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New Molecular Targets for the Pharmacotherapy of Obesity

, , , M.D., DSc, and .

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Last Update: April 8, 2015.

ABSTRACT

Obesity is a complex medical problem with to date poor pharmacotherapy-based management. Phentermine, benzphetamine, phendimetrazine, and diethylpropion, which are approved only for short-term use in the USA, and orlistat, which reduces fat absorption, have failed to combat the obesity epidemic. However, current insights provided by the new biology are leading to the development of novel anti-obesity drugs with central/anorexigenic effects. As such, combined phentermine and topiramate (Qsymia) and lorcaserin (Belviq) were both approved in 2012 by the FDA for the body weight management of adults who are obese as well as overweight, with risk factors such as high blood pressure, high cholesterol or diabetes. In late 2014 two more anti-obesity drugs also won approval for usage in clinical practice: the diabetes drug liraglutide (Saxenda), and combined bupropion and naltrexone (Contrave). Given that current drug therapy does not cure obesity but only achieves moderate reduction in weight loss, moreover with authority for use time-limited, and that when drug therapy is discontinued weight is expected to rise, the aim of current research is to develop more potent anti-obesity drugs while substantially improving the above parameters. This chapter provides information concerning potential molecular targets of the homeostatic system and new anti-obesity drugs at present in development. For compete coverage of related areas, visit www.endotext.org.

INTRODUCTION

Weight loss strategies based on diet, exercise, and behavior modification are characterized by lack of success in the long term for the majority of patients. This is partly because the reduction in energy expenditure that inevitably attends weight loss makes weight loss maintenance over a long period even more difficult; in one report, maintenance of body weight at 10% below the baseline weight in obese subjects was associated with an 8 kcal/kg reduction in total energy expenditure (1). On the other hand, the public health implications of the current obesity pandemic render imperative the need for effective anti-obesity therapeutic intervention. The pharmacotherapy of obesity is, however, rife with unsafe and abusive practices, but also with failures and withdrawals of anti-obesity drugs mainly due to a poor safety and efficacy profile. The most recent withdrawals of fenfluramine and dexfenfluramine (linked to valvulopathy), rimonabant (linked to epilepsy and suicidal mood) and sibutramine (linked to adverse cardiac effects) merely proved the rule applied to anti-obesity drug records. In the meantime, the recent gains in our understanding of energy homeostasis and the complex central and peripheral mechanisms that underlie the balance between energy intake and expenditure have been shown capable of providing more effective molecular targets for obesity. Needless to say, the new drugs need to fulfill the strict safety and efficacy standards established by the US Food and Drug Administration (FDA) for the development of anti-obesity pharmacotherapeutics. These require trials of ≥1 year’s duration and enrolment of >4,500 subjects (3,000 subjects randomized to active doses of the product and no fewer than 1,500 subjects randomized to placebo) (2). In order to grant approval for a weight loss pill, the FDA looks for at least a 5% reduction in weight over a year. Since 2012, the FDA has approved an implantable device for treating obesity (VBLOC Vagal Blocking therapy; Maestro System, EnteroMedics) and four prescription weight loss drugs: phentermine plus topiramate, and lorcaserin, both approved in 2012, and only recently the diabetes drug liraglutide, and combined bupropion , an antidepressant, and naltrexone, an anti-addiction drug. These offer another option for adults who are obese, or overweight, with risk factors such as high blood pressure, high cholesterol or diabetes. Recent reports also indicate that combined bupropion and naltrexone is shortly due to win approval recommendation in Europe. Phentermine, benzphetamine, phendimetrazine, and diethylpropion, which are approved only for short-term use in the USA, have more side effects and the potential for abuse. It should be emphasized that no drug therapy cures obesity, since when drug therapy is discontinued, weight is expected to rise.

TARGETED PHARMACOTHERAPY OF OBESITY

Novel insights provided by the new biology point to the presence of a complex homeostatic system in which information about the energy reserve status and the 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, or not, feeding according to energy requirements. Peripheral peptide hormones are released postprandially and travel in the circulation to their cognate receptors, which are expressed in the homeostatic regulatory centers in the CNS, notably the arcuate nucleus (ARC) of the hypothalamus and the dorsal vagal complex (DVC) in the medulla. The ARC is home to neurons expressing the key orexigenic neurotransmitters, agouti-related peptide (AgRP) and neuropeptide Y (NPY), as well as anorexigenic neurotransmitters, proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). At the same time, food intake is modulated by various mechanisms that enable a homeostatic response to counterregulate the effect of modulating any single mechanism. With this knowledge, new drug therapy has begun to focus on combination treatments using multiple agents to target more than one of these mechanisms, thereby achieving more favorable weight loss outcomes. In addition, combined treatments may actually provide a better safety profile given that many of these agents are already established drugs that are tolerated and approved.

CENTRALLY-ACTING ANTI-OBESITY DRUGS / MODULATORS OF MONOAMINE NEUROTRANSMISSION

Leptin, leptin analogues and leptin sensitizers

Leptin is a protein primarily secreted from the adipose tissue. It directly stimulates the anorexigenic POMC neurons and inhibits the orexigenic NPY neurons in the ARC of the hypothalamus, thus promoting satiety and weight loss (3). Its circulating levels increase with increasing adiposity (3) and decline following body weight reduction; the latter might be implicated in the total and resting energy expenditure reduction seen after weight loss. The discovery of leptin in 1994 was a seminal event in obesity research. It helped to establish that body weight should be viewed as a disorder with a strong biological basis rather than simply the result of poor lifestyle choices. Studies with congenitally leptin-deficient super-obese subjects revealed that administration of physiological doses of leptin decreases food intake and body weight (4,5). Obese individuals however, despite having increased circulating leptin levels, are leptin-resistant. Whether administration of leptin could overcome leptin resistance and exert an anti-obesity effect was tested in a placebo-controlled study with 47 obese men and women given varying doses of recombinant human leptin (0.03 mg/kg and 0.30 mg/kg, respectively) for 24 weeks and advised to eat 500 kcal less than body requirements each day. A dose-dependent decrease in body weight was shown, ranging from -1.3 kg in the placebo group to -1.4 kg in the 0.03 mg/kg leptin-treated group, and to -7.1 kg in the 0.30 mg/kg leptin-treated group (6). These results suggest that leptin resistance can be overcome with high doses of leptin, but whether the effect can be sustained long-term is not known. Reports were similar from animal studies testing the effect of protein tyrosine phosphatase-1B (PTP1B) blockade (7,8) (that promotes leptin resistance), or the chemical chaperones that repair ER stress and increase leptin sensitivity, including 4-phenyl butyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) (9) (that cause decreases in food intake and reductions in body weight. Whether these anti-obesity effects can be sustained or not is still not clear though. Weight loss is associated with reduction in energy expenditure, which makes weight loss maintenance in the long term even more difficult (1). Restoration of leptin concentrations to pre-weight loss concentrations, via administration of the human hormone leptin analogue metreleptin, mitigated weight loss counterregulation (10-12). Taken together, there is a growing likelihood of a role for leptin as an adjuvant therapy to a primary weight loss agent, in order to maintain weight loss by reversing the total and resting energy expenditure reduction seen after weight reduction.

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 metreleptin (pramlintide/metreleptin) were tested, and showed a significant weight reduction of 12.7 ± 0.9% (11.5 ± 0.9 kg) without plateauing in obese patients during a 20-week trial period (13). The sponsors subsequently announced positive results from a 28-week proof-of-concept study with pramlintide and metreleptin combination treatment in overweight or obese subjects. The combination treatment reduced body weight on average by 12.7%, significantly more than treatment with pramlintide alone (8.4%), which translates to about 10 pounds more of weight loss with the combined treatment. Remarkably, subjects receiving pramlintide/metreleptin continued to lose weight to the end of the study, compared to those treated with pramlintide alone, whose weight loss had stabilized toward the end of the study. The magnitude of weight loss was found to be dosage- and baseline body mass index (BMI)-dependent. Patients with a starting BMI less than 35 kg/m2 experienced the best weight loss efficacy by the combined treatment (14). A year later the results of the 52-week blinded, placebo-controlled Phase II extension study of pramlintide/metreleptin were announced. The results indicated sustained and robust weight loss through the combined treatment; again, the most robust efficacy was seen in patients with a BMI less than 35 kg/m2 (14). Although the pramlintide/metreleptin combination seemed to be the next promising anti-obesity drug to be marketed, the spsonsors discontinued its development in 2011, following commercial reassessment of the program (15).

Melanocortin-4 receptor agonists

The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. Leptin inhibits the release of the orexigenic neuropeptides orexin and melanocortin-concentrating hormone (MCH) in the lateral hypothalamic area (LHA) through the release of CART and melanocyte-stimulating hormone (α-MSH). The latter derives from the cleavage of POMC by prohormone convertase-1 and acts via melanocortin-3 and -4 receptors (MC3R, MC4R) activation. α-MSH emerged as a promising novel anti-obesity drug, and intranasal administration of the melanocortin sequence MSH/ACTH4-10 to normal-weight subjects was shown to acutely increase subcutaneous white adipose tissue lipolysis (16) and decrease body fat by 1.7 kg, when administered for six weeks (17). It eventually proved not to induce any significant reduction in body weight or body fat when compared with placebo in a 12-week study of 23 overweight men (18).

In preclinical studies, obese primates treated for eight weeks with the MC4R agonist RM-493 lost an average of 13.5% of their body weight, with significant improvements in both insulin sensitivity and cardiovascular function. In June 2014, the results from the first human Phase II tria were released, testing the hypothesis that an MC4R agonist increases resting energy expenditure in obese subjects. A total of 12 obese but otherwise healthy individuals were randomized and completed both RM-493 and placebo periods in this double-blind, placebo-controlled, two-period crossover study. Analysis of the data indicates that short-term treatment with RM-493 increased resting energy expenditure significantly (by 6.4% vs placebo), thus suggesting RM-493 may be clinically effective for treating obesity. Further studies are needed to address its safety due to the role of melanocortins in cardiovascular and sexual function. For example, Phase I/II trials with the α-MSH analogue, Melanotan II, caused dose-dependent penile erections.

Melanin-concentrating hormone (MCH) antagonists

The melanocortin-concentrating hormone (MCH) has been shown to be another important orexigenic neuropeptide in the LHA. Its release is stimulated by NPY and inhibited by leptin, while it exerts its orexigenic effects through the MCH1 receptor (MCHR1) (19). Similarly to NPY, MCH also exerts pleiotropic functions such as locomotor activity, sensory processing, anxiety, aggression, and learning. Thus, despite the role of MCH in hunger stimulation, MCHR1 blockade as an anti-obesity target is questionable, because such inhibition could elicit undesirable side effects. In animal models, MCH antagonists have consistently demonstrated efficacy in reducing food intake acutely and in inhibiting body weight gain when given chronically (20,21). Five compounds have reached testing in human subjects. Although they were reported as well-tolerated, none has proceeded to advanced Phase II studies for rigorous testing of their efficacy in causing chronic weight loss. A major issue with many lead compounds is increased cardiovascular risk due to drug-induced QTc prolongation (22). Among others, the MCHR1 antagonist AMG 076 entered Phase I safety and tolerability testing in 2004, but there have been no subsequent reports of its status since 2005. The MCHR1 antagonist GW-856464 also entered Phase I studies in 2004; however, in 2010 it was reported that low bioavailability precluded further development. The MCHR1 antagonist NGD-4715 was safe and well-tolerated in a Phase I clinical trial, but its development ceased in 2013. Similarly, despite the reported tolerability and indication of efficacy of the MCHR1 antagonist ALB-127158, its development was terminated before the initiation of Phase II studies. Finally, the longest (28-day) Phase I study with BMS-830216, a pharmacological antagonist of MCH signaling (23)produced no indications of weight loss or reduced food intake and the compound did not proceed to Phase II studies

Subtype-selective serotonin-receptor agonists

Central serotonin participates in feeding behavior and energy balance modulation and reduces food intake in animals and human beings, thus agonists to appropriate serotonin receptors are potentially valuable drugs. Two selective serotonin reuptake inhibitors (SSRIs), fluoxetine and sertraline, were shown to induce weight loss in obese subjects. The serotonin (5-HT) system directly modulates the hypothalamic POMC (anorexigenic) and NPY (orexigenic) networks, enhancing satiety and causing hypophagia. These effects are mediated by 5-HT2C and 5-HT1B receptors, located on hypothalamic POMC and NPY neurons, respectively. Through the 5-HT1B receptors, serotonin inhibits the NPY/Agrp neurons, decreasing the GABAergic inhibitory input to POMC cells, while through the 5-HT2C receptors it directly activates the anorexigenic POMC neurons. Via these actions, serotonin increases α-MSH and decreases AgRP release into the hypothalamic melanocortin system, promoting satiety. As activation of the 5-HT1B receptor has been implicated in both primary pulmonary hypertension (24) and valvulopathy (25), the 5-HT2C receptor subtype has been proposed as a target for therapeutic intervention. Several potent and selective 5-HT2C receptor agonists proved to be effective in suppressing food intake and inducing weight loss in rodents,including WAY-163909 (26), CP-809101 (27), and vabicaserin (28); however, only lorcaserin (APD356) has moved into clinical testing. Based on the outcome of the BLOOM (29) BLOSSOM trials (30), in 2012 the FDA approved lorcaserin as an addition to a reduced-calorie diet and exercise for patients who are obese (BMI ≥30 kg/m2) or overweight (≥27 kg/m2) with at least one medical comorbidity, such as type 2 diabetes, hypertension, high cholesterol or sleep apnea (31). The efficacy of lorcaserin appears similar to that of orlistat (mean difference in weight loss between active and placebo treated groups approximately 3 to 4 kg) and perhaps slightly less than that of phentermine-topiramate and sibutramine, which is no longer available in most countries. A specific AgRP inhibitor (TTP-435) is currently in Phase II clinical trials, having shown promising appetite suppressant efficacy (32).

Bupropion

Modulation of monoamine neurotransmitters, such as dopamine, norepinephrine, and serotonin, can be highly effective in suppressing appetite, but adverse effects like cardiovascular events and addiction are major concerns in their use in weight management. Bupropion is a dopamine and norepinephrine-reuptake inhibitor that has been marketed as an anti-depressant and for smoking cessation. Previous animal studies have clearly shown a dose-dependent satiety effect of brupopion following intraperitoneal injection (33). The acute effects of dopamine and noradrenaline reuptake inhibition on energy homeostasis demonstrated their additive effects on short-term food intake (34,35). Bupropion increases dopamine activity and POMC neuronal activation, thereby reducing appetite and increasing energy expenditure (36). Whether the acute meal terminating effects of bupropion documented in animal studies could be translated into long-term weight loss efficacy in humans was addressed by three clinical trials with overweight and obese adults (37-39) using different treatment doses (100 to 400 mg/d) and duration (up to 24 weeks). They have all shown bupropion to have dose-dependent modest weight reducing efficacy, plus a safe profile. One study that assessed the anti-obesity efficacy of bupropion over two years reported maintenance of the weight loss during the continuation phase (39), while another demonstrated its efficacy even in depressed patients (38). Although the weight loss effect of bupropion was superior in non-depressed patients compared to those suffering from depression, the fact that bupropion was well-tolerated and effective in this particular group of patients provides a potential valuable adjunctive therapy to elevate mood in depressed subjects in whom weight gain secondary to antidepressant therapy is an issue. Cardiovascular effects, such as a rise in blood pressure and tachycardia, were usually mild, while the risk of seizure, which was high with the original bupropion formulation, has been significantly reduced with the advent of bupropion-SR and bupropion-ER.

An interesting finding of the previous studies was that the rather modest weight loss effect of bupropion reached a plateau by 24 weeks of treatment (37,38). This could be explained by the molecular pathophysiology of the weight reducing effects of bupropion which directly stimulates the hypothalamic POMC neurons that in turn release α-MSH and β-endorphin. α-MSH mediates the anorectic effect of POMC activation, whereas β-endorphin exerts negative feedback on POMC neurons via opioid receptors (40). Ththe latter possibly points to one of the compensatory mechanisms that limits long-term efficacy of bupropion and other weight loss modalities. Naltrexone on the other hand blocks opioid receptors on the POMC neurons, preventing feedback inhibition and further increasing POMC activity. Monotherapy with opioid antagonists that decreased short-term food intake was tested (41) Naltrexone failed to produce consistent or clinically meaningful weight loss. , even at large doses (300 mg/d) (42-44), implying that a single opioid mechanism is unlikely to explain all aspects of ingestive behaviour. In Phase III clinical trials, the combined bupropion/naltrexone therapy induced significantly greater weight loss on a diet and exercise program over 56 weeks compared to monotherapy and placebo (45). In September 2014, the FDA approved the drug for body weight management in adults who are obese, but also for those not obese but overweight with risk factors such as high blood pressure, high cholesterol or diabetes.

Zonisamide

Given the pathophysiology behind the anti-obesity efficacy of the selective serotonin-receptor agonists and the dopamine-reuptake inhibitors, an ideal drug would combine serotonergic and dopaminergic activity. This is exactly the case of zonisamide, a marketed antiepileptic drug that exerts dose-dependent biphasic dopaminergic (46) and serotonergic (47) activity. Its weight loss efficacy was investigated by a double-blind, placebo-controlled trial which reported a 32-week mean weight loss of 9.2 kg (1.7 kg) (9.4% loss) for the zonisamide group (dose administered up to 600 mg/d) compared with 1.5 kg (0.7 kg) (1.8% loss) for the placebo group (P<0.001); zonisamide was generally well-tolerated with only a few adverse effects (48). The findings were similar when the long-term effectiveness and tolerability of zonisamide for weight control was examined in psychiatric outpatients using various psychotropic medications; the mean BMI reduction achieved was 0.8±1.7 kg/m2 and ranged from -2.9 kg/m2 to 4.7 kg/m2 (p<0.001), while the drug was generally safe and well-tolerated (49). Zonisamide was also assessed in the treatment of binge-eating (BE) disorder where it proved to be effective in reducing binge-eating frequency, severity of illness, and weight; however, the reports regarding its tolerability were conflicting (50,51).

Whether the anti-obesity efficacy of zonisamide is increased when it is combined with bupropion (dopamine and norepinephrine -reuptake inhibitor) has been evaluated in a few Phase II clinical trials with different combined doses; the bupropion SR/zonisamide SR combination is marketed under the trade name Empatic. In its 24-week, double-blind, placebo-controlled Phase IIb trial (52), patients completing 24 weeks of bupropion SR 360 mg/zonisamide SR 360 mg therapy lost 9.9% of their baseline body weight, or 22 pounds, compared to 1.7% for placebo patients (p<0.001). Of patients who completed 24 weeks of therapy, 82.6% lost at least 5% of their baseline body weight and 47.7% lost at least 10% of their baseline body weight compared to 18.9% and 5.7% of placebo patients, respectively (p<0.001 for both). Patients experienced significant weight loss as early as by their first post-baseline visit at week four. Importantly, and patients continued to lose weight through to the end of the trial period with no evidence of a weight loss plateau. Early results showed that patients lost an average of 14% over 48 weeks. Improvements were observed in key markers of cardiometabolic risk such as waist circumference, triglycerides, fasting insulin, and blood pressure. The most commonly reported adverse events for all patients were headache, insomnia, and nausea. The most common adverse events leading to discontinuation were insomnia, headache, and urticaria (hives). There were no serious adverse events attributed by investigators to the study drug. There were no statistically or clinically meaningful differences between the drug and placebo on measures of cognitive function, depression, suicidality or anxiety. These reports revealed a significant weight-reduction effect for the combination bupropion/zonisamide. However, the safety concerns (53-55) will need to be addressed in the upcoming Phase III studies before firm conclusions about its safety profile can be drawn.

Topiramate

Topiramate is another anticonvulsant agent associated with weight loss. It is a sulphamate-substituted fructose that is approved as an antiepileptic/antimigraine agent and has multifactorial effects on the CNS, including action on the orexigenic GABA systems causing appetite suppression (56). A 6-month dose-ranging study in obese human subjects addressing its anti-obesity efficacy at doses of 64, 96, 192, and 384 mg/day (in divided twice-daily dosing) concluded that all doses produced significantly greater weight loss compared to placebo, and that weight loss in the 192 mg/day group was similar to the 384 mg/day group (57). This is important as topiramate has been associated with several neuropsychiatric effects, especially when administered at high doses (of 192 mg/d or more). Another study investigating the weight loss efficacy and safety of topiramate doses of 96, 192, and 256 mg/day over a 1-year period in obese subjects using the immediate release form tablets (before the development of the controlled-release formulation). Clinically significant weight loss (7.0, 9.1, and 9.7% of their baseline body weight for the doses of 96, 192, and 256 mg/day, respectively, was reported compared to 1.7% body weight loss in the placebo group (P<0.001) plus improvements in blood pressure and glucose tolerance (58). Finally, several other studies investigated the therapeutic effect of topiramate in patients with binge-eating disorder and bulimia (59) that are both associated with obesity; the results were very promising regarding control of symptoms in both disorders.

Because of dose-related side effects seen with topiramate treatment including suicidality, metabolic acidosis, acute myopia, and secondary angle closure glaucoma, a lower dose of topiramate was used (in a special controlled release formulation) in a novel anti-obesity drug called in combination with phentermine. Phentermine is an amphetamine derivative which has central anorectic effects and is still prescribed in the USA for the short-term treatment of obesity. Based on the positive results from three Phase III studies, CONQUER (60) EQUIP (61), and EQUATE in more than 3,750 patients in 93 sites as well as on the results from the 2-year extension study of the study completers from the CONQUER study cohort (SEQUEL) (62), in 2012 the FDA approved phentermine and topiramate extended-release as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of at least 30 kg/m², or at least 27 kg/m² (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus or dyslipidemia. Meanwhile however, approval was denied by European regulatory authorities, who cited potential risk to the heart and blood vessels, psychiatric side effects, and cognitive side effects in explaining their decision.

Neuropeptide Y (NPY) inhibitors

The ARC NPY neurons inhibit the anorexigenic POMC neurons (via NPY Y1 and Y5 receptors) and promote the release of the orexigenic neuropeptides orexin and MCH in the LHA, thus promoting food intake. Therefore, NPY blockade could be a promising target for body weight management. Animal experiments (in mice) have shown that pharmacologic blockade or genetic deletion of the Y1- and Y5-receptors reduces food intake and weight, with Y1-receptor signaling appearing to be the major mediator of the orexigenic effects of NPY. However, NPY is the most abundant central neuropeptide and regulates many functions beyond feeding; thus, targeting NPY neurons/Y receptors specifically for obesity is not easy and could result in unacceptable side effects. In addition, experimental medical blockade of NPY signaling with the Y5-receptor antagonist MK-0577 failed to cause any significant weight loss in a 1-year clinical trial (63). On the other hand, the oral, once-daily, centrally acting selective Y5-receptor antagonist velneperit, previously known as S-2367 induced a mean placebo-adjusted weight loss of 5.0% from the baseline weight (p <0.0001) over 54 weeks of therapy (64). Taken together, Y5-receptor antagonists seem to achieve limited efficacy with regard to weight loss. However, the combined Y1/Y5-receptor antagonism may prove more effective, though we are not aware of any Y1/Y5-receptor antagonist in development to date. In contrast to Y1 and Y5, the Y2- and Y4-receptors are the targets of the satiety hormones PYY and pancreatic polypeptide (PP), respectively, and, as mentioned below, two drugs, a Y2/Y4-receptor agonist (obinepitide and a selective Y4-receptor agonist (TM30339;), are in Phase I/II clinical trials and are yielding results that appear quite promising as regards weight loss.

Dopamine antagonists

The mesolimbic dopamine system was shown to play a critical role in compulsive overeating or binge eating, which is one of the main reasons why people become overweight or obese. There is some evidence that blocking the action of dopamine in animals can reduce food intake, particularly of foods that are high in fat and sugar. GSK 598809 is a D3 antagonist that blocks dopamine. Preliminary data from human studies failed to show any significant effect on body weight control (65,66).

Sympathomimetics

Tesofensine

Tesofensine is a presynaptic inhibitor of norepinephrine, dopamine, and serotonin. Similarly to sibutramine, it suppresses appetite and may result in significant weight loss, as this was shown when given for the treatment of Parkinson’s disease (67), but also in a multi-dose dose-ranging trial where 203 obese patients were randomly assigned to tesofensine (0.25, 0.5, and 1.0 mg) or placebo once daily (68). Phase II testing of the drug has been completed. After 24 weeks, mean weight reduction was greater in the tesofensine groups (-6.7, -11.3, -12.8 kg, for the three doses, respectively) compared with placebo (-2.2 kg). The company needs to move on to Phase III studies to investigate further the efficacy and safety of tesofensine.

Another sympathomimetic lisdexamfetamine dimesylate at certain doses appears effective in decreasing binge-eating days in patients with binge-eating disorder (BED) compared with placebo, according to a study published online by JAMA Psychiatry (69). The study included 259 and 255 adults with BED in safety and intention-to-treat analyses, respectively. Patients received lisdexamfetamine 30, 50 or 70 mg/day or placebo. BE days per week decreased in the 50 mg and 70 mg groups but not in the 30 mg group compared with placebo. Confirmation of these findings in ongoing clinical trials may result in improved pharmacologic treatment for moderate to severe BED.

The cannabinoid-1 receptor (CB1) antagonists

Among other neurotransmitter systems, the cannabinoid system modulates the hypothalamic melanocortin and NPY feeding networks. It has been shown that administration of cannabinoid-1 receptor (CB1) agonists and antagonists induces hyperphagia and hypophagia, respectively. These observations led to development of rimonabant, a cannabinoid-1 receptor antagonist, for the treatment of obesity, which was shown quite effective in promoting weight loss; however (70), it increased the incidence of mood-related disorders. As a result, rimonabant was withdrawn from the market and the development of other cannabinoid-1 receptor antagonists for the treatment of obesity has also been discontinued.

Human chorionic gonadotropin (hCG)

Human chorionic gonadotropin (hCG) in the form of subcutaneous injection and oral or sublingual diet drops have been advertised as aiding in weight loss of one to two pounds daily, absence of hunger, and maintenance of muscle tone. Clinical trials, however, failed to support this claim (71-74). In fact, the Food and Drug Administration has recommended that consumers avoid buying over-the-counter weight loss products which contain HCG. One might ask why the HCG diet has then so many enthusiastically supporting it. The reason may be that this diet needs to be accompanied by severe calorie restriction, to only 500-800 calories per day. Needless to say, anyone following such recommendations is bound to lose weight, if only short-term. Most crucially, though, since HCG has been reported to induce serious side effects, this drug should not be used for the treatment of obesity. In addition, very low calorie diets have not been shown to be superior to conventional diets for long-term weight loss, plus they have risks, such as gallstone formation, irregular heartbeat, and an imbalance of electrolytes. Therefore, if weight loss is the goal, there are safer ways to make it happen.

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. Apart from feeding, a number of satiation signals optimize these processes by influencing gastrointestinal motility and secretion. Several peptides have been identified that mediate this GI system-brain communication including satiety signals such as gastrin releasing peptide (GRP), cholescystokinin (CCK), peptide YY (PYY), glucagon-like peptide-1 (GLP-1), pancreatic polypeptide, 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. Some of the GI and pancreatic peptides implicated in the regulation of food intake act directly on regions of the brain involved in the regulation of food intake, including the ARC in the hypothalamus and the area postrema, while others act outside of the CNS, for example modulating the activity of neurons such as the vagus nerve, which projects to the nucleus of the solitary tract in the brain stem.

Upper-intestinal satiation

CCK and CCK1R agonists

CCK is the first described intestinal satiation peptide (75); it is produced by the mucosal I cells of the duodenum and jejunum, and the enteric nervous system, in response to luminal nutrients, especially lipids and proteins. Through endocrine and/or neural mechanisms, CCK regulates numerous GI functions, including satiation, by acting on two CCK-specific receptors: the CCK receptor 1 (CCK1R), expressed mainly in the GI system, and the CCK2R that predominates in the brain. The vagus nerve plays a critical role in CCK-induced satiation as it attains CCK1R (76,77) this indicating the afferent pathway through which CCK relays satiation signals from the GI to the hindbrain region (78,79). Corroborating this hypothesis is the well-documented attenuation of CCK-induced satiation following abdominal subdiaphragmatic vagotomy (80,81). In addition, CCK inhibits gastric emptying, thereby augmenting gastric distention and mechanoreceptor stimulation, which in turn augments the anorectic effects of CCK (82,83). Despite the satiety effect of CCK, its potential as an anti-obesity target is questionable. Human studies with intravenously infused CCK carboxy-terminal octapeptide (CCK-8) have shown decreases in meal size and duration in a dose-dependent manner (84-87). However the CCK satiating effects were very short-lived, usually not lasting more than 30 minutes, which raises issues as to its importance in long-term body weight regulation. In an animal study, chronic CCK administration with up to 20 peripheral injections per day, although reducing meal size, was associated with increased meal frequency, leaving body weight unaffected (88). Finally, the reports from trials testing CCK1R agonists as potential anti-obesity drugs were disappointing (89). It is currently suggested that there might be a role for CCK in body weight regulation not as a monotherapy but possibly as an adjunctive/synergistic therapy to long-term adiposity signals, such as leptin (90).

Lower-intestinal satiation

Glucagon-like peptide-1 analogues

The dominant role of GI in satiation (91,92) is mediated not only by the gastric mechanoreceptors and upper intestinal neuropeptides such as CCK, but also by gut satiation peptides that are secreted from lower-intestine enteroendocrine cells in response to ingested food. They in turn diffuse through interstitial fluids to activate nearby nerve fibers and/or enter the bloodstream to function as hormones and augment the perception of GI fullness by acting in specific parts of the CNS. There is a well-defined duodenal-ileal communication (the ileal brake) via which the proximal intestine informs the distal intestine as to meal quality and content so that the latter modulates/restricts feeding duration, proximal GI motility, and gastric emptying, while it also regulates metabolic responses to nutrient intake. GLP-1 appears to engage such a mechanical and behavioral brake effect on eating and is produced primarily by L cells in the distal small intestine and colon. Along with glucagon and oxyntomodulin, GLP-1 is cleaved from proglucagon, which is expressed in the gut, pancreas, and brain. The GLP-1 equipotent bioactive forms GLP17–36 and GLP17-37 are rapidly inactivated in the circulation by dipeptidyl peptidase-4 (DPP4). Therefore, GLP-1 analogues that have a slightly different molecular structure but a significantly longer duration of action compared to wild GLP-1 have been used for therapeutic interventions in patients with diabetes, in whom they significantly improved glycemic control, fasting plasma glucose, β-cell function, and probably β-cell regeneration. Currently, the GLP-1 analogues used in clinical practice for diabetes control are exenatide, lixisenatide, and liraglutide. Beyond the improved glycemic control achieved, clinical studies have also demonstrated anorectic effects and significant weight loss via these agents (93-98). Although the exact mechanisms by which GLP1 induces anorexia are not as yet fully known, it is suggested that vagal and possibly direct central pathways are involved (99,100). The GLP-1 receptor R (GLP1R) is the principle mediator of the anorectic effects of GLP-1 (101) and is expressed by the gut, pancreas, brainstem, hypothalamus, and vagal-afferent nerves (102).

The FDA has recently approved the diabetes drug liraglutide for the treatment of obesity The SCALE Obesity and Prediabetes trial evaluated liraglutide in obese but non-diabetic people and in overweight but non-diabetic people. The study included 3,731 individuals who were treated with liraglutide 3 mg or a placebo. Patients were also counseled on diet and exercise. At the end of the 56 week trial, the liraglutide group lost an average 8% (7.2kg) of their body weight compared to 2.6% (2.8kg) in the placebo group (103); net weight loss was 4.4kg. The product will have a boxed warning stating that thyroid C-cell tumors have been seen in rodents but the risk in humans is not currently known. Furthermore, clinicians ought to check lipase, amylase, and calcitonin after starting treatment, while the drug should not be used in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2 (104).

Some other long-acting GLP-1 analogues are currently being investigated for diabetes treatment but also for weight loss. Once-daily 13-week treatment with 20 μg or 30 μg of lixisenatide reduced body weight significantly more compared to placebo (-3 kg for lixisenatide 20 μg; p<0.01, -3.47 kg for lixisenatide 30 μg; p<.01, -1.94 kg for placebo) (105). Current findings regarding CJC-1134-PC, which is a conjugate of exendin-4 and recombinant human albumin and represents a once-weekly glucagon-like peptide-1 receptor agonist, suggest that it provides similar reduction in body weight compared with exenatide twice-daily. It may have a more favorable adverse event profile which might improve patient compliance and probably total weight loss in the long term (106). Finally, albiglutide and taspoglutide are two novel GLP-1 analogues currently being investigated. A recent review that examined the efficacy, safety, and perspective for the future of the once-weekly GLP-1 receptor agonists exenatide once weekly, taspoglutide, albiglutide, LY2189265 and CJC-1134-PC, and compared them to the currently available agonists, exenatide BID and liraglutide QD, concluded that the long-acting agonists are not superior compared to the currently used exenatide BID and liraglutide QD regarding weight loss (107).

In a separate development, an orally administered PYY3-36 and GLP-1 combination has beenformulated using a sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) carrier (108). Early studies revealed that the neuropeptides delivered orally in this way have a pharmacodynamic profile consistent with the reported pharmacology, were rapidly absorbed by the gastrointestinal tract, and reached concentrations several-fold higher than those seen naturally postprandially (109,110). 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 (108).

PYY

PYY is a 36-amino acid peptide (PYY1-36), a member of the pancreatic polypeptide-fold (PP-fold) family which also includes PYY, NPY, and PP and interacts with a family of receptors (mainly Y2R). It is 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 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 (111), 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 or altering fluid intake, nor was it followed by compensatory hyperphagia (112). Another study confirmed the above findings, reporting dose-dependent reduction of food intake (maximal inhibition, 35%; P<0.001 vs control) and calorie intake (32%; P<0.001) after intravenous infusions of several different concentrations of PYY3-36 (113). Sloth et al. showed for the first time the significantly higher energy expenditure following PYY3-36 intravenous infusion compared with PYY1-36 or control. In a recent study, the effect of infused PYY3-36 on energy intake was compared to that of OXM or the combined PYY3-36/OXM treatment; the results demonstrated that energy intake was significantly less with the combined treatment compared to PYY3-36 or OXM monotherapy (114). Whether these findings pointed to a weight loss efficacy of PYY was evaluated in a 12-week trial of 133 obese patients who were randomly assigned to intranasal PYY3-36 (200 or 600 mcg three times a day before meals) or placebo, in conjunction with diet and exercise. At the 200 mcg dose, PYY3-36 failed to reduce body weight, while 60% of patients treated with the high PYY3-36 dose (600 mcg three times a day) dropped out due to nausea and vomiting, so that no meaningful inference could be drawn from the few patients who completed the study on 600 μg (115). These findings are in contrast to those in rodents (116,117) and nonhuman primates (118) where PYY3-36 preparations reduce body weight. One suggested explanation is that the PYY3-36 effect is critically modulated by the time of injection. As the main antiorexigenic effect of PYY is by Y2R-mediated NPY inhibition, PYY is obviously more effective at times that the orexigenic NPY is increased. In accordance with this theory is the reported weight loss effect of PYY3-36 when injected in rodents in the fasting state or in the early dark cycle — times when NPY is naturally induced (119).

PYY3-36 is structurally similar to pancreatic polypeptide (PP); PYY3-36 acts mainly through Y2R, while PP acts through Y4R. Obinepitide (TM30338, a synthetic dual-analogue of PYY3-36 and PP that stimulates both Y2/Y4-receptors, has been developed. Pre-clinical studies have shown that obinepitide efficiently reduces weight in obese mice. Furthermore, initial studies in humans have shown that once-a-day subcutaneous administration of obinepitide in obese human subjects inhibited food intake, at a statistically significant level, up to at least nine hours after dosing (120).

Oxyntomodulin

Oxyntomodulin (OXM) is a 37-amino acid anorexigenic peptide hormone produced in the L-cells of the distal small intestine and colon, where it colocalizes with GLP-1 and PYY. Animal studies have shown weight reduction and improved glucose metabolism following chronic OXM injections beyond that explained by food intake restriction, suggesting an additional effect of OXM on energy expenditure (121,122). Just like GLP1, OXM is a proglucagon gene product and 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 GLP1 (121,123). Centrally however, GLP1 and OXM have different targets, as OXM activates neurons in the hypothalamus (122), whereas GLP1 acts in the hindbrain and other autonomic control areas (124). In human studies, acute anorectic effect of OXM was demonstrated by intravenously infused OXM (125), while the reduction in food intake was also seen and retained during chronic administration in a 4-week trial with OXM injections three times a day 30 minutes before meals in a group of overweight and obese volunteers (n = 14), OXM reduced nutrient intake (35% ± 9%) resulting in significant weight loss compared to placebo (2.3 ± 0.4 kg vs 0.5 ± 0.5 kg, respectively) (74). The findings of another study with twelve overweight or obese human volunteers who underwent a randomized, double-blinded, placebo-controlled study were similar; an ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3-36 or OXM or combined PYY3-36/OXM. Again, OXM significantly reduced energy intake compared to placebo, although the combined treatment had superior effects compared to PYY3-36 or OXM monotherapy (114). Human studies have also clearly demonstrated the direct effect of OXM on energy expenditure (126); this effect was later confirmed by indirect calorimetry (127). These modest but favorable results suggest significant promise for OXM-based therapies for obesity. In addition to the established action of OXM on appetite, another mechanism that potentially plays a role in energy intake and glucose metabolism is gastric emptying. Intravenous infusion of OXM reduced gastric emptying in humans (128). Whether reduction in gastric emptying is involved in the acute and long-term metabolic effects of OXM is not yet clear. Nevertheless, the immediate future will reveal OXM’s role in obesity management. However, as for other peptide hormones, their clinical application is limited by their short circulatory half-life, a major component of which is cleavage by DPP-IV. Therefore, structurally modified analogues with an altered OXM pharmacological profile have been produced with longer duration of action and a good safety profile and positive effects on body weight (and glucose metabolism) management in animal studies (129,130), this bringing closer their usage in human clinical trials. Furthermore, the crystal structure of OXM has been determined, and this advance should facilitate the rational design of oxyntomodulin peptidomimetics to be tested as oral anti-obesity pharmaceuticals. Even so, despite the promising weight reduction efficacy of OXM, only a small number of development projects appear to be at an advanced stage. TKS1225 is an OXM analogue. The present status of this molecule is unknown. OXY-RPEG has been engineered via its proprietary reversible pegylation technology to increase its half-lifeand increased potency. In preclinical testing, OXY-RPEG was significantly superior to twice daily injections of OXM in the reduction of food intake and the degree and durability of weight loss.

Ghrelin vaccines and ghrelin inhibitors

Ghrelin is a 28-amino acid peptide produced primarily by the stomach and proximal small intestine (131). It is the only known circulating orexigenic hormone and signals both on vagal afferents and in the arcuate nucleus where it powerfully enhances NPY orexigenic signaling (132,133). Its levels increase before meals and are suppressed by the ingested nutrients, with carbohydrates being the most effective ones (compared to proteins and lipids), as its suppression results from neurally transmitted (nonvagal) intestinal signals, augmented by insulin. An experimental ghrelin vaccine, CYT009-GhrQb, was discontinued in 2006 as it did not have the expected effects on weight loss.A novel one conjugated to the hapten, keyhole limpet hemocyanin (KLH), tested in rodent models, was shown to decrease feeding and induce weight loss (134). NOX-B11is a ghrelin-neutralizing RNA spiegelmer, that attaches to the active form of ghrelin and blocks its ability to bind to its receptor, thus blocking the orexigenic activity of exogenously administrated ghrelin in rats (135). However, NOX-B11 did not affect basal food intake in nonfood-deprived rats, thus this treatment may only be efficacious when plasma ghrelin levels are high, such as before a meal or during times of food restriction (dieting).

Since the discovery that the effects of ghrelin are primarily mediated by the GH secretagogue receptor (GHSR) 1a, there have been multiple potent, selective, and orally bioavailable ghrelin antagonists produced with good pharmacokinetic (PK) profiles that are currently in preclinical testing. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat), for example, showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice (136). Moreover, the discovery of ghrelin O-acyltransferase (GOAT) as the enzyme that catalyzes ghrelin octanoylation, which confers its biological activity, revealed several therapeutical possibilities including the design of drugs that inhibit GOAT and block the attachment of the octanoyl group to the ghrelin third serine residue; such GOAT inhibitors could potentially prevent or treat obesity (137).

Fat-specific satiation peptides:

Enterostatin and apolipoprotein A-IV

Enterostatin and apolipoprotein A-IV appear to be GI peptides that are specifically stimulated by fat ingestion and subsequently regulate intake and/or metabolism of lipids. Although peripheral and central enterostatin administration decreases dietary fat intake in animals (while enterostatin-receptor antagonists did the opposite) (138), its administration to humans has thus far shown no effects on food intake, appetite, energy expenditure or body weight (139). Similarly, apolipoprotein A-IV, which is synthesized and secreted exclusively by the small intestine (primarily by the jejunum, but also by the duodenum and ileum), acts as a satiety factor that is downregulated by leptin (140,141) and upregulated by insulin and PYY in both rodents and humans (142,143). Although exogenous administration of apolipoprotein A-IV was quite effective concerning meal size, food intake, and weight gain reduction in rats (144,145), we still lack data regarding apo A-IV therapeutic administration in humans and its effects on body weight.

Pancreatic satiation peptides:

Pancreatic polypeptide (PP)

Pancreatic polypeptide (PP) is a 36-amino acid peptide which is structurally similar to PYY. It is primarily produced in the pancreas in response to ingestion of food and in proportion to caloric load (146). Animal studies have shown that peripheral administration of PP decreases feeding (through Y4R in the area postrema), whereas centrally administrated PP increases it (through Y5R deeper in the brain) (147). In humans, intravenous infusion of PP (10 pmol/kg/min) (supra-physiological levels of PP) in ten healthy volunteers (men and women of normal body weight) caused a sustained decrease in both appetite and cumulative 24-hour energy intake by 25.3 +/- 5.8% (148). the findings of another study addressing the anorexigenic effect of a lower infusion rate of PP (5 pmol/kg/min) in lean fasted volunteers were similar, holding promise for potential use as an anti-obesity agent (149). Another trial studying whether combined treatment with PP/PYY3-36 is superior regarding weight loss compared to either agent alone concluded that PP and PYY3-36 do not inhibit feeding additively in humans (150). Again, this study was conducted on lean subjects. Conversely, as previously mentioned, a synthetic analogue (TM30338) of both PYY3-36 and PP, which acts as an agonist of both the Y2 and Y4 receptors, yielded very promising results as concerns early meal termination when administered once-a-day subcutaneously in obese human subjects (120). Similarly, initial reports of a selective Y4-receptor agonist (TM30339;) currently under development were also quite promising as concerns effect on reduction of food intake and weight loss.

Amylin and amylin analogues

Amylin is a 37-amino acid neuroendocrine peptide hormone cosecreted postprandially with insulin by pancreatic β-cells. Among other properties, amylin has / exerts centrally mediated glucoregulatory and anorexigenic actions (151), inhibiting gastric emptying and glucagon secretion as well as decreasing meal size and calorie intake (fat specific) (152) in a dose-dependent manner. These are vagus-independent actions and are exerted via binding to specific amylin receptors in the hindbrain area postrema (153,154), which is in contrast to the peripheral neural mechanisms engaged by most other gut peptides involved in energy homeostasis system regulation. The anorectic efficacy of amylin along with its glucoregulatory actions were investigated in human studies with the usage of pramlintide which is administered by subcutaneous injections; the latter suggests its potential role as a stable, soluble, nonaggregating, equipotent amylin analogue that retains a broad range of the pharmacodynamic and pharmacokinetic profile of the native hormone, including receptor binding, and differs from amylin by only three amino acids (102,103,155,156). Studies in patients with type 1 and type 2 diabetes have shown great improvement in glycemic control plus sustained reductions in food intake and meal size, as well as mild progressive weight loss, following acute and long-term adjunctive pramlintide treatment (120 μg) (157-159); the most common adverse event associated with pramlintide usage was transient, mild-to-moderate nausea. This weight loss is noteworthy because it occurred in subjects with type 2 diabetes, on concomitant insulin therapy, and in the face of a significant A1C reduction, factors that all favor weight gain. Similarly to the GLP-1 analogues discussed previously, pramlintide is currently approved for the treatment of type 1 and type 2 diabetes. Whether pramlintide could constitute a potent anti-obesity agent was investigated in well-designed trials addressing this issue. In such a study (16-week randomized, double-blind, placebo-controlled), 204 obese non-diabetic individuals were treated with self-administered subcutaneous injections of pramlintide (nonforced dose escalation ≤ 240 μg) or placebo three times a day 15 minutes before meals without concomitant lifestyle intervention (160). According to the results, pramlintide was generally well-tolerated and approximately 90% of the pramlintide-treated subjects were able to escalate to the highest dose of 240 μg three times a day. In contrast to the placebo-treated subjects who experienced minimal changes in body weight over the 16-week treatment period, the pramlintide-treated subjects attained significant weight loss from baseline as early as week 2, which was progressive up to week 16, with no evidence of a plateau. At week 16, the placebo-corrected reduction in body weight after pramlintide treatment was statistically significant compared with placebo (3.7 ± 0.5%, P < 0.001; 3.6 ± 0.6 kg, P < 0.001). Furthermore, the reduction in weight in pramlintide-treated subjects was accompanied by a significant reduction in waist circumference compared with placebo-treated subjects after 16 weeks of treatment (evaluable 4.3 ± 0.6 vs. 0.7 ± 0.9 cm, P < 0.01). At the end of the 16-week trial, 31% of the subjects treated with pramlitide achieved ≥ 5% weight loss compared to just 2% of the placebo group (P < 0.001). Interestingly, 8 weeks after treatment cessation, the pramlintide-treated subjects had on average regained one third of the overall weight loss observed by week 16. These findings constitute a proof of concept that pramlintide may have therapeutic use as an anti-obesity agent. Remarkably, at this higher dose (240 μg three times a day), the mean reduction in body weight with pramlintide treatment over 16 week was approximately twice that previously observed over a similar time-frame in insulin-treated subjects with type 2 diabetes who were treated with lower pramlintide doses (120 μg). This could suggest that higher doses of pramlintide might be necessary to achieve significant weight loss, although it is not yet clear whether concurrent insulin treatment was the main cause of that difference.

Previous animal studies have shown that amylin treatment significantly enhanced hypothalamic anorexigenic leptin signaling (161), 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%) (161,162). Recently, the weight-lowering effect of combined amylin/leptin agonism in human obesity was evaluated using the analogues pramlintide/metreleptin, respectively. As previously discussed (see leptin), three trials (13,14) addressing the weight loss efficacy of the combined treatment over 20, 28, and 52 weeks, respectively) reported sustained and robust weight loss by the combined treatment. Ddevelopment was discontinued following commercial reassessment of the program (15). A Phase II study of davalintide, a second-generation analogue of amylin, for the treatment of obesity has also completed. In this study however, the weight loss efficacy and tolerability profile of davalintide was not superior to pramlintide, and was inferior to the pramlintide/metreleptin combination, this resulting in deciding to halt further development of davalintide (14). In view of the above, studying peptide hormones in combination as integrated neurohormonal approaches may hold promise for the effective treatment of obesity. Based on this premise, the anti-obesity effect of the combined treatment amylin/PYY3-36 was evaluated in an animal study, given that they both may have the potential for short-term signals of meal termination with anorexigenic and weight-reducing effects (163). Statistical analyses revealed that food intake suppression with the combined treatment was synergistic, whereas body weight reduction was additive; this particular combination has not as yet been studied in humans.

On the other hand, preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeting distinct regulatory pathways of the energy homeostasis system may produce robust additive or synergistic effects on weight loss. On this basis, the safety and efficacy of the combined treatment with pramlintide/phentermine and pramlintide/sibutramine was evaluated in a randomized placebo-controlled study with 244 obese or overweight nondiabetic subjects (164). The participants received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 microg t.i.d.), pramlintide sc (120 microg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 microg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. The results suggest that the weight loss achieved at week 24 with either combination treatment was greater 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; mean +/- s.e.), without any major adverse events. In view of recent withdrawal of sibutramine from the market due to adverse cardiovascular events and the short period of time licensed usage of phentermine for weight loss, the pramlintide/phentermine combination could be used as short term anti-obesity agent.

PERIPHERAL MODULATORS OF THE EFFICIENCY OF DIGESTION, METABOLISM, AND LIPOGENESIS

Lipase inhibitors

Apart from early termination of food intake augmented by the centrally acting appetite suppressants, another potential therapeutic anti-obesity approach is the induction of a negative energy balance through the inhibition of nutrient, particularly fat, absorption. Lipase inhibitors inhibit gastric and pancreatic lipases in the lumen of the gastrointestinal tract to decrease systemic absorption of dietary fat. Orlistat is currently the only marketed anti-obesity drug of this category licensed for the treatment of obesity (including weight loss and weight maintenance). The only other pancreatic and gastrointestinal lipase inhibitor currently in clinical development is ATL-962 .

A short-term (12-week) randomized, placebo-controlled study of weight reduction addressing the efficacy, safety, and tolerability of cetilistat in obese patients reported that cetilistat produced a clinically and statistically significant weight loss in obese patients to similar extents at all doses examined compared to placebo (60 mg t.i.d. 3.3 kg, P<0.03; 120 mg t.i.d. 3.5 kg, P=0.02; 240 mg t.i.d. 4.1 kg, P<0.001), plus it significantly improved other obesity-related parameters including waist circumference, serum cholesterol and low-density lipoprotein cholesterol levels. Cetilistat treatment was also well-tolerated and the common orlistat-induced GI adverse events, such as flatus with discharge and oily spotting, occurred in only 1.8-2.8% of subjects in the cetilistat-treated group (165). The combined results from three Phase I clinical studies designed to investigate the efficacy, pharmacodynamics, and tolerability of a range of cetilistat doses [50 mg t.i.d. (n = 7), 60 mg t.i.d. (n = 9), 100 mg t.i.d. (n = 7), 120 mg t.i.d. (n = 9), 150 mg t.i.d. (n = 16), 240 mg t.i.d. (n = 9) and 300 mg t.i.d. (n = 9)] compared with placebo or orlistat [120 mg t.i.d. (n = 9)] in healthy volunteers (166) were published. They report that cetilistat is equipotent with orlistat regarding fecal fat excretion; it however achieves a much better tolerance profile, as the number of episodes of steatorrhea per subject in the orlistat group (4.11) was 2.5-fold greater than that of the cetilistat-treated group. The different tolerance profile between the two lipase inhibitors, seems to be related to the physical form of the fat in the intestine (rather than the amount of fat) resulting from each medication. Thus, cetilistat acts more like a detergent, whereas orlistat may promote the coalescence of micelles, leading to oil-drops and increased gastrointestinal adverse events. Finally, a recent 12-week trial compared the efficacy and safety of cetilistat (40, 80 or 120 mg three times daily) and orlistat (120 mg t.i.d.) relative to placebo in obese patients with type 2 diabetes on metformin (167). According to this study, similar reductions in body weight were observed in patients receiving cetilistat (80 or 120 mg t.i.d.) or orlistat; these reductions were significant compared to placebo (3.85 kg, P = 0.01; 4.32 kg, P = 0.0002; 3.78 kg, P = 0.008). Furthermore, treatment with cetilistat (80 or 120 mg t.i.d.) or with orlistat significantly improved glycemic control relative to placebo; again, cetilistat was well-tolerated and showed fewer discontinuations due to adverse events than in the placebo and orlistat groups. Based on the above findings, this novel lipase inhibitor is currently at the furthest stage in the clinical development of new drugs of this class.

Growth Hormone (GH) and GH lipolytic domain synthetic analogues

Besides its growth effects, GH also possesses significant metabolic properties, including lipolysis induction. On the other hand, GH dynamics change with increasing adiposity and GH circulating levels and response to stimuli are repressed in obesity (168). Taken together, it may be surmised that GH administration could be an effective therapeutic option for weight loss and fat mass reduction in obese individuals. However, the majority of the 16 clinical trials on GH administration in obesity indicated little or no beneficial effects of GH treatment on body weight (169). There is a recent report from an Australia-based biotechnology company for the development of a modified fragment of amino acids 177-191 of GH (hGH177-191) (AOD-9604) that mimics the lipolytic effects of GH without producing growth effects. AOD-9604 however failed to induce significant weight loss in a 24-week trial of 536 subjects (170) and its development as an anti-obesity agent was terminated.

β3-Adrenoreceptor Agonists

The β3-adrenergic receptor is expressed in adipocytes; its activation by cognate β-agonists cause lipolysis and increase thermogenesis. Thyroid hormones increase thermogenesis via the thyroid hormone receptor β subtype; however, to date, every attempt to develop selective thyroid hormone receptor agonists which are effective in adipose tissue without systemic side-effects has failed. In 2000, a selective human β3-agonist, L-796568, was developed (171). Although its acute (4-hour period) administration in overweight human subjects was associated with significant increase in energy expenditure (by ~8%) (172), a 28-day clinical trial investigating the efficacy of chronic use of L-796568 in overweight and obese non-diabetic men receiving the drug (350 mg/d) failed to display any significant changes in body composition or 24-hour energy expenditure (173). The ineffectiveness of β3-adrenreceptor activation to induce significant and sustained lipolysis in humans may be explained by the fact that human white adipose tissue expresses minimal levels of β3-adrenoreceptors; similarly, their expression is also low within human brown adipose tissue. Eli Lilly is currently sponsoring A Phase II weight loss efficacy study to address the effectiveness of the β3-agonist LY-377604 combined with sibutramine in inducing weight loss in overweight/obese men and women is in progress.

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Previous studies have shown enhanced conversion of inactive cortisone to active cortisol through the expression of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in cultured omental adipose stromal cells (174); the autocrine action of cortisol may be crucial in the pathogenesis of central obesity and features of the metabolic syndrome, such as insulin resistance. The reports relating to effectiveness of carbenoxolone (nonselective 11β-HSD inhibitor) in reducing central obesity are conflicting (175,176). Currently, several pharmaceutical companies are developing selective 11β-HSD1 inhibitors which are effective in adipose tissue and may be more efficacious in improving insulin sensitivity and reducing weight. Preliminary data from animal studies evaluating the weight loss efficacy of T-BVT, a new 11β-HSD1 pharmacological inhibitor that homes specifically to white adipose tissue, are very promising regarding its anti-obesity effectiveness and amelioration of multiple metabolic syndrome parameters (177).

Angiogenesis Inhibitors

Increasing adiposity is associated with expansion of the adipose capillary bed. Several vascular growth factors are produced by enlarged adipocytes, for example, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and angiogenin, which may in turn facilitate the expansion of adipose tissue. Thus anti-angiogenesis may eventually form part of the therapeutic approach for the management of body weight. This hypothesis is strengthened by studies where the experimental administration of anti-angiogenic agents in mice from different obesity models resulted in significant weight reduction and adipose tissue loss (178,179). Remarkably, also noted were adaptations in food intake, metabolic rate, and preferred energy substrate; these findings appear to point to fat tissue modulation by the altered vasculature and could underlie the regulatory effect of angiogenesis on physiological processes in adipogenesis. Although there are a large number of foods and beverages containing naturally occurring inhibitors of angiogenesis (e.g. green tea, oranges, strawberries, lemons, red wine, ginseng, garlic, tomato, olive oil, etc.), no convincing clinical trials have as yet been conducted investigating their anti-obesity effect. Currently a Phase II trials for the use of the anti-angiogenic/anti-MMP drug ALS-L1023 in the treatment of obesity is underway (180).

Sirtuin 1 (SIRT1) Activators

Sirtuin 1 (SIRT1) is a member of the sirtuin family of proteins that comprises seven members in mammals (SirT1-T7). Sirtuins have gained considerable attention due to their importance as physiological targets for treating diseases associated with aging. They contribute to cellular regulation interacting with metabolic pathways and may serve as entry points for drugs. SIRT1 in particular has gained popularity as it has been linked with the French Paradox and the calorie restriction-mediated longevity and delayed incidence of several diseases associated with aging, such as cancer, atherosclerosis, and diabetes Tthe calorie restriction-induced modulations have been demonstrated in organisms ranging from yeast to mammals (181). White adipose tissue (WAT) seems to be a primary factor in the longevity brought about through calorie restriction, as mice engineered to have reduced levels of WAT live longer (182). Corroborating this is the finding that food withdrawal is followed by SIRT1 binding to and repression of genes controlled by the fat regulator PPAR-γ (peroxisome proliferator-activated receptor-γ), including genes mediating fat storage which in turn activates of fat mobilization and lipolysis and reduces WAT mass (183). In addition to PPAR-γ, SIRT1 also interacts with PGC-1α, inducing the expression of mitochondrial genes involved in oxidative metabolism and fatty acid oxidation, while it also enhances leptin sensitivity by repressing PTP1B. The weight restricting effects of SIRT1 were further supported by experiments with resveratrol (RSV), a potent allosteric SIRT1 activator, which was shown to protect mice from diet-induced obesity (184). Furthermore, mice treated with SRT1720, a potent, selective synthetic activator of SIRT1, were resistant to diet-induced obesity due to enhanced oxidative metabolism in skeletal muscle, liver, and brown adipose tissue, indicating the positive metabolic consequences of specific SIRT1 activation (185). Currently, several pharmaceutical companies are investigating specific SIRT1 activators in Phase I and Phase II trials for the treatment of type II diabetes and obesity (186) to define their utility in the treatment of obesity and metabolic diseases.

The Emerging Role of Cyclic GMP Signaling in Anti-Obesity Pharmacotherapy

Cyclic nucleotides, including 3-5-cyclic guanosine monophosphate (cGMP) and 3-5-cyclic adenosine monophosphate (cAMP), are second messengers important in many biological processes. Knowledge about the role of cAMP in the regulation of energy homeostasis has been extended thanks to its intimate relationship with AMPK (AMP-activated protein kinase) signaling; intracellular cAMP activates the AMPK signaling pathway. AMPK regulates energy balance at both cellular and whole-body levels (187). Activation of AMPK facilitates fatty acid oxidation and mitochondria biogenesis, which promotes energy expenditure (188). Interestingly, activation of AMPK in the hypothalamus promotes food intake behavior (189). eg. physiologic processes in the same direction, and induces weight loss by mutual reinforcement. Moreover, practical, off-the-shelf approaches might be possible, given the existence of an established market for medications targeting cGMP pathways, with FDA- and EMA-approved drugs such as sildenafil and linaclotide.

ALTERNATIVE AND COMPLEMENTARY TYPES OF TREATMENT OF OBESITY

Acupuncture is among the oldest healing practices in the world and is today becoming one of the most rapidly growing complementary therapies. In the USA, the National Institutes of Health consensus panel recommends acupuncture as a useful clinical procedure and thus created the National Center for Complementary and Alternative Medicine with the aim of integrating complementary therapies into mainstream clinical practice. The majority of animal studies addressing its effect on body weight management concluded that acupuncture (in different forms) is effective in decreasing food intake and inducing weight loss (200-203). It was shown that it acts on the satiety centre situated in the hypothalamic ventromedial nucleus and also influences the feeding centre in the lateral hypothalamic area. Acupuncture was shown to increase the expression of the anorexigenic peptides a-MSH, obestatin and CART (200), in the hypothalamic ARC and to downregulate the orexigenic peptide NPY (in ARC) and ghrelin (in the stomach) (201). Finally, it exerts a regulatory action on serotonin and its metabolism in the raphe nuclei, thus further decreasing hunger.

The usefulness of acupuncture in treating obese patients has been studied over recent decades (204). A meta-analysis of 29 randomised controlled trials with different types of acupuncture (205) found that acupuncture was associated with significant body weight reductions compared with lifestyle measures, placebo or sham treatments and conventional medication (average weight reduction with acupuncture 1.72 kg vs lifestyle measures; 1.56kg vs placebo or sham treatments and 1.90kg vs conventional medication, respectively). Another systematic review showed that acupuncture was more effective than placebo or lifestyle modification in reducing body weight and was as efficacious as conventional anti-obesity drugs but with fewer reported adverse effects. A recent review of the literature (206) has clearly shown that acupuncture (in different forms) exerts beneficial effects on obesity, including reduction in body weight, body mass index, waist and hip circumference,

COMBINATION APPROACHES TO OBESITY TREATMENT – AN EYE ON THE FUTURE

As long as the prevalence of obesity is on the rise , the need for better tolerated and more efficacious pharmacotherapies will increase. Recent advances in our knowledge about energy homeostasis regulation at the molecular level are enabling novel anti-obesity drugs to be designed targeting specific molecules crucial for energy balance modulation. There are drugs in development that induce satiety signaling, others that repress hunger or modulate nutrient absorption and others that affect metabolism and lipogenesis in such a way that energy expenditure exceeds energy intake. Experience however from multiple agents that have been evaluated has shown that a medication that targets only one mechanism produces weight loss of 5%-10%. This amount of weight loss may be sufficient to improve the metabolic profile and ameliorate cardiovascular risk factors; it is however far from what obese subjects would expect cosmetically, which usually means a weight reduction of 20%-25%, similar to that offered by bariatric surgeries. The FDA recently approved three anti-obesity drugs, of which two are combinations of two different agents that target different regulators of the appetite/feeding system. Data from bariatric surgery weight loss and subsequent eating behaviour modulations suggest that the mechanisms of long-term weight loss following bariatric surgery are insufficient to account for the resulting body weight loss alone (207-209) and that alteration of previously described gut hormones and neuroendocrine signaling may be actively involved in postoperative changes in eating behavior and appetite (210, 211). In addition, a shift away from pharmacological agents that act on pathways in the CNS could lead to drugs with fewer side effects and more favorable risk/benefit ratios. Therefore, pharmacological intervention for the management of obesity in the future will most likely be a combination of the above neuropeptides in a manner that mimics the changes underlying the surgically induced weight loss. However, the road to the achievement of ‘bariatric pharmacotherapy’ is still a long one, with the most optimistic predictions indicating a promising and successful attainment of potent pharmacotherapy of obesity over the next decade. In the meantime, current conventional therapeutic strategies (i.e. diet, physical exercise, anti-obesity drugs, implantable devices for vagal blockage and/or bariatric surgery) along with alternative and complementary types of treatment including acupuncture constitute the main therapeutic tools for the management of obesity in clinical practice. Tables 1 and 2 summarize current anti-obesity agents as well as studies on combined drugs that are in progress.

Table 1Anti-obesity drugs currently approved and in progress and expected weight loss

DrugDrug descriptionCompanyDrug/Placebo/ Net weight loss (kg)
Phentermine (Adipex-p, Acxion, Duromine, Metermine, Suprenza) *Amphetamine derivative / sympathetic effects6.8 / 2.8 / 4.0
Orlistat (Xenical) *Lipase inhibitorRoche Holding Ltd7.3 / 3.5 / 3.0
TesofensinePresynaptic inhibitor of norepinephrine, dopamine, and serotoninNeuroSearch12.8 / 2.2 / 10.6
VelneperitY5-receptor antagonistShionogi USA, Inc7.1 / 4.3 / 2.8
MetreleptinLeptin analogueTakeda Pharmaceutical Company Limited
PramlintideAmylin anallogAmylin Pharmaceuticals, Inc.
PTP1B blockerLeptin sensitizer
PBALeptin sensitizer
TUDCALeptin sensitizer
BMS-830216MCH antagonistBristol-Myers Squibb
Lorcaserin (Belviq)*5-HT2C receptor agonistsArena Pharmaceuticals8.2 / 3.4 / 4.8
TTT-435AgRP inhibitorTransTech Pharma
Bupropiondopamine and norepinephrine -reuptake inhibitor6.0 / 2.8 / 3.2
Zonisamideserotonin-receptor agonist and dopamine-reuptake inhibitor9.2 / 1.5 / 7.8
TopiramateGABA inhibitor4.5 / 1.7 / 2.8
ObinepitideY2/Y4-receptor agonist7TM Pharma
TM30339Y4-receptor agonist7TM Pharma
GI181771XCCK1R agonistGSK
LixisenatideGLP1R agonistZealand Pharma
CJC-1134-PCGLP1R agonistConjuChem Biotechnologies Inc.
AlbiglutideGLP1R agonistGSK
TaspoglutideGLP1R agonistRoche
LY2189265GLP1R agonistEli Lilly
Liraglutide (Saxenda)*GLP1R agonistNovoNordisk7.2 / 2.8 / 4.4
PYY3–36Y2R agonist
OXMGLP1R agonist2.3 / 0.5 / 1.8
TKS1225OXM analogueThiakis/Wyeth/Pfizer
OXY-RPEGOXM analoguePROLOR Biotech
NOX-B11Ghrelin vaccinePfizer
GOAT inhibitorsGhrelin inhibitors
ATL-962 (Cetilistat)Lipase inhibitorAlizyme4.3 / 2.8 / 1.5
AOD-9604GH lipolytic domain analoguePhosphagenics
T-BVTWhite adipose tissue selective 11β-HSD1 inhibitor
SRT1720SIRT1 activators
  • Approved by the FDA

Table 2Combined treatments currently approved and investigational drugs for the treatment of obesity and expected weight loss

DrugStudy phaseDrug/Placebo/ Net weight loss (kg)
Pramlintide/MetreleptinII12.7 /no placebo / 12.7
Bupropion/Naltrexone (Contrave)*Approved by the FDA 20148.2 / 1.9 / 6.2
Bupropion/Zonisamide (Empatic)IIb7.2 / 2.9 / 4.3
Topiramate/Phentermine (Qsymia)*Approved by the FDA 201214.7 / 2.5 / 12.2
PYY3–36 /GLP-1 combinationII
PYY3–36/OXMII
obinepitide (PP/PYY3-36)II
amylin/PYY3–36II
pramlintide/phentermineII
pramlintide/sibutramineII
β3-agonist LY-377604/ sibutramineII
ALS-L1023II
  • Approved by the FDA

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