolic disturbances involved in the pathogenesis of obesity, increase fat loss achieved by lifestyle management, reduce visceral fat stores, improve programme adherence and weight loss maintenance, diminish obesity-related health risks, prevent morbidity and mortality and improve the quality of life. The anti-obesity agents should exhibit only minor side effects, be preferentially administered orally and be distributed at affordable price. A decrease 5% of body weight in response to obesity treatment is considered appropriate in terms of signicant reduction of cardiometabolic health risks [5].

Scepticism about the drug treatment of obesity: withdrawal of antiobesity drugs from the market
The drugs widely used for the treatment of obesity in the past included amphetamine analogues, fenuramine and dexfenuramine, rimonabant, orlistat and sibutramine. Three years ago, three anti-obesity drugs orlistat, sibutramine and rimonabant were available in Europe. After sibutramine was withdrawn from the market in 2010, only orlistat has been available for the long-term treatment of obesity. Side effects which caused the withdrawal of anti-obesity drugs were primarily related to the mechanisms of their action. Sympathomimetic anorectics: Since the 1950s, several drugs of the phenethylamine class were used for the treatment of obesity (amphetamine, phentermine, diethylpropion and phenylpropanolamine). These sympathomimetic agents act by releasing noradrenaline and dopamine from presynaptic vesicles in the lateral hypothalamus. Mazindol is a sympathomimetic drug that belongs to the tetracyclic chemical class and blocks the reuptake of noradrenaline by presynaptic neurones. The increase in noradrenaline release within the synaptic cleft
Copyright 2012 John Wiley & Sons, Ltd.

is associated with the stimulation of beta2-adrenergic receptors and results in inhibition of appetite. However, the simultaneously observed dopamine release is responsible for addiction. In routine clinical practice, these drugs, except for phentermine, are only of limited use and are not currently approved for long-term use. Most of them were withdrawn from the market because of adverse events that included cardioexcitatory and psychostimulatory effects and addiction. In April 2000, the European Medicines Agency (EMEA) recommended the withdrawal of several weight loss drugs including phentermine, diethylpropion, and mazindol. In many countries, catecholaminergic drugs such as phentermine, ephedrinecaffeine mixture, diethylpropion and mazindol are still available for short-term use. Phentermine has been used for over 50 years and is currently the most widely prescribed anti-obesity drug in the United States. Fenuramine and dexfenuramine: Fenuramine and dexfenuramine elevate serum levels of serotonin (5HT) in the CNS by stimulation of 5HT release and inhibiting its reuptake. The increased level of 5HT appears to stimulate the hypothalamus and thus activates melanocortin 4 receptor (MC4R), which results in decreased food intake and anorexia. However, the accumulation of serotonin in peripheral tissues leads to serious side effects such as heart valve disease and pulmonary hypertension. Both fenuramine and dexfenuramine were voluntarily withdrawn from the market in 1997. Rimonabant blocks cannabinoid receptors (CB1) and this way modulates energy balance and metabolism at different levels, including receptors within the gastrointestinal tract and adipose tissue as well as receptors in the brain which are involved in the regulation of food intake and hedonic rewarding [18,19]. Rimonabant affected both receptors located inside and outside the CNS. Its benecial cardiometabolic effects were signicantly related to peripheral action. Adverse events related to depression, anxiety and suicidal ideation resulted in withdrawal of rimonabant from the market in 2009. Sibutramine selectively inhibits reuptake of serotonin, noradrenaline and dopamine in the hypothalamus. The stimulation of the central alpha1 and beta1 adrenergic receptors induces increased satiety, while the stimulation of peripheral beta3 adrenergic receptors mediates a modest increase in thermogenesis. Over a 13-year period, sibutramine was administered to millions of obese patients. However, the stimulation of the noradrenergic system also resulted in increased blood pressure and heart rate in some patients treated with sibutramine. Because of cardiovascular risks related to sibutramine treatment, the EMEA demanded a long-term trial in patients who are at high risk of cardiovascular disease. In response to this demand, the Sibutramine Cardiovascular Outcomes Trial (SCOUT), reported by some authors as a trial that killed the drug [20], was initiated. SCOUT was a double-blind, randomized, placebo-controlled trial which enrolled over 10 000 overweight or obese subjects aged >55 years and having cardiovascular disease or type 2 diabetes. It is important to note
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that over 90% of the recruited subjects were contraindicated according to the drug labelling and that non-responders were not excluded from the study. Sibutramine led to a signicant weight reduction and decrease in waist circumference. Around 9800 patients who had been followed up for 6 years had a higher rate of cardiovascular events, higher rate of non-fatal myocardial infarction and non-fatal stroke. Over a 3.4-year follow-up period, the occurrence of non-fatal myocardial infarction or stroke signicantly differed (P < 0.02) between both groups sibutramine group 11.4% versus placebo group 10.0% [21]. Due to this increased risk of non-fatal heart attacks and strokes, in 2010 sibutramine was withdrawn from the market. However, a 3-year prospective observational study of 15 686 patients in New Zealand did not demonstrate a higher risk of death from cardiovascular events in sibutramine-treated patients [22].

Selective thyroid hormone mimetics which could exhibit benecial effects on body weight and lipid prole without cardiotoxic effects have not until now progressed beyond phase 1 clinical trials [28,29].

Anti-obesity drugs used in the past: weight loss

Due to the normalization of regulatory and or metabolic abnormalities, anti-obesity drugs induce additional weight loss to that induced by lifestyle modication placebo. Table 1 shows mean weight losses in 108 trials with anti-obesity drugs. The table covers major metaanalysis of randomized clinical trials [3032] as well as individual clinical trials with anti-obesity drugs carried out during the past 3 years. All studies were placebocontrolled except for a study in which a combination of pramlintide with metreleptin was applied. The duration of pharmacotherapy varied from a couple of weeks to periods exceeding 1 year. Placebo-administered groups achieved mean weight loss of 2.79 kg, while mean weight loss in the drug-treated groups was 6.51 kg. Weight reductions widely varied, from minor weight losses after intestinal lipase inhibitor cetilistat to major weight reductions observed with the administration of tesofensine and combination drugs (Table 1).

Scepticism about the drug treatment of obesity: failure of clinical trials with novel anti-obesity drugs
Failures of clinical trials with several novel anti-obesity drugs contributed to disappointment concerning the perspectives in pharmacotherapy of obesity. Both taranabant and otenabant, CB1 antagonists, were shown as efcient anti-obesity agents but were abandoned during late phase clinical trials due to depression and anxiety [23]. Ecopipam, a dopamine (D1 D5) receptor antagonist, was also excluded from further clinical trials due to its adverse events on mood [24]. Trials with axokine, a ciliary neurotrophic factor, were discontinued due to the low percentage of responders and to the development of antibodies [6]. Growth hormone (GH) analogues have also been administered to obese subjects in order to normalize GH levels, increase energy expenditure and lipid mobilization as well as to reduce visceral fat stores. Low efcacy of AOD9604 in clinical trials interrupted further trials with GH analogues. Clinical trials with topiramate as a monotherapy conrmed its efcacy in terms of weight loss. However, further work has been stopped because of neurotoxicity and negative effects on cognitive function. Several pharmaceutical companies discontinued clinical trials with cholecystokinin (CCK) agonists [25] and with neuropeptide Y (NPY) antagonists [6] because of a lack of signicant weight reduction. Studies with beta3-adrenoreceptor agonists as the drugs for the treatment of obesity and diabetes started in the 1980s. Experimental results demonstrated that these compounds stimulate thermogenesis and fat oxidation while concomitantly improving insulin sensitivity and preserving fat free mass. However, in spite of enormous effort of multiple pharmaceutical companies and research laboratories, the efcacy and safety of beta3adrenoreceptor agonists in clinical trials have not been proved [26,27].
Copyright 2012 John Wiley & Sons, Ltd.

Anti-obesity drugs used in the past: reduction of abdominal obesity

Anti-obesity drugs used in the past induced weight loss accompanied by a reduction in abdominal obesity and cardiometabolic health risks. Studies on cardiometabolic health risks with orlistat, sibutramine and rimonabant included large cohorts (up to thousands of subjects) while those with other drugs were performed in smaller cohorts. Signicantly greater reduction in waist circumference in comparison with placebo was demonstrated with multiple anti-obesity drugs including dexfenuramine ()10.5 cm versus 5.7 cm) [33], sibutramine ()9.2 cm versus 4.5 cm) [34], orlistat ()5.1 cm versus )3.1 cm) [35], rimonabant ()8.5 cm versus )4.5 cm) [36], diethylpropion ()8.8 cm versus )4.6 cm) [37] and phentermine ()7.3 cm versus 3.3 cm) [38].

Anti-obesity drugs used in the past: improvement in lipid prole

Weight loss induced by anti-obesity drugs has resulted in an improvement in lipid prole. Dexfenuramine treatment induced signicant decreases in cholesterol and triglyceride concentrations in obese subjects [39]. The sibutramine and rimonabant treatment was associated with an increase in high-density lipoprotein (HDL) cholesterol and a decrease in triglycerides [34,40]. The orliDiabetes Metab Res Rev 2012; 28(Suppl 2): 820. DOI: 10.1002/dmrr.2349

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stat administration induced a decline of total and low density-lipoprotein (LDL) cholesterol [35]. An improvement in lipid prole was also shown in trials conducted with drugs indicated for the short-term treatment of obesity such as phentermine [41] and diethylpropion [37].

Anti-obesity drugs used in the past: improvement in glycaemic control

Anti-obesity drugs positively affect glycaemic control in obese diabetic patients. A study conducted in a small cohort of obese patients with type 2 diabetes, who had been poorly controlled by insulin and metformin, revealed a signicant reduction in glycated haemoglobin (HbA1c) level (from 8.5% to 7.1%) after a 12-week treatment with dexfenuramine [42]. Meta-analysis on the efcacy of orlistat and sibutramine in obese patients with type 2 diabetes found modest reductions in HbA1c: )0.4% after orlistat and )0.7% after sibutramine administration [43]. Similarly, a 0.7% reduction in HbA1c levels was observed after rimonobant treatment in metformin- or sulphonylurea-treated overweight obese patients with type 2 diabetes [44]. In addition to the improvement in glycaemic control in obese diabetics, anti-obesity drugs may prevent the development of diabetes in obese patients. The XENical in the prevention of diabetes in obese subjects (XENDOS) study demonstrated that a 4-year treatment of obese patients with orlistat reduced a risk of type 2 diabetes development by 37.3% [45].

during the treatment with sibutramine. This may be due to the simultaneous suppression of sympathetic nervous activity by diet and exercise and or to the clonidine-like effect of sibutramine, which is mediated through activation of central alpha-2 adrenoreceptors [49]. The interaction of the drug-induced noradrenergic stimulation with a suppression of sympathetic nervous activity by lifestyle intervention may be responsible for the recently reported lack of a rise in blood pressure in response to treatment with catecholaminergic anti-obesity agents such as phentermine [38] and diethylpropion [37].

Other benecial effects of the treatment with anti-obesity drugs

Experiences with orlistat and sibutramine in the treatment of obesity and related conditions were reviewed [48,50,51]. In addition to obesity, benecial effects of both drugs in the treatment of non-alcoholic fatty liver disease, polycystic ovary syndrome and binge eating disorder were observed. The treatment with sibutramine was associated with the improvement in eating attitudes determined by the Eating Inventory [52]. Improvement in quality of life was demonstrated after both orlistat [35] and sibutramine treatment [53,54]. Moreover, a systematic review of 14 articles on orlistat (nine studies), sibutramine (four studies) and rimonabant (one study) proved the cost-effectiveness of pharmacological treatment of obesity [55].

Potential novel anti-obesity drugs Anti-obesity drugs used in the past: blood pressure changes
Anti-obesity drugs which do not affect peripheral sympathomimetic activity lead to modest reduction in both systolic and diastolic blood pressure. Meta-analysis of longterm changes in blood pressure in response to orlistat treatment (12 trials including 5540 patients) revealed a decrease in both systolic ()1.9 mmHg) and diastolic ()1.5 mmHg) blood pressure [46]. Similarly, long-term studies with rimonabant (three trials including 2273 patients) demonstrated a reduction in systolic ()1.8 mmHg) and diastolic ()1.2 mmHg) blood pressure [32]. In the subgroup of patients with hypertension at baseline, systolic blood pressure change was )7.5 mmHg for rimonabant-treated patients versus )4.7 mmHg for placebo whereas diastolic blood pressure change was )5.2 versus )3.0 mmHg [47]. On the other hand, in trials with sibutramine (six trials including 1495 patients), a drug which possesses peripheral sympathomimetic activity, a modest increase in systolic (+0.5 mmHg) and diastolic (+1.7 mmHg) blood pressure was observed [46]. However, according to the review of Tziomalos et al. [48], some studies reported no change in blood pressure
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Several recently developed drugs such as cetilistat, lorcaserin, tesofensine, metreleptin, peripheral CB1 antagonists, gut hormone analogues and drug combinations should be taken into account as potential anti-obesity drugs. Cetilistat is a newly developed lipase inhibitor that, in both non-diabetic and diabetic subjects, leads to a weight reduction similar to that observed in orlistat. In contrast to orlistat and placebo, cetilistat exhibits fewer discontinuations due to adverse events and improves glycaemic control [56,57]. More long-term studies on the side effects and efcacy are required. Phase 3 trials are currently being carried out in Japan. Lorcaserin is a novel selective agonist of the serotonin 2C receptor in the hypothalamus and thus acts as an appetite suppressant. Due to its selective mode of action in the CNS, it does not exhibit the negative side effects on heart valves and pulmonary artery pressure that are observed with fenuramine or dexfenuramine administration. Clinical trials showed a reduction in body weight (Table 1) and improvement in cardiovascular risk factors [waist circumference, fasting blood glucose, total cholesterol, LDL cholesterol, triglyceride, homeostatic model assessment (HOMA), high sensitive C-reactive
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protein (hs-CRP) and brinogen]. Recently published results concluded that lorcaserin administered in conjunction with a lifestyle modication programme had been associated with dose-dependent weight loss and had been greater than with placebo [58]. Some side effects such as nausea, headache, dry mouth, dizziness, fatigue, vomiting and urinary tract infection were reported but in general, lorcaserin was well tolerated. In October 2010, the Federal Drug Administration (FDA) rejected its approval due to concerns about a possible link between the drug and mammary tumours in rats. In addition, demonstration of weight loss effects in more diverse patient populations, such as type 2 diabetes mellitus, was requested [59]. Arena Pharmaceuticals, the company which developed the drug, stated that it expects to resubmit the New Drug Application at the end of 2011. Tesofensine is a serotoninnoradrenalinedopamine reuptake inhibitor affecting appetite. Initially, this drug was studied as a potential agent for the treatment of Alzheimers disease and Parkinsons disease but the results were not satisfactory in terms of the treatment of these diseases. However, weight loss was noted as a side effect during the drugs administration. An initial phase 2 trial of tesofensine in the treatment of obesity demonstrated a decrease in hunger, lower food intake and weight loss twice that of currently approved drugs (Table 1) [60]. Patients who received placebo and lifestyle modication lost an average 2.0% of their initial weight whereas those treated with tesofensine 0.5 mg day lost 9.2% and with a dose of 1.0 mg day lost 10% of their baseline weight. A moderate increase in energy expenditure at night and in 24 h fat oxidation rate may contribute to a negative energy balance and a large weight loss after tesofensine [61]. Tesofensine administration favourably affected abdominal obesity, lipid prole, adiponectin and insulin levels and HbA1C. Tesofensine-related side effects included dry mouth, insomnia, constipation and nausea. The administration of tesofensine was not accompanied by any psychiatric adverse events such as depression or anxiety. However, an increase in pulse rate and a small increase in blood pressure at the highest dose should be seriously considered in future clinical studies. The company that developed tesofensine (NeuroSearch A S) is now seeking a partner to help with subsequent clinical trials that are required by the drug regulatory agencies. Metreleptin represents a recombinant leptin. Its daily administration has been proved to be an efcient treatment for the rare monogenic obesity caused by leptin gene mutation leading to leptin deciency [62]. However, patients with common obesities exhibit hyperleptinaemia compared with normal weight subjects. The treatment of weight loss-induced relative leptin deciency, described in some individuals with common obesities, with low-dose recombinant leptin should be further investigated [63]. Melanocortin 4 receptor (MC4R) agonists: MC4R gene mutations are the most common forms of monogenic
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obesities with a frequency of 0.56.0% in individuals with early-onset obesity. Several MC4R agonists have already been synthesized [64]. Two of these were able to activate mutated human MC4R with impaired endogenous agonist response [65]. First clinical trials with these compounds have recently been initiated. Peripheral CB1 antagonists: Favourable metabolic consequences of the obesity treatment by blockage of CB1 receptors were partly caused by its direct effects in the peripheral tissues, which included reduced lipogenesis in adipose tissue and liver, increased adiponectin secretion by adipocytes and glucose uptake in muscle cells. New peripherally acting CB1 antagonists which do not cross the bloodbrain barrier and thus are devoid of CNSrelated anxiety and depression while retaining their benecial metabolic effects in peripheral tissues have recently been developed [66]. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have initially been investigated as a new class of oral antidiabetic drugs [67,68]. SGLT2 is a low-afnity transport system that is specically expressed in the kidney. Blocking SGLT2 decreases reabsorption of glucose and sodium in the renal proximal tubule which results in increased diuresis, enhanced glucose and energy loss with subsequent reduction in blood glucose and body weight [69]. In response to the weight reduction observed in the studies performed in patients with diabetes, several SGLT2 inhibitors are now undergoing clinical trials for their potential use in the treatment of obesity. However, the efcacy as well as safety issues, concerning mainly the development of urinary tract infection and fungal genitourinary infections, in patients treated with SGLT2 inhibitors should be further investigated in larger cohorts. 11beta hydroxysteroid dehydrogenase type 1 (11betaHSD1) inhibitors selectively inhibit intracellular conversion of cortisone to cortisol. An increased activity of 11beta-HSD1 is associated with the development of abdominal obesity, type 2 diabetes and metabolic syndrome. Experimental studies demonstrated an improvement in metabolic prole after administration of 11beta-HSD1 inhibitors in rodents [70]. Pilot short-term clinical trials with a novel 11beta-HSD1 inhibitor conducted in diabetic patients showed a dose-dependent weight loss, reduction in fasting plasma glucose as well as an improvement in insulin sensitivity, lipid prole and blood pressure [71].

Gut hormones
Most of the centrally acting anti-obesity drugs in the past affected nonspecic neurotransmitter pathways and thus exhibited multiple adverse events. On the contrary, gut hormones, which affect specically food intake and energy homeostasis, represent new opportunities for the development of anti-obesity drugs which may have relatively few nonspecic side effects compared with centrally acting drugs [72]. Several gut hormones such as glucagon-like peptide-1 (GLP-1), amylin, oxyntomodulin,
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pancreatic polypeptide, CCK and ghrelin have been investigated as potential peripheral targets in the development of novel anti-obesity drugs. GLP-1 analogues are the most promising and advanced targets. GLP-1 is synthesized by intestinal L-cells and its receptors are in both the CNS and peripheral tissues. It plays a role in meal termination and possibly satiety. Dose-dependent reduction in food intake in animals and lean and obese humans has been shown. Exenatide (Byetta), a short half-life of native GLP-1 analogue, is already on the market as an adjunct to current diabetes therapies. It improves glycaemic control and leads to weight reduction [73]. Nausea represents the most frequent side effect. In some patients, antibodies against this agent can develop and sometimes may lead to reduced efcacy. Another disadvantage of this drug is the necessity of twice-daily subcutaneous administration. A once-weekly injected drug called exenatide LAR is currently under development and has similar side effects. Another GLP-1 analogue, liraglutide (Victoza), has already been approved for the treatment of type 2 diabetes. When injected daily in type 2 diabetics it had a positive effect on fasting plasma glucose, HbA1c, body weight and systolic blood pressure [74]. A 20-week trial of liraglutide in the treatment of obesity had better outcome in relation to body weight, waist circumference and blood pressure than placebo and orlistat [75]. Nausea and vomiting were transient side effects which rarely led to a discontinuation. The disadvantage is the injectable form of the drug. A recent study showed that liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors [76]. Patients who completed the 2-year study with liraglutide in a dose of 2.4 3.0 mg maintained a 2-year weight loss of 7.8 kg from the baseline [76]. The study revealed that an administration of liraglutide 2.4 3.0 mg prevents the development of prediabetes and metabolic syndrome. Their prevalence at 2-year follow-up decreased by 52% in prediabetec subjects and by 59% in subjects with metabolic syndrome. Long-acting oral GLP-1 analogue is under development and a phase I trial started in 2010. Pramlintide is a synthetic amylin analogue. Amylin is a peptide of 37 amino acids co-secreted with insulin by the endocrine pancreas [77,78]. Its primary site of action is the brainstem. The physiological effects of amylin receptor agonism include decreased food intake, slowing of the rate of gastric emptying and reduction in postprandial glucagon release in a glucose-dependent manner [79]. Pramlintide acetate, an analogue of the pancreatic hormone amylin, was originally developed for diabetes and is now available in the United States as an injectable antihyperglycaemic drug. It was found that pramlintide reduces appetite, food intake, enhances satiety and delays gastrointestinal motility. Clinical trials assessing the use of pramlintide for weight loss in obese patients without type 2 diabetes revealed weight loss of up to 8 kg after 1 year [80,81]. The most common side effect observed with pramlintide administration was
Copyright 2012 John Wiley & Sons, Ltd.

mild to moderate nausea, which decreased over time [81]. The development of the second generation amylin analogue as davalintide was discontinued because of antibody formation. PYY analogues: Peptide YY3-36 is a 36-amino acid polypeptide synthesized by entero-endocrine cells of L-type, mainly in the distal gut which slows gastric emptying via Y2-receptor and modulates energy expenditure and fuel portioning. Its peripheral administration causes a reduction in food intake in rodents and humans [82]. In 2008, trials with nasal spray PYY3-36 were stopped as the obtained results did not meet the primary endpoints [83]. However, recent experimental studies pointed out to the role of PYY3-36 in food intake regulation after roux-en-Y gastric bypass surgery and a potential therapy with pharmacological doses of PYY3-36 in patients with insufcient weight loss or weight regain after bariatric surgery [84]. Pancreatic polypeptide (PP) is a 36-amino acid peptide secreted by the pancreas and colon. It has highest afnity to Y4 receptors and reduces food intake by inducing satiety. TM-30339 induced weight loss in mice and good safety and tolerability was reported. However, gastrointestinal discomfort appeared. Dual analogue of PP and PYY, obinepitide, with agonist activity both for Y2 and Y4 receptors induced greater weight loss in mice and is now in phase I II clinical trials. A daily subcutaneous administration in obese subjects inhibited food intake [6]. Oxyntomodulin (OXM) is co-secreted with PYY3-36 from intestinal L-cells and contains 37 amino acids. It binds to three different receptors (specic OXM receptor, GLP-1 receptor and glucagon receptor) in the hypothalamus and inhibits food intake. After 4 weeks of subcutaneous OXM administration to obese individuals, an average weight loss of 2.3 kg was observed versus 0.5 kg with administration of placebo [77]. Recently co-administration of oxyntomodulin and PYY3-36 has been studied in overweight and obese humans. It was shown to be additive in terms of food intake, leading to a reduction in energy intake by 42% in comparison with the saline control [85]. Further studies are required to prove gut hormone combination as a useful strategy for the treatment of obesity. CCK-1 agonists: CCK is secreted by I-cells in the intestine and satiety is mediated by CCK1 receptors [77]. CCK affects more satiation than satiety. This mode of action could lead to compensation through increasing frequency of food consumption. Because of nonsignicant weight loss, several pharmaceutical companies discontinued the development of CCK agonists as antiobesity drugs after phase II of clinical trials. A recently discovered orally active, gut-selective CCK1 receptor agonist reduces food intake in rodents with minimal systemic exposure [86]. Ghrelin is a 28-amino acid polypeptide secreted by the stomach which stimulates eating, increases food intake and activates reward-seeking circuits [87]. Several ghrelin receptor blockers (GHS-R 1a) were synthesized but did not reach the clinical phase of investigation. Similarly, an anti-ghrelin vaccine has been introduced so far only in animal experiments [88].
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Do we need anti-obesity drugs?

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Hormonal treatment of visceral obesity

Pioneering studies on the neuroendocrine abnormalities in visceral obesity were conducted by P. Bjo rntorps group in Gothenburg. In addition to perturbation of the hypothalamic-pituitary-adrenal axis, the role of suppressed GH and testosterone secretion in the accumulation of visceral fat was highlighted [89]. New perspectives on testosterone treatment of visceral obesity and metabolic syndrome have recently been reviewed [90]. While the clinical trials with GH analogue in the treatment of obesity were discontinued due to the adverse events, the recently developed growth hormonereleasing hormone analogue, tesamorelin, was shown to reduce visceral adipose tissue and to improve lipid prole without deteriorating glucose parameters in human immunodeciency virus (HIV)-infected patients with excess abdominal fat [91]. In November 2010, tesamorelin was approved by the US FDA for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy [92]. To date, no trials with tesamorelin have been conducted in the treatment of common obesities associated with enlarged abdominal fat stores.

Combination drugs: past and future

Combination therapy was introduced for the treatment of obesity many years ago aiming to increase both safety and efcacy of the treatment with combined administration of two drugs in decreased doses. This philosophy in terms of weight loss was approved by several clinical trials with combination drugs. As shown in Table 1, administration of combination drugs is associated with a greater weight loss when compared with the monotherapy with anti-obesity agents. The most common drug combinations used in the past for the treatment of obesity were ephedrine caffeine mixture and fenuramine phentermine combination. Ephedrine caffeine mixture was effective in improving and maintaining weight loss and preserving fat free mass [93]. However, its cardioexcitatory and psychostimulatory side effects led to the withdrawal of this combination from the market in most countries. Recently, a successful treatment of the rare hypothalamic obesity with ephedrine caffeine mixture was reported in three case studies [94]. Fenuramine phentermine combination (Fen Phen) due to its efcacy in terms of weight loss became (Table 1) [95] widely prescribed drug and achieved over 18 million prescriptions in the United States in 1996. Later on, it was withdrawn from the market because of an increased risk of valvular heart disease [96]. In this case, the serotonin-releasing effect of dexfenuramine was potentiated by phentermine, a drug which suppresses the clearance of serotonin [97]. As a result, the valvular damage similar to that seen in patients with the
Copyright 2012 John Wiley & Sons, Ltd.

carcinoid syndrome was described after Fen Phen administration. Fen Phen experience demonstrated that special attention should be paid not only to the benecial effects of drug combination but also to a possible potentiating of side effects. Bupropion SR naltrexone SR combination (CONTRAVER) represents a combination of two already existing medications naltrexone and bupropion in their sustained released forms. Naltrexone, a pure opioid antagonist, is a synthetic relative of oxymorphone and naloxone. Bupropion, an antidepressant of the aminoketone class, is a dopamine and noradrenaline reuptake inhibitor which stimulates melanocortin pathways. Its administration leads to a loss of appetite and a decrease in food intake. The mechanism by which the combination induces weight loss is not entirely understood. The hypothalamic melanocortin pathways and the mesolimbic reward system are the target of this combination. Bupropion stimulates the proopiomelanocortin neurones, whereas naltrexone blocks the autoinhibitory feedback that is associated with a decline in weight reduction [59]. The 32 mg naltrexone and 400 mg bupropion showed the best benet to risk ratio. Patients receiving bupropion SR/naltrexone SR combination showed weight loss and improvements in cardiometabolic risk factors (waist circumference, hs-CRP, HDL-cholesterol) and has been especially found to be benecial in obese persons with diabetes and major depression [59]. Two 56-week multicentre, randomized, double-blind, placebo-controlled trials of this drug combination were conducted. In the Greenway trial [98], 870 subjects completed the programme which apart from the drug therapy consisted of a mild hypocaloric diet and an exercise programme. The Wadden study included 793 patients in whom an intensive programme of behaviour modication had also been prescribed [99]. Participants receiving naltrexone SR 32 mg lost more weight than the subjects on the 16 mg dosage. Both studies have shown benets of greater body weight reduction with the drug-treated patients when compared with those treated with dietary changes or behaviour therapy alone (Table 1). Improvements in cardiometabolic risk factors after bupropion naltrexone administration were clearly demonstrated, e.g. a decrease in waist circumference, insulin resistance and improvement in lipid prole. This combination reduced hunger, and led to greater control over eating and food craving. At the end of both studies, an overall decrease in systolic blood pressure from baseline was reported. The drug was generally well tolerated. The most common adverse events were nausea, constipation, headache, vomiting, dry mouth and dizziness and mostly occurred during the rst weeks of treatment. In treated patients, no associations with depression or suicidal ideation were reported. Several clinical trials (COR-I, COR-II, COR-Diabetes, COR-BMOD) including 4500 patients in the phase 3 testing demonstrated the effectiveness of bupropion nalterexone combination in terms of weight loss and improvement in cardiometabolic health risks. In spite of
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V. Hainer and I. A. Hainerova

that, in February 2011, the FDA declined its approval due to concerns about the long-term cardiovascular safety in overweight and obese subjects. According to the announcement from June 2011, Orexigen Therapeutics, a company producing bupropion SR naltrexone SR combination (ContraveR), feels that the demands raised by the FDA for further cardiovascular risk studies are unrealistic and is open to possible opportunities for its anti-obesity drug outside the United States. Phentermine CR Topiramate CR combination (QnexaR) combines already two separate existing medications topiramate and phentermine. Topiramate is a gamma-aminobutyric acid (GABA) agonist and has been used as an anticonvulsant, antidepressant and to treat migraine headaches. Phentermine is approved in the United States as a short-term treatment for weight loss (recommended dose 37.5 mg day) and topiramate is registered for treatment of seizures (400 mg day) or migraine headache prevention (100 mg). Topiramate has anti-craving and weight loss effect. The mechanism is still unknown. In the combination it is possible to use a lower dose due to its slow-release effect which leads to fewer side effects. In recent clinical trials, with topiramate phentermine combination in addition to weight loss, a reduction in blood pressure, and improvement in lipid prole was described. In a study of Gadde et al., which included 2487 patients, a mean weight loss of 10.2, 8.1 and 1.4 kg was achieved with phentermine 15.0 mg topiramate 92.0 mg, phentermine 7.5 mg topiramate 46.0 mg, and placebo respectively [100]. Reduction in waist circumference, diastolic blood pressure, benecial effect on triglyceride and HbA1c levels and improvement in sleep apnoea were demonstrated in subsequent clinical trials. Recent studies reported improvements in liver function and signicant reductions in the use of concomitant medications for cardiometabolic diseases in phentermine CR topiramate CR-treated patients [101,102]. No major adverse events were observed. The most common side effects were dry mouth, paresthesia, constipation, insomnia, dizziness and dysgeusia. In October 2010, the FDA rejected its approval due to a potential association with birth defects, heart and psychiatric problems [59]. Vivus Inc, a company which developed phentermine topimarate combination, reanalysed the results of a 2-year study which demonstrated the medications safety. No suicidal thoughts and no adverse effects on the heart were shown. Issues concerning cognitive memory, sleep and depression were actually less common during the second year of treatment. No birth defects were found in newborns of the 15 women who have given birth while previously taking part in trials with the phentermine CR topiramate CR combination. In response to the arguments on the drug safety, in February 2012 the FDAs advisory group voted in favour of its approval by 202. However, the FDA should decide if they take into account this advice and approve Qnexa on 17 April 2012. The integrated neurohormonal approach to the treatment of obesity involves a complex interplay between leptin as a long-term adiposity signal and amylin as a
Copyright 2012 John Wiley & Sons, Ltd.

short-term satiation signal. Treatment with amylin leptin (pramlintide metreleptin) combination over a 20-week period led to signicantly greater weight loss than treatment with pramlintide or metreleptin alone [103]. In addition, pramlintide metreleptin combination reduced levels of triglycerides ()8%), total cholesterol ()9%), LDL cholesterol ()8%), fasting blood glucose ()4 mg dl), insulin ()22%) and decreased insulin resistance, HOMA index by 25% [103]. Transient mild nausea and injection site problems were reported as adverse events [103]. However, the formation of antibodies set aside further studies with this combination. The amylin analogue pramlintide in combination with either phentermine or sibutramine leads to a weight loss at 24 weeks with either combination treatment [104] (Table 1). The weight loss was greater than with pramlintide alone or with placebo. In both combination groups, elevations of heart rate and diastolic blood pressure from baseline were demonstrated. However, the majority of patients receiving these treatments remained within normal blood pressure ranges [104]. Bupropion SR zonisamide SR combination (EmpaticR) includes two already approved medications in sustained released forms an antidepressant bupropion and an anticonvulsant zonisamide. Zonisamide acts as a GABA receptor activator. Bupropion zonisamide inuences energy balance through an effect in the hypothalamus. Only preliminary studies with bupropion zonisamide have been reported [105]. It induced greater weight loss than either drug alone or than the combination of bupropion and naltrexone. The mechanism is not fully understood but is probably due to the effect on GABA, serotonin and dopamine-regulated processes. During an early stage study of 729 obese subjects tested over a 24week period, nearly three quarters of the patients lost at least 5% of their body weight and nearly half of them lost at least 10% of their weight. Insomnia, headache and nausea are the common side effects reported in some patients on this combination. No serious unfavourable adverse events have been reported. The results of the phase 3 trials in larger groups of patients are expected in the near future.

New targets in the drug treatment of obesity

Aiming at less common potential causes of obesity may represent new challenges in the treatment of obesity. It has been demonstrated that reduced sleep duration [106], adenovirus infection [107], high titres of anti-MC4R antibodies [108], etc. are associated with obesity. It should be evaluated if some cases of obesity could be treated with specic hypnotics, antivirotic agents or drugs modulating autoimmune response. An intestinal microbiota has also been thought as a future target for weight management by a selective modulation of the intestinal microora [109,110].
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Do we need anti-obesity drugs?

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We do need anti-obesity drugs

We have to take into account that the treatment of obesity is an efcient tool in the prevention of multiple co-morbidities such as cardiovascular diseases, diabetes and certain cancers. According to Willett, the inherent problem is that most pharmacological strategies do not address the underlying causes of ill health in Western countries, which are not drug deciencies. An effective pharmacological treatment of obesity may be an exception because the adverse health consequences are so numerous and the condition being overweight has become the norm [111]. It has been clearly demonstrated that the drugs used in the treatment of obesity in the past as well as novel compounds recently tested in clinical trials provide additional weight loss and reduction in cardiometabolic health risks compared to that obtained by a lifestyle modication alone. In addition, studies of several drugs (sibutramine, exenatide, orlistat, rimonabant and lorcaserin) have shown that discontinuation of their administration or replacement with placebo had been followed by weight regain [34,73,112114]. Gut hormone analogues and combination drugs represent promising antiobesity agents both with regard to their efcacy and safety. However, a perspective for the treatment by antiobesity drugs will require changes in the attitudes of doctors, health authorities, drug-regulating agencies and the general public towards obesity. Obesity should be handled as other complex diseases, e.g. hypertension. Important hereditary components in the pathogenesis of obesity must be considered and obesity cannot be accepted as an entirely lifestyle disease. Lifelong administration of anti-obesity drugs normalizing regulatory and or metabolic abnormalities coupled with obesity should be expected in future. Thus, further studies assessing the effects of anti-obesity drugs on morbidity and mortality endpoints in appropriate target subjects will be required in future. Nevertheless, these require-

ments cannot lead to unrealistic demands by the drug regulating agencies with regard to approval of the new anti-obesity drugs. Although pharmacotherapy of obesity was considered as a rapidly moving discipline a couple of years ago, its perspective could be seriously hindered by recent rejections of approval of new anti-obesity medications by the FDA. For the future, we have to implement an efcient multilevel obesity management network which should ensure a way to get the right anti-obesity drugs into the hands of the right, well-educated doctors who will be responsible for appropriate prescriptions in the indicated patients [115].

Addenum
This year the U.S. Food and Drug Administration approved two novel antiobesity drugs for the treatment of obesity in adults. Lorcaserin (BelviqR) was approved on June 27 and phentermine/topiramate combination (QsymiaR) on July 17.

Acknowledgements
The manuscript was supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00023761 (Institute of Endocrinology, Prague, Czech Republic) and the Czech research project of MSM VZ No. 0021620814.

Conicts of interest
V. H. participated as an investigator in the SCOUT Study supported by the Abbott Laboratories. No other potential conicts of interest relevant to this article were reported.

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