clinical obesity

doi: 10.1111/cob.12064

Review

New molecular targets in the pathophysiology of obesity and available treatment options under investigation G. Valsamakis1,2, K. Lois1,2, S. Kumar2 and G. Mastorakos1

1

Endocrine Unit, 2nd Department of Obs and

Gynae, Areteeion University Hospital, Athens Medical School National and Kapodistrian University of Athens, Athens, Greece; 2

WISDEM Centre for Diabetes, Endocrinology

and Metabolism, Warwick Medical School, University of Warwick, Coventry, UK

Received 26 August 2013; revised 12 May 2014; accepted 14 May 2014

Address for correspondence: Dr Georgios Valsamakis, 2nd Department Obs and Gynae, Endocrine Unit, Areteion University Hospital, 37A Leoforos Pendelis Ave, Vrilissia/Athens 15235, Greece. E-mail: [email protected]

Summary The pharmacotherapy of obesity has historically recorded an overall poor safety and efficacy profile largely because of the complex mechanisms involved in the pathophysiology of obesity. It is hoped that a better understanding of the regulation of body weight will lead us to the development of effective and safer drugs. Recent advances in our understanding of the regulation of energy homeostasis has allowed the design of novel anti-obesity drugs targeting specific molecules crucial for the modulation of energy balance, including drugs that induce satiety, modulate nutrient absorption or influence metabolism or lipogenesis. Almost a decade after the Food and Drug Administration approved the first weight loss medication, it recently approved two novel anti-obesity drugs Belviq (lorcaserin) and Qsymia (topiramate and phentermine), thus signalling the beginning of a new era in the pharmacotherapy of obesity. It is believed that the next generation of weight-loss drugs will be based on combination treatments with gut hormones in a manner that mimics the changes underlying surgically induced weight loss thus introducing the so called ‘bariatric pharmacotherapy’. An in-depth understanding of the interrelated physiological and behavioural effects of these new molecules together with the development of new treatment paradigms is needed so that future disappointments in the field of obesity pharmacotherapy may be avoided. Keywords: Molecules, pharmacotherapy, obesity.

Introduction The need for better comprehension of the new molecular targets in obesity The Food and Drug Administration (FDA) of the United States has announced that today 30% of US citizens are obese and 64% are overweight with the rates of overweight children and adolescents having doubled compared with two decades ago (1). It is now well established that obesity is a multifactorial and chronic disease with significant comorbidities and that it is caused by an imbalance © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

between energy intake and expenditure. The mechanisms that regulate energy balance are influenced by other physiological functions, such as mood, memory, sexual behaviour and learning (2). Thus the ideal anti-obesity drugs would be expected to produce sustained weight loss with minimal side effects. The strict safety and efficacy standards established by the FDA for the development of anti-obesity pharmacotherapeutics require trials of ≥1 year duration and the inclusion >4500 subjects (3000 subjects randomized to active doses of the product and no fewer than 1500 subjects randomized to placebo) plus at least 5% reduction in weight over a year (1) with no associated 209

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Table 1 Anti-obesity drugs in progress

Drug

Drug description

Company

Metreleptin Pramlintide PTP1B blocker PBA TUDCA BMS-830216 Lorcaserin (Belviq) Bupropion

Leptin analogue Amylin analog Leptin sensitizer Leptin sensitizer Leptin sensitizer MCH antagonist 5-HT2C receptor agonists Dopamine and norepinephrine-reuptake inhibitor Serotonin-receptor agonist and dopamine-reuptake inhibitor GABA inhibitor Y5-receptor antagonist Y2/Y4-receptor agonist Y4-receptor agonist CCK1R agonist GLP1R agonist GLP1R agonist GLP1R agonist GLP1R agonist GLP1R agonist GLP1R agonist Y2R agonist GLP1R agonist Ghrelin vaccine Ghrelin inhibitors

Bristol-Myers-Squibb/Astra Zeneca Amylin Pharmaceuticals, Inc.

Zonisamide Topiramate S-2367 Obinepitide TM30339 GI181771X Lixisenatide CJC-1134-PC Albiglutide Taspoglutide LY2189265 Liraglutide PYY3–36 Oxyntomodulin NOX-B11 GOAT inhibitors ATL-962 (Cetilistat) Beloranib AOD-9604 T-BVT SRT1720

Selective methionine aminopeptidase 2 (MetAP2) inhibitor GH lipolytic domain analogue White adipose tissue selective 11β-HSD1 inhibitor SIRT1 activators

Bristol-Myers Squibb Arena Pharmaceuticals

Shionogi USA, Inc 7TM Pharma 7TM Pharma GSK Zealand Pharma ConjuChem Biotechnologies Inc. GSK Roche Eli Lilly NovoNordisk

Pfizer Alizyme Zafgen Inc Phosphagenics

serious side effects that would put patients’ health at risk. The standards, however, have led to the rejection of several weight-loss drugs including fenfluramine/dexfenfluramine, rimonabant, sibutramine, and more recently, the bupropion/naltrexone combination. There have, however, been considerable gains in our knowledge about the energy homeostasis system. Notably, greater insight into the manner in which information about energy reserve status as well as meal quality and content is relayed from the periphery (gastrointestinal tract, pancreas and adipose tissue) via specific orexigenic and anorexigenic peptides and hormones to the central nervous system (CNS), which in turn drives feeding behaviour according to energy requirements, has enabled the pinpointing of effective molecular targets for novel anti-obesity drugs (Table 1). On the other hand, experience from previous agents has shown that medications that target only one mechanism in some cases have inadequate efficacy, while in others, sustained weight loss of 5–10% was not sufficient to persuade patients or prescribers to continue long-term medication (3). One of the challenges in obesity manage-

ment is the need to improve understanding of the mode of action and behavioural effects of each molecule-target and explore its combined role with other molecules within the human homeostatic system. Thus, the pharmaceutical resolution of obesity appears to lie in combination treatments with agents that will target different molecules of the energy homeostasis system, will have an additive effect on weight loss and will match the patient’s metabolic needs while concurrently producing a beneficial side effect profile.

New molecular targets Centrally acting anti-obesity drugs and modulators of monoamine neurotransmission Leptin, leptin analogues and leptin sensitizers Leptin is a protein primarily secreted by adipose tissue. It directly stimulates the anorexigenic proopiomelanocortin (POMC) neurons and inhibits the orexigenic neuropeptide Y (NPY) neurons in the arcuate nucleus (ARC) of the hypothalamus, thereby promoting satiety and weight loss © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

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(4). Studies with congenitally leptin-deficient obese subjects revealed that leptin administration at physiological doses dramatically decreases food intake and body weight (5). It was shown that leptin’s circulating levels drop following body weight reduction (6), the latter might be implicated in energy expenditure reduction (specifically non-resting) seen after weight loss (7). Based on these findings, restoration of leptin concentrations to pre-weight loss concentrations, via administration of metreleptin (leptin analogue), mitigated weight-loss counter-regulation (8,9). Thus, there appears to be a potential role for leptin as an adjuvant therapy to a primary weight loss agent to achieve maintenance of weight loss by countering the energy expenditure reduction seen after body weight reduction. Obese individuals seem to be leptin-resistant. Whether administration of leptin could overcome leptin resistance and exert an anti-obesity effect was tested in a placebocontrolled study with obese individuals given varying doses of recombinant human leptin (0.03 mg kg−1 and 0.30 mg kg−1, respectively) for 24 weeks and advised to eat per day 500 kcal less than the daily requirement. A dosedependent decrease in body weight was shown, ranging from −1.3 kg in the placebo group to −7.1 kg in the 0.30 mg kg−1 recombinant human leptin-treated group (P = 0.01) (10). In another randomized, double-blind, placebo-controlled, multicentre study with 284 overweight and obese subjects, recombinant leptin was administered by subcutaneous injection (10 mg twice daily), however, no statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo in any group (11). The modest effects of leptin treatment are likely due to the presence of leptin resistance for which several mechanisms have been proposed (12–14). Whether these anti-obesity effects, which need to be investigated in more extensive human studies, can be sustained is still not clear. Recently, leptin-sensitizing effects were attributed to pramlintide, a synthetic analogue of the pancreatic peptide hormone amylin. The anti-obesity properties of the combined treatment with pramlintide and the human hormone leptin analogue metreleptin (pramlintide/metreleptin) were therefore tested: they showed a significant weight reduction of 12.7 ± 0.9% (11.5 ± 0.9 kg), significantly more was observed with either treatment alone (P < 0.01), without obese patients reaching a weight plateau during a 20-week trial period. The study was extended to 28 and 52 weeks (phase II extension study) (15,16) demonstrating that subjects receiving pramlintide/metreleptin continued to lose weight until the end of the study compared with those treated with pramlintide alone, whose weight loss had stabilized towards the end of the 28-week study. The magnitude of weight loss was dosage- and body mass indexdependent as patients with a starting body mass index < 35 kg m−2 experienced the best weight loss result of the combined treatment. Another 24-week, randomized, © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

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double-blind, active-drug-controlled, proof-of-concept study was conducted in obese or overweight subjects. In the latter, combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (−12.7 +/− 0.9%; least squares mean +/− standard error) than treatment with pramlintide (−8.4 +/− 0.9%; P < 0.001) or metreleptin (−8.2 +/− 1.3%; P < 0.01) alone (evaluable, n = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/ metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time (17). However, although the pramlintide/metreleptin combination seemed to be the next promising anti-obesity drug to be marketed, Amylin Pharmaceuticals, Inc. and Takeda Pharmaceutical Company Limited discontinued its development (18). The main reason cited was that it did not work in modestly obese subjects, this possibly because of neutralizing antibody formation (19). Subtype-selective serotonin-receptor agonists – other neuropeptide modulators Central serotonin (5-HT) levels participate in feeding behaviour and energy balance modulation, and two selective serotonin reuptake inhibitors, fluoxetine and sertraline, induce weight loss in obese subjects (20,21). Serotonin enhances satiety signals and suppresses hunger by acting on 5-HT2c and 5-HT1B receptors located on hypothalamic POMC and NPY neurons. The 5HT2c receptor has arisen as a potential target for anti-obesity therapeutic intervention, but among several potent and selective 5-HT2c receptor agonists only, lorcaserin (ADP356) (22,23) has moved to ‘full’ clinical testing. The Lorcaserin Phase III programme (BLOSSOM, BLOOM and BLOOM-DM [Diabetes Management]) showed that 47.2% of patients treated with lorcaserin 10 mg twice daily lost at least 5% of their body weight compared with 25% of the placebo group. Their average weight loss achieved with lorcaserin after a year was 5.9% (12.7 lbs) compared to 2.8% (6.3 lbs) with placebo. Patients who stopped the drug after 1 year regained the weight. Anxiety, memory impairment, confusion, dizziness, depression, cough, headaches, nausea, constipation, blurred vision, cold sweats, bladder pain and increased heart rate are the most common side effects reported (23,24). The FDA has recently approved lorcaserin (Belviq), as an addition to a reduced-calorie diet and exercise, for use in chronic weight control (25). On the other hand, the European Medicines Agency in its assessment concluded that although a modest benefit in terms of weight loss was seen, there were safety concerns about the potential risks of tumours (with long-term use), valvulopathy and depression. The Committee for Medicinal Products for Human Use (CHMP) was of the opinion

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that the benefits of Belviq did not outweigh its risks. After this, the company stated that it would not be able to address all of the CHMP’s concerns within the timetable for the application and decided to withdraw its application (26). Topiramate and phentermine Topiramate is an anticonvulsant agent with weight loss properties (27). It has multiple effects on the CNS including action on γ-amino butyric acid systems causing appetite suppression (28). A 6-month dose-ranging study in obese human subjects investigating its anti-obesity efficacy at doses of 64, 96, 192 and 384 mg per day concluded that all doses produced significantly greater weight loss compared with placebo, and that weight loss of the 192 mg per daytreated group was similar to that of the 384 mg per day-treated group. Meanwhile in another randomized, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192 and 256 mg per day at 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192 and 256 mg per day treatment groups lost 7.0, 9.1 and 9.7%, respectively (29,30). This is important as topiramate has been associated with suicidality, metabolic acidosis, acute myopia and secondary angle closure glaucoma when administered at high doses (of 192 mg per day or more) (31). Furthermore, the UK Epilepsy and Pregnancy Register reported an increased prevalence of oral clefts (3.2%) among infants exposed to topiramate monotherapy and a 16-fold increase in risk compared with the risk in their background population (0.2%) (32). This resulted in a safety announcement being issued by the FDA that if the decision is made to use topiramate in women of childbearing age, effective birth control and a negative pregnancy test should be used before each prescription (33). Topiramate was also effective in reducing body weight in obese patients with binge eating disorders (mean weight loss 5.9 kg) and was associated not only with significantly greater reductions in binge frequency (topiramate: 94%, placebo: 46%) but also in improving blood pressure and glucose tolerance further to reducing body weight (P < 0.001) in obese subjects with cardiovascular comorbidities (34,35). An assessment has been made of the weight loss efficacy of topiramate (at doses of 46 and 92 mg which are lower than those usually associated with side effects) in combination with phentermine (an amphetamine derivative with central anorectic effects currently used in the United States for short-term treatment of obesity) in a special controlledrelease formulation has been estimated in obese and morbidly obese individuals. The results of the three phase III studies were as follows (i) CONQUER: a randomized, placebo-controlled study: at 56 weeks change in body weight was −1.4 kg, −8.1 kg P < 0·0001, and −10.2 kg,

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P < 0·0001 in the patients assigned to placebo, phentermine 7.5 mg plus topiramate 46.0 mg and phentermine 15.0 mg plus topiramate 92.0 mg, respectively. (ii) EQUATE: a trial that evaluated weight loss achieved with two doses of Qsymia (topiramate/phentermine) vs. that achieved with placebo among 756 patients over 28 weeks. Patients taking full-dose and mid-dose Qsymia achieved an average weight loss of 9.2% and 8.5%, respectively, as compared with 1.7% reported for the placebo group. (iii) EQUIP: a study that found that at 56 weeks, in addition to an average weight loss of 14.4% of initial body weight among those who completed the study at the top dose of Qsymia, severely obese patients had improvements in blood pressure, glucose, triglycerides and cholesterol (36,37). The anti-obesity drug Qsymia suppresses appetite and reduces body weight in a dose-dependent manner at the cost of increased frequency and severity of side effects (e.g. depression, anxiety, sleep disorders, headaches, constipation, increased heart rate, sometimes disturbances in attention, amnesia and memory impairment) when the high dose of topiramate was used. Furthermore, teratogenicity is a safety concern with regard to phentermine/topiramate (38). Based on these findings, the FDA initially rejected Qsymia (39). The medication was, however, recently approved, thus constituting the second diet drug approved in 2012. In February 2013, the European Medicines Agency’s CHMP confirmed its decision to decline the Marketing Authorization Application for Qsymia (phentermine/topiramate Extended Release) for the treatment of obesity in the European Union. In view of its effect on increasing heart rate, CHMP indicated that a preapproval cardiovascular outcomes trial would be necessary to establish long-term safety (40). Neuropeptide Y inhibitors The ARC-located NPY neurons inhibit the anorexigenic POMC neurons (via NPY Y1 and Y5 receptors) and stimulate the release of the orexigenic neuropeptides orexin and Melanin Concentrating Hormone (MCH) in the Lateral Hypothalamic Area (LHA), thus promoting food intake (41). Pharmacologic blockade or genetic deletion of the Y1 and Y5 receptors reduced food intake and weight in animal studies. However, NPY is the most abundant central neuropeptide and regulates many functions beyond feeding (42) thus targeting NPY neurons/Y receptors particularly for obesity is not easy. In addition, human studies investigating the Y5-receptor antagonist MK-0577 failed to find any significant weight loss in a 1-year clinical trial (43) while the selective Y5-receptor antagonist S-2367 (Shionogi USA, Inc., New Jersey, USA) induced a mean placebo-adjusted weight loss of just 3% over 54 weeks of therapy (44). Possibly, the combined Y1/Y5-receptor antagonism may prove more effective although we are not aware of any Y1/Y5-receptor antagonist in development to date. While Y1 and Y5 are the targets of the orexigenic © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

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NPY, the Y2 and Y4 receptors are the targets of the satiety hormones peptide YY (PYY) and pancreatic polypeptide, respectively. Preliminary data from phase I and II clinical trials with a Y2/Y4-receptor agonist (obinepitide; 7TM Pharma, Horsholm, Denmark) and a selective Y4-receptor agonist (TM30339; 7TM Pharma) are quite promising as regards their weight loss efficacy (45,46). Naltrexone/bupropion This is an oral, sustained-release combination (Contrave) consisting of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. The mechanism of action of the compound involves complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite (47). Initially, Contrave was not approved by the FDA, which requested a randomized, double-blind, placebo-controlled trial to demonstrate that the risk of major adverse cardiovascular events in obese and overweight subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile. Further cardiovascular risk data are pending and are currently being collected. In a doubleblind, placebo-controlled study of 1496 obese or overweight subjects with dyslipidemia and/or hypertension, the participants were randomized 2:1 to combined naltrexone sustained-release (32 mg per day) plus bupropion sustained-release (360 mg per day) (NB32) or placebo for up to 56 weeks. Significantly (P < 0.001) greater weight loss was observed with NB32 vs. placebo at week 28 (−6.5% vs. −1.9%) and week 56 (−6.4% vs. −1.2%). More NB32-treated participants (P < 0.001) experienced ≥5% weight loss vs. placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. It was not associated with increased events of depression or suicidality vs. placebo (48).

Gastrointestinal and pancreatic peptides that regulate food intake The gut–brain axis plays an important role in food consumption regulation. During food intake, information regarding meal quality and content and short-term alterations in nutrient status is relayed from the gastrointestinal (GI) tract and pancreas to the brain which in turn determines meal size. Following food, a number of satiation signals optimize these processes by influencing GI motility and secretion. Several peptides have been recognized as mediating this GI system-brain communication including satiety signals such as gastrin releasing peptide, © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

cholescystokinin, PYY, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), glucagon and amylin, and the orexigenic peptide ghrelin. While the anorexigenic peptides are secreted during feeding, ghrelin is secreted before meals and acts to increase hunger and meal initiation. Lower-intestinal satiation Glucagon-like peptide-1 analogues. The role of GI tract in satiation (49) is mediated by the gut satiation peptides that are secreted by lower-intestine enteroendocrine cells in response to ingested food. They in turn diffuse through interstitial fluids to activate nearby nerve fibres and/or enter the bloodstream to function as hormones and augment the perception of GI fullness by acting in specific parts of the CNS. GLP-1 is produced primarily by the L cells of the distal small intestine and colon. The GLP-1 analogues (exenatide and liraglutide), currently used in clinical practice for diabetes control, have demonstrated anorectic effects and significant weight loss properties (50–52). The GLP-1 receptor R (GLP1R) is the principle mediator of the anorectic effects of GLP-1 expressed mainly in the gut, pancreas, brainstem, hypothalamus and vagal-afferent nerves (49). The GLP-1 analogues are not currently approved for obesity treatment. Researchers did a randomized, doubleblind, placebo-controlled 20-week trial, with an 84-week open-label extension. All 564 individuals were randomly assigned, with a telephone or web-based system, to one of four liraglutide doses (1.2, 1.8, 2.4 or 3.0 mg, n = 90–95) or to placebo (n = 98) administered once a day subcutaneously, or orlistat (120 mg, n = 95) three times a day orally (52). The study assessed the effect of liraglutide on bodyweight and tolerability in obese individuals without type 2 diabetes. Weight change analysed by intention to treat was the primary endpoint. An 84-week open-label extension followed. Participants on liraglutide lost significantly more weight than those on placebo (P = 0.003 for liraglutide 1.2 mg and P < 0.0001 for liraglutide 1.8– 3.0 mg) and orlistat (P = 0.003 for liraglutide 2.4 mg and P < 0.0001 for liraglutide 3.0 mg). Mean weight loss with liraglutide 1.2–3.0 mg was 4.8, 5.5, 6.3 and 7.2 kg compared with 2.8 kg with placebo and 4.1 kg with orlistat, and was 2.1 kg (95% confidence interval 0.6–3.6) to 4.4 kg (2.9–6.0) greater than that with placebo. More individuals (76%, n = 70) lost more than 5% weight with liraglutide 3.0 mg that with placebo (30%, n = 29) or orlistat (44%, n = 42). Liraglutide reduced blood pressure at all doses, and reduced the prevalence of pre-diabetes (84–96% reduction) with 1.–3.0 mg per day. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment (52). Recently, the SCALE study, a randomized phase III trial with obese and overweight participants who lost 5% of

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initial weight achieved with a low-calorie diet, assessed the efficacy of liraglutide in maintaining weight loss. Subjects were assigned to liraglutide 3.0 mg per day or placebo (subcutaneous administration) for 56 weeks: weight decreased an additional mean 6.2% with liraglutide and 0.2% with placebo together with improvements in some cardiovascular disease-risk factors (53). More participants receiving liraglutide (81.4%) maintained the ≥5% run-in weight loss, compared with those receiving placebo (48.9%) (odds ratio 4.8 (3.0; 7.7), P < 0.0001), and 50.5% vs. 21.8% of participants lost ≥5% of randomization weight (odds ratio 3.9 (2.4; 6.1), P < 0.0001). Liraglutidetreated participants in the study achieved a cumulative weight loss of ∼12 kg calculated from the start of the lowcalorie diet (53). Higher doses of liraglutide than those used for the treatment of diabetes are needed for weight loss (2.4 to 3.0 mg vs. 1.2 to 1.8 mg for diabetes control) but there is as yet no clear evidence of their side effect profile in humans as these are currently under investigation. This is worrisome in the light of a slightly increased incidence of medullary thyroid tumours in two non-human species at clinically relevant liraglutide doses (54). A randomized, placebo-controlled, double-blind, 20-week study with an 84-week extension evaluated routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight. In year 1, more participants reported >1 episode of nausea/vomiting on treatment with liraglutide 1.2–3.0 mg (17–38%) than with placebo or orlistat (both 4%, P < 0.001). Most episodes occurred during dose escalation (weeks 1–6), with ‘mild’ or ‘moderate’ symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only four out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, vs. 6.3 kg for those with none (a treatment difference of 2.9 kg, P = 0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P < 0.001) or orlistat (P < 0.05). The study concludes that transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-oflife improvements (55). Although the full side effect profile will not be known until more long-term data are available, it has been established that their most common adverse effects are GI-related, (e.g. nausea, vomiting) and occur early in therapy but usually resolve after 4–8 weeks (56). Some other long-acting GLP-1 analogues are currently being investigated for diabetes treatment and for weight loss, such as lixisenatide (by Zealand Pharma, Glostrup, Denmark) (57), albiglutide (by GSK, Brentford, Middlesex, UK) and taspoglutide (by Roche, Basel, Swizerland). Pre-

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liminary data from a phase II study with CJC-1134-PC (from ConjuChem Biotechnologies Inc., Los Angeles, CA, USA), a conjugate of exendin-4 and recombinant human albumin, a GLP-1 receptor agonist, administered once weekly suggest that it provides similar reduction in body weight compared with the twice daily exenatide but may have a more favourable adverse event profile which might improve compliance in the long term (58). Furthermore, Emisphere has formulated an orally administered GLP-1 and PYY3–36/GLP-1 combination using a sodium N-[8-(2hydroxybenzoyl) amino] caprylate carrier (59). In this randomized, double-blind, placebo-controlled, four-way cross-over trial with 12 male subjects, oral GLP-1 (2 mg tablet) alone and the combination of oral GLP-1 (2 mg tablet) plus PYY3–36 (1 mg tablet) showed enhanced fullness at meal onset and induced a significant reduction in energy intake (60). Larger studies are needed to show possible weight loss benefits. Peptide YY. PYY is a 36-amino acid peptide (PYY1–36), produced postprandially in response and proportionally to caloric load, by the distal-intestinal L cells along with oxyntomodulin (OXM) and GLP-1. Just like GLP-1 and OXM, PYY1–36 is rapidly proteolyzed by Dipeptidyl Peptidase-4 (DPP4); however, unlike the other two neuropeptides, the cleaved product PYY3–36, is bioactive. Human studies have shown that PYY delays gastric emptying and promotes satiety (predominantly via Y2 receptors), while short-term intravenous administration of PYY3-36 at doses generating physiologic postprandial blood excursions was shown to decrease calorie intake by approximately 30% in lean and obese subjects, without causing nausea, affecting food palatability, altering fluid intake or else was followed by compensatory hyperphagia (61,62). In a recent study, the PYY3–36/OXM combined treatment resulted in much greater reduction of energy intake compared with PYY3–36 and OXM monotherapy (63). Despite evidence of significant reduction of calorie intake, the weight loss efficacy of PYY is still not documented (64). This being in contrast to results in rodents and non-human primates (65). Oxyntomodulin. OXM is a 37-amino acid anorexigenic hormone produced by the L cells of the distal small intestine and colon, where it co-localizes with GLP-1 and PYY. It is believed to modulate the energy homeostasis system at least in part via GLP1R although its GLP1R binding affinity is about 100 times lower than that of GLP-1 (66). Centrally, GLP-1 and OXM have different targets; OXM activates neurons in the hypothalamus and GLP-1 in the hindbrain and other autonomic control areas (67). Several human studies have demonstrated its efficacy as a satiety signal and modest weight loss agent when intravenously infused or injected in overweight and obese volunteers. © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

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Participants self-administered saline or OXM subcutaneously in a randomized, double-blind, parallel-group protocol. Injections were self-administered for 4 weeks, three times daily, 30 min before each meal. Body weight was reduced by 2.3 +/− 0.4 kg in the treatment group over the study period compared with 0.5 +/− 0.5 kg in the control group (P = 0.010) (68,69). Human studies have shown an additional effect of OXM on energy expenditure, beyond that of food intake restriction (70). Structurally modified analogues with longer duration of action (71,72) are likely to be available for obesity management in the near future. Ghrelin vaccines and ghrelin inhibitors. Ghrelin is a 28-amino acid peptide produced primarily by the stomach and proximal small intestine (73). It represents the only known potent orexigenic hormone (74). Its levels increase before meals and are suppressed by the ingested nutrients. The idea of blocking ghrelin’s activity has been explored with the experimental usage of an anti-ghrelin vaccine (NOX-B11) that attaches to active ghrelin and blocks its ability to bind to its receptor (75). The above agents, however, have not so far achieved the weight loss targets. The discovery of ghrelin’s main receptor (the Growth Hormone (GH) secretagogue receptor 1a) led to the development of some potent, selective and orally bioavailable ghrelin antagonists that are currently being tested in preclinical trials (76). Finally, the identification of ghrelin O-acyltransferase as the enzyme that catalyzes ghrelin octanoylation, which confers its biological activity, may lead to the design of ghrelin O-acyltransferase inhibitors that could potentially prevent or treat obesity (77).

Pancreatic satiation peptides Pancreatic polypeptide. PP is a 36-amino acid peptide, primarily produced in the pancreas in response to ingestion of food and in proportion to caloric load. It acts as a satiety hormone and reduces food intake predominantly via stimulation of the anorexigenic a-Melanocyte stimulating hormone signalling pathway by direct action on local Y4 receptors within the ARC (78,79). In normal body weight humans, intravenous infusion of PP at supraphysiological or even at lower doses confirmed the sustained decrease in both appetite and cumulative 24-h energy intake (80,81). Based on these findings, a selective Y4-receptor agonist (TM30339; 7TM Pharma) was developed and proved to be highly efficacious with respect to long-term body weight reduction in pre-clinical studies (81) and TM30338 (obinepitide), a synthetic analogue of two natural gut hormones with satiety effects PP and PYY (acts predominantly on Y2 receptors) that acts as an agonist of both the Y2 and Y4 receptors has also caused early meal termination when administered once a day subcutaneously in obese human subjects (45,82). Both of these agents are currently in phase © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

I/II clinical trials; therefore it is still early to make final decisions regarding efficacy in weight loss. Amylin and amylin analogues. Amylin is a 37-amino acid neuroendocrine peptide hormone co-secreted postprandially with insulin by pancreatic β cells. Among other properties, amylin has anorexigenic actions inhibiting gastric emptying and glucagon secretion but also decreasing meal size and calorie intake (fat specific) in a dosedependent manner. These are vagus-independent actions and are exerted via binding to specific amylin receptors in the hindbrain area postrema (83–85). Based on studies in patients with type 1 and type 2 diabetes in which the amylin analogue pramlintide (120 μg/day) has shown sustained reductions in food intake and mild progressive weight loss in addition to improvement in glycaemic control (despite concomitant insulin therapy), a phase II, 16-week, randomized, double-blind, placebo-controlled study with obese non-diabetic individuals addressed particularly its efficacy as an anti-obesity agent (86,87). According to the findings of this study, self-administered subcutaneous injections of pramlintide 240 μg three times a day resulted in significant reduction in waist circumference (P < 0.01) and 3.7% mean weight loss (progressive up to week 16, with no evidence of a plateau) compared with placebo (P < .001). The findings of another 4-month randomized controlled trial were similar, a study with obese patients treated with different doses of pramlintide (120, 240 and 360 μg b.i.d. and t.i.d.) or placebo demonstrating the dose-dependent weight loss efficacy of pramlintide (88). When blindly extended to 1 year, weight loss was regained in the placebo group but maintained or continued in all but the pramlintide 120 μg b.i.d. arm, thus demonstrating pramlintide’s ability to achieve sustained body weight restriction (89). Previous animal studies have shown that amylin treatment significantly enhanced hypothalamic anorexigenic leptin signalling (90) while the combination treatment with amylin and leptin led to marked, synergistic reductions in food intake (up to 45%) and fat-specific weight loss (up to 15%) (91). Recently, the weight-lowering effect of the amylin/leptin combination was evaluated in obese human subjects via usage of their analogues pramlintide and metreleptin (15) (Please see ‘Leptin, leptin analogues and leptin sensitizers’ heading). In summary, studying peptide hormones in combination as integrated neurohormonal approaches may hold promise for the effective treatment of obesity (Table 2). In this direction, the combined treatment with amylin/PYY3–36 was shown to suppress food intake (in a synergistic manner) and to reduce body weight (in an additive manner) in animals (92); this particular combination has not been studied in humans yet. Another anti-obesity approach is based on the usage of combinations of agents targeting

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Table 2 Combined treatments in development for the treatment of obesity Drug

Study phase

Pramlintide/metreleptin Bupropion/naltrexone (Contrave) Bupropion/zonisamide (Empatic) Topiramate/phentermine (Qsymia) PYY3–36 /GLP-1 combination PYY3–36/OXM Obinepitide (PP/PYY3-36) Amylin/PYY3–36 Pramlintide/phentermine Pramlintide/sibutramine β3-agonist LY-377604/ sibutramine ALS-L1023

II Rejected by the FDA IIb Approved by the FDA II II II II II II II II

distinct regulatory pathways of the energy homeostasis system. Thus, pramlintide (120 mg t.i.d. sbc)/phentermine (37.5 mg orally) and pramlintide (120 mg t.i.d. sbc)/ sibutramine (10 mg orally) were evaluated in a 24-week randomized controlled trial with 244 obese or overweight, non-diabetic subjects (93). The results support statistically greater weight loss with either combination treatment than with pramlintide alone or placebo (P < 0.001; 11.1 +/− 1.1% with pramlintide + sibutramine, 11.3 +/− 0.9% with pramlintide + phentermine, −3.7 +/− 0.7% with pramlintide; −2.2 +/− 0.7% with placebo). However, as sibutramine has been withdrawn from the market because of adverse cardiovascular events and phentermine is licensed only for short-term usage, the pramlintide/ phentermine combination could be employed as a shortterm anti-obesity agent.

Peripheral modulators of the efficiency of digestion, metabolism and lipogenesis 11β-hydroxysteroid-dehydrogenase inhibitor Based on the autocrine and paracrine actions of cortisol in the pathogenesis of central obesity and features of the metabolic syndrome, the role of carbenoxolone as a nonselective 11β hydroxysteroid-dehydrogenase inhibitor in central obesity reduction has been studied; the results are conflicting (94). On the other hand, preliminary data from animal studies with T-BVT (a new 11β- hydroxysteroiddehydrogenase 1 pharmacological inhibitor that homes specifically to the white adipose tissue), could be proven valuable regarding its anti-obesity efficacy and amelioration of multiple metabolic syndrome parameters in humans (95).

Conclusions The need for new treatment paradigms Recent advances in our knowledge about energy homeostasis regulation at the molecular level are enabling novel

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anti-obesity drugs to be designed targeting specific molecules crucial for energy balance modulation. Mechanisms that regulate energy balance overlap with other physiological functions and are influenced by social, cognitive and psychological factors (2). Thus investigations into molecular targets involved in energy balance modulation should focus not only on feeding behaviour but also on their effects on mood, sexual behaviour, learning and memory. In recent years, two novel anti-obesity drugs have won approval by the FDA, Belviq (lorcaserin) and Qsymia (topiramate and phentermine), thus signalling the beginning of a new era in the pharmaceutical pharmacotherapy of obesity. Medications that target only one mechanism produce and maintain weight loss below the successes achieved with bariatric surgery. Thus, the field of pharmaceutical management of obesity has its sights set on combinations of agents targeting different molecules and bringing about an additive effect on weight loss (Table 2). Currently, research is directed towards development of combination treatments based on gut hormones in a way that mimics the changes underlying surgically induced weight loss. However, as these hormones are not orally available and are rapidly cleared from the circulation, efforts need to focus on developing routes of administration that will overcome these hurdles while also making pharmacotherapy in obesity cost-effective. Regrettably, the road to the manufacture of an effective and safe drug for the treatment of obesity is still long, however, it is hoped that over the next decade, success may be achieved in the production of such a compound. Of importance is the fact that agents must not only meet the requirements for selectivity of action and safety profile but also efficacy in weight loss and maintenance as well as in long-term prevention and treatment of obesity comorbidities, such as diabetes mellitus, cardiovascular disease and hypertension. A further future aspiration is for the pharmacotherapy of obesity to stratify patient populations into different types of obesity, such as we see in other therapeutic fields such as breast and colon cancer.

Conflicts of Interest Statement George Valsamakis has no relationship to companies, has no stock shares or holdings and has not received any speakers fees from companies. Kostas Lois has no relationship to companies, has no stock shares or holdings and has not received any speakers fees from companies. Sudhesh Kumar sat on advisory board for NovoNordisk, has no stock shares or holdings and has not received any speakers fees from companies. George Mastorakos has no relationship to companies, has no stock shares or holdings and has not received any speakers fees from companies. © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 209–219

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Author contributions GV wrote and supervised the manuscript, KL contributed to the writing of the manuscript, SK and GM contributed to the revision of the manuscript.

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