Pharmacotherapy for Obesity Abstract and Introduction Abstract Despite the requirement for effective and safe pharmacotherapies to tackle the obesity epidemic, there is currently only one drug, orlistat, licensed for this purpose, but the effectiveness of this drug falls far short of the medical needs. Recent advances in the understanding of energy balance control have highlighted a number of new biological targets for the treatment of obesity. Some pharmacological approaches for bodyweight loss have yielded promising results in clinical trials. However, finding the correct balance between efficacy and safety has proven challenging. Given the high unmet need and our growing understanding of the complexity of bodyweight homeostasis, novel, more efficacious and better tolerated treatments for obesity are clearly required. In this article, we provide an overview of currently available anti-obesity agents, the reasons for the failure of a number of recent drug candidates and discuss future strategies for pharmacological interventions to treat obesity. Introduction Obesity is associated with a wide range of metabolic and cardiovascular conditions that substantially increase the risk of stroke, coronary heart disease and myocardial infarction. [1] The combination of widespread consumption of the energy-dense Western diet with an increasingly sedentary lifestyle has increased the global prevalence of obesity and the associated causes of mortality and morbidity. The WHO reported that in 2008, 500 million adults were obese globally, which is expected to rise to 700 million by 2015. [201] Approximately two-thirds of US adults are overweight or obese [2] and the obesity rate in English men increased from 13.2% in 1993 to 23.1% in 2005 and in English women from 16.4 to 24.8% during the same period. [202] Diet and exercise remain the most commonly prescribed strategies for weight loss, but have proved unsuccessful for many affected individuals. [3] Therefore, industrial interest in the development of effective pharmacological therapies has been sustained. The approval criteria demanded of novel anti-obesity drugs as set out by the US FDA were revised in 2007, [203] necessitating a 5% or more mean placebo-subtracted weight loss after 1 year of therapy or a minimum of 35% of participants achieving more than 5% weight loss. The European Medicines Agency (EMA) guidelines similarly require a 10% or more weight loss over 1 year, which should be more than 5% above that achieved by placebo. [4] As an important secondary end point, the EMA also stipulate prevention of weight gain after cessation of therapy. Of note, both agencies also call for evidence of improvements in metabolic comorbidities as these are known to affect the cardiovascular risk more than weight loss alone. Treatments that induce weight reduction without specifically reducing cardiovascular risk are considered of primarily cosmetic benefit and would be less likely to gain approval for clinical use.
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Pharmacotherapy for ObesityAbstract and IntroductionAbstract
Despite the requirement for effective and safe pharmacotherapies to tackle the obesity epidemic, there is currently only one drug, orlistat, licensed for this purpose, but the effectiveness of this drug falls far short of the medical needs. Recent advances in the understanding of energy balance control have highlighted a number of new biological targets for the treatment of obesity. Some pharmacological approaches for bodyweight loss have yielded promising results in clinical trials. However, finding the correct balance between efficacy and safety has proven challenging. Given the high unmet need and our growing understanding of the complexity of bodyweight homeostasis, novel, more efficacious and better tolerated treatments for obesity are clearly required. In this article, we provide an overview of currently available anti-obesity agents, the reasons for the failure of a number of recent drug candidates and discuss future strategies for pharmacological interventions to treat obesity.
Introduction
Obesity is associated with a wide range of metabolic and cardiovascular conditions that substantially increase the risk of stroke, coronary heart disease and myocardial infarction. [1] The combination of widespread consumption of the energy-dense Western diet with an increasingly sedentary lifestyle has increased the global prevalence of obesity and the associated causes of mortality and morbidity. The WHO reported that in 2008, 500 million adults were obese globally, which is expected to rise to 700 million by 2015.[201] Approximately two-thirds of US adults are overweight or obese [2] and the obesity rate in English men increased from 13.2% in 1993 to 23.1% in 2005 and in English women from 16.4 to 24.8% during the same period.[202] Diet and exercise remain the most commonly prescribed strategies for weight loss, but have proved unsuccessful for many affected individuals. [3] Therefore, industrial interest in the development of effective pharmacological therapies has been sustained.
The approval criteria demanded of novel anti-obesity drugs as set out by the US FDA were revised in 2007,[203] necessitating a 5% or more mean placebo-subtracted weight loss after 1 year of therapy or a minimum of 35% of participants achieving more than 5% weight loss. The European Medicines Agency (EMA) guidelines similarly require a 10% or more weight loss over 1 year, which should be more than 5% above that achieved by placebo.[4] As an important secondary end point, the EMA also stipulate prevention of weight gain after cessation of therapy. Of note, both agencies also call for evidence of improvements in metabolic comorbidities as these are known to affect the cardiovascular risk more than weight loss alone. Treatments that induce weight reduction without specifically reducing cardiovascular risk are considered of primarily cosmetic benefit and would be less likely to gain approval for clinical use.
Despite these high demands for new drug approval, the market for a safe and efficacious drug is still potentially huge. However, the value of currently approved therapies that have effects on weight do not reflect this potential, which is evidence of their limited efficacy and/or unacceptable side-effect profiles. Persistent efficacy and safety, however, is of particular important in the management of obesity, which, as a chronic condition, requires ongoing therapy over decades to achieve and maintain weight loss.
This article provides an overview of the efficacy and safety of weight-loss therapies and addresses the therapeutic targets of past and current pharmacotherapies, as well those in advanced clinical development.
Pharmacotherapy of ObesityTreatments designed to induce weight loss focus on reducing energy intake (by decreasing food absorption or by decreasing appetite), increasing energy expenditure or a combination of both effects. Safe drugs that target fat storage mechanisms have not so far been identified. There are four broad categories into which current and future agents can be divided: peripherally acting agents reducing the efficiency of digestion; agents modifying the homeostatic regulation of food intake and energy expenditure, which can be further divided into those with central and peripheral actions; and agents that act to inhibit food intake by acting on the brain's reward centers.
Peripherally Acting Agents Reducing the Efficiency of DigestionOrlistat
Orlistat (Xenical®; Roche) is the only anti-obesity drug that remains on the market after the withdrawal of sibutramine in 2010. This stable analog of lipstatin, a naturally occurring lipase inhibitor produced by Streptomyces toxytricini, is indicated for the treatment of obesity in conjunction with a reduced-calorie diet. Orlistat acts locally to potently inhibit pancreatic and gastric lipase and thus the hydrolysis of triglycerides. As a result, only approximately two-thirds of dietary triglyceride intake is absorbed by the small intestine. Orlistat has been shown to be modestly efficacious (120 mg three-times daily) in several long-term randomized clinical trials where it induced weight loss of approximately 2–4 kg more than diet and exercise alone.[5–7] The most common side effects are diarrhea, flatulence, bloating, abdominal pain and dyspepsia. After independent reports of liver injuries (including six cases of liver failure between 1999 and 2008),[204] the FDA has recently approved a label revision for orlistat containing an additional a warning of possible severe liver injury. Compounds that inhibit glucosidase (acarbose and miglitol) and thus the digestion of starches, which induces carbohydrate absorption, have little effect on weight.
Modulation of Appetite & Energy ExpenditureThe balance of energy intake and expenditure by the brain relies on the complex integration of signals originating in the periphery with those from diffuse neuronal networks within the brain itself. In response to these signals, the brain produces a coordinated response to any change in nutritional status to maintain energy homeostasis. This response can take the form of altered appetite and/or energy expenditure.
Putative satiety hormones and neurotransmitters involved in energy regulation circuits have been key targets for obesity drug development over the last decade (Figure 1). Despite this focus, there are no current anti-obesity treatments targeting these circuits. In fact, all three anti-obesity agents under FDA review in 2010 (a 5-HT2C receptor agonist lorcaserin, a phentermine–topiramate combination (Qnexa®; VI-0521, Vivus) and a naltrexone–bupropion combination (Contrave®, Orexigen Therapeutics Inc.) have been rejected and previously effective agents (phentermine, rimonabant and sibutramine) have been withdrawn due to safety concerns. In examining what went wrong with these drugs, it is important to consider whether their failings are indicative of all drugs of their specific classes or indeed likely to be drawbacks of all centrally acting agents. This could have implications for drugs targeting the CNS currently in early-stage clinical trials.
Figure 1.
The brain integrates multiple peripheral and neural signals to control the regulation of energy homeostasis, maintaining a balance between food intake and energy expenditure. Peripheral factors indicative of long-term energy status are produced by adipose tissue (leptin and adiponectin) and the pancreas (insulin), whereas the acute hunger signal ghrelin (produced in the stomach) and satiety signals such as the gut hormones PYY(3–36), PP, amylin and OXM indicate near-term energy status. The incretin hormones GLP-1, GIP and potentially OXM improve the response of the endocrine pancreas to absorbed nutrients. Further feedback is provided by nutrient receptors in the upper small bowel and neural signals indicating distention of the stomach's stretch receptors, which are primarily conveyed by the vagal afferent and sympathetic nerves to the nucleus of the solitary tract (NTS) in the brainstem. The arcuate nucleus (ARC) of the hypothalamus, which is located between the third ventricle and the median eminence, integrates these energy homeostatic feedback mechanisms. It accesses the short- and long-term hormonal and nutrient signals from the periphery via semi-permeable capillaries in the underlying median eminence and receives neuronal feedback from the NTS. These collated signals act on two distinct subsets of neurons that control food intake in the ARC, which act as an accelerator and a brake respectively. The first subset coexpresses the orexigenic (appetite-stimulating) agouti-related peptide and neuropeptide Y (NPY) neurotransmitters, acting as an accelerator in the brain to stimulate feeding. The other neuronal population releases the anorexigenic cocaine- and amphetamine-regulated transcript and pro-opiomelanocortin neurotransmitters, both of which inhibit feeding. Both neuronal populations innervate the paraventricular nucleus, which, in turn, sends signals to other areas of the brain. These include
hypothalamic areas such as the ventromedial nucleus, dorsomedial nucleus and the lateral hypothalamic area, which modulate this control system. Neural brain circuits integrate information from the NTS and multiple hypothalamic nuclei to regulate overall body homeostasis.
CCK: Cholecystokinin; DVC: Dorsal vagal complex; GIP: Glucose-dependent insulinotropic peptide; GLP-1: Glucagon-like peptide-1; OXM: Oxyntomodulin; PP: Pancreatic polypeptide; PYY: Peptide YY.
Centrally Acting Agents Affecting the Homeostatic Regulation of Food IntakeA variety of potentially satiety-enhancing drugs have been developed targeting different hypothalamic circuits. Meal-induced hormonal and neuronal signals travel from the GI tract to the area postrema and nucleus tractus solitarius in the brainstem. From here, sensory input is transmitted to other centers (including the amygdale and nucleus accumbens). Dopaminergic, opioid and endocannabinoid signaling assign reward value to meals consumed. Inputs from these pathways appear to be integrated with circulating signals of nutritional state, such as fatty acids and the adipocyte hormone leptin, which are detected in the arcuate nucleus (Figure 1).[8] Leptin is known to stimulate the activity of neurons expressing pro-opiomelanocortin (POMC), while inhibiting neurons expressing neuropeptide Y (NPY).[9,10] POMC neurons in turn stimulate the release of α-melanocyte-stimulating hormone (α-MSH), activating the melanocortin receptor 4 (MC4R), leading to a reduction in food intake and increase in energy expenditure.[11] By contrast, activation of NPY-Y1 and Y5 receptors is known to cause increases in food intake and reduction in energy expenditure. [12] NPY-expressing neurons also release agouti-related peptide (AgRP), an endogenous antagonist of the MC4R.[13]
Many of the neuropeptide receptors expressed centrally are also expressed peripherally and thus actions of agonists or antagonists of these receptors cannot be assumed to induce weight loss by central mechanisms alone.
Melanocortin 4 Receptor Agonists
The melanocortin 4 receptor is known to be crucial to the regulation of appetite. MC4R-null mice are hyperphagic and obese[14] and MC4R deficiency is the most common monogenetic cause of obesity in humans.[15] At least in theory, MC4R agonists could induce weight loss both in MC4R-deficient individuals, who retain some functional MC4R receptors and the obese population more generally. However Merck's MK-0493, an orally active, selective MC4R agonist, caused no significant reduction in energy intake or bodyweight in Phase II clinical trials.[16] The dose of MK-0493 was limited by nausea and vomiting seen at high doses and efficacy was not achievable at doses below the threshold for these adverse effects. Merck also reported increases in blood pressure in animal studies using MK-0493 and the authors concluded that "taken together, our results suggest that an MC4R agonist is not likely to provide clinically meaningful reductions in bodyweight at doses that are well tolerated." Rhythm showed promising preclinical results in obese primates when treated with their peptide MC4R agonist (RM-493) in June 2010 and Rhythm say this peptide will shortly enter Phase I clinical trials. Merck's MK-0493 also seemed promising at the preclinical stage but was only tested in rodents, whereas RM-493 showed efficacy in primates and thus may be more predictive of the results of human trials.
Targeting the Serotonin System
Serotonergic signaling appears able to modulate the activity of NPY/AgRP and POMC-expressing neurons in the arcuate nucleus of the hypothalamus,[17] which have well-characterized roles in the regulation of appetite and energy expenditure. Anti-obesity treatments targeting the serotonin (5-HT)
system are typically derived from β-phenethylamine, which has the same basic structure as the neurotransmitters dopamine, noradrenaline and adrenaline and mediate their effects by influencing noradrenergic, dopaminergic and serotonergic neurotransmission. Of the 14 recognized 5-HT receptor subtypes, the 5-HT1B, 5-HT2C and 5-HT6 receptors, which are distributed widely within the CNS, are of particular interest for the modulation of bodyweight.[18] Activation of these receptor subtypes, either directly using receptor agonists, or indirectly by increasing the availability of endogenous 5-HT, leads to reduced food consumption, whereas decreasing 5-HT receptor activation produces the opposite effect.
Serotonin-reuptake Inhibitors
Sibutramine (Meridia® Abbott), was approved by the FDA in 1997 as the first agent blocking the reuptake of noradrenaline and 5-HT on the market.[19,20] Cardiovascular concerns were reported quite early, but it was a further 13 years before a study of sufficient size and duration was completed affirming these concerns. The Sibutramine Cardiovascular Outcomes (SCOUT) trial, which analyzed 10,000 patients with pre-existing cardiovascular disease over a period of 3.4 years, reported a clearly higher cardiovascular risk in patients taking sibutramine compared with placebo (11.4 vs 10%; p = 0.02).[21] Based on these findings, sibutramine has undergone a revision process and was finally withdrawn from the European and US market last year.[205]
A second serotonin-reuptake inhibitor is currently in development. Tesofensine (NS2330) is described in clinical trials as an inhibitor of the reuptake of noradrenaline, dopamine and 5-HT, [22,23] which was initially developed for the treatment of Alzheimer's and Parkinson's diseases. Tesofensine was reported to cause some weight loss in obese patients being treated for both these diseases and hence the drug was subsequently assessed in dose-dependent weight loss studies, where it induced promising weight reductions of 2.1% (0.125 mg dose), 8.2% (0.25 mg), 14.1% (0.5 mg) and 20.9% (1 mg) after 14 weeks of therapy.[23] The authors emphasized that this made tesofensine of comparable efficacy to sibutramine.[23] In a Phase IIb dose-dependent trial over 24 weeks,[24] tesofensine also had beneficial effects on hyperlipidemia and glucose metabolism. However, dose-dependent adverse effects on blood pressure and heart rate were reported, and patients in the 1 mg group displayed increased anger and hostility. In fact, tesofensine appears to show the same selectivity in inhibiting noradrenaline and 5-HT uptake over dopamine uptake as does sibutramine and thus is likely to have a similar side-effect profile.[25,26] Although serious psychiatric adverse reactions were denied by the investigators, it will be interesting to see whether this is substantiated in Phase III trials.
Serotonin Receptor Agonists & Antagonists
Among the wide spectrum of serotonin (5-HT) receptors, three subtypes are of particular interest in the modulation of bodyweight: the 5-HT1B, 5-HT2C and 5-HT6 receptors. Evidence suggests that a 5-HT1B receptor agonist reduces food intake in rodents.[18] However, the 5-HT1B receptor agonists currently used in the treatment of migraine are associated with cardiovascular side effects such as chest pain and myocardial infarction,[27–29] precluding any attempt to further evaluate this target for anti-obesity therapy. Selective 5-HT6 receptor antagonists and partial agonists have demonstrated promising hypophagic effects and efficacious weight loss in rodent studies. The effects of these ligands are apparently behaviorally selective and they are well tolerated.[30] Currently, drugs targeting the 5-HT6 receptors are primarily considered as a potential treatment for Alzheimer's disease. Further characterization of the role of 5-HT6 receptors in energy homeostasis is desirable before they can be seriously considered as targets for anti-obesity agents.
Analogs of the 5-HT2C receptor are of special interest for obesity treatment. Fenfluramine and its more active isomer, dexfenfluramine, were widely prescribed in the 1980 and 1990s, but escape from their effect after a few months was a significant clinical problem and a rare, although usually fatal, complication was pulmonary hypertension. They induce weight loss via the formation of an active
metabolite, D-norfenfluramine, a potent 5-HT2C agonist.[31] Consistent with rodent studies, the anorexigenic activity of dexfenfluramine in humans can be attenuated by the nonselective 5-HT2C receptor antagonist ritanserin.[32] Consequently, the combination of fenfluramine and phentermine was widely prescribed in the mid-1990s as a very effective appetite suppressant, leading to approximately 10% weight loss.[33] Phentermines are amphetamine-like compounds that act by releasing noradrenaline from presynaptic vesicles in the lateral hypothalamus. The combination was withdrawn from the market in 1997 after dexfenfluramine was shown to be associated with cardiac valvulopathy[34,35] and pulmonary hypertension.[36] Both side effects appear to be the result of the concomitant 5-HT2B receptor activation[31,37] and thus selective 5-HT2C agonists may be efficacious without the adverse effects of 5-HT2B agonism. The development of compounds with the required selectivity between 5-HT2C and other receptor subtypes, however, turned out to be difficult.
The first drug designed as a selective 5-HT2C receptor agonist with a functional selectivity of about 15–100-times over that for 5-HT2A and 5-HT2B receptors, was lorcaserin (APD-356). In a recent Phase III clinical study[38] 3182 obese patients were randomly assigned to receive 10 mg lorcaserin or placebo twice daily over 1 year. An average weight loss of 5.8 kg was reported in the lorcaserin group compared with 2.2 kg in the placebo group. After 2 years, patients who switched to placebo for the second year gained back the lost weight, whereas subjects who continued with lorcaserin regained some weight, leaving a placebo-subtracted weight loss of only 2 kg after 2 years. Overall, 50% of patients in the lorcaserin group failed to lose the required 5% bodyweight, and some of them lost nothing or even gained weight. Although lorcaserin was found not to cause any major mood-related adverse effects or cardiac valvulopathy in this 2-year study, its relative lack of efficacy compared with orlistat makes it unlikely to be a useful treatment for the majority of obese patients. Owing to this relative lack of efficacy and some remaining concerns about safety, the FDA expert panel voted against approval in October 2010, and the developers have been asked to provide additional evidence about the safety of lorcaserin before approval will be considered again. [206]
NPY Receptor Ligands
The neuropeptide NPY is thought to stimulate appetite by activation of the Y1 and Y5 receptors in the hypothalamus. As a result, antagonists at these receptors have been produced with the aim of blocking this orexigenic effect. Merck developed an orally available Y5 receptor antagonist MK-0557; however, in a 52-week multicenter, randomized double-blind placebo-controlled human trial, only a 1.6 kg placebo-subtracted weight loss was seen in the Y5 antagonist-treated group. [39] Numerous Y1 receptor antagonists have been developed, including BMS-193885 (Bristol-Myers Squibb), which showed promising effects on bodyweight in rats[40] but has not been tested in humans. The Y2 receptor is expressed presynaptically and activation of this receptor is thought to inhibit the release of NPY,[41] thus reducing food intake. PYY3–36 is an anorectic hormone, released from the gut postprandially in proportion to the calories consumed.[42] PYY is thought to mediate its effect by agonism of Y2 receptors in the arcuate nucleus of the hypothalamus [42] and also on the vagus nerve.[43,44] Obese individuals are characterized by lower levels of PYY3–36 and its anorexigenic effect appears to be preserved in obese patients, making PYY3–36 an attractive therapeutic target.[45] Several studies in humans have shown that intravenous infusions of a single dose [46] and graded infusions of PYY3–36 [47] reduce appetite and food consumption by more than 30% in lean and obese subjects. However in a Phase II clinical trial, intranasally delivered PYY3–36, which produces a poorly sustained rapid spike in blood levels, proved to be ineffective at inducing weight loss at a low dose, and problems with nausea and vomiting were encountered at high doses.[48] Nausea is a frequent side effect of all appetite inhibitors, perhaps because it is merely a physiological extreme form of appetite inhibition, an inseperable high-dose effect. Nausea is a known side effect of pharmacological doses of PYY3–36 [49] and thus the potential of Y2 agonists as treatments for obesity may be limited by this adverse effect. Nonetheless, Y2 agonists continue to be developed, and one peptide agonist RG7089 (Roche) reportedly entered Phase I clinical trials in 2009; however, the results have not yet
been reported and this peptide is not currently listed in Roche's development pipeline. [207] In addition, Roche have reported preclinical studies showing PEGylated PYY3–36 (RO5095932) had beneficial effects on glucose homeostasis and weight loss in leptin receptor-deficient mice and this drug is currently in Phase I clinical trials in combination with metformin (clinicaltrials.gov trial number NCT01017302).[208] If PYY3–36 acts in the CNS, it is unclear if pegylation limits access.
Neuropeptide Y and the NPY receptors are widely expressed in the brain and in the periphery [50] and have been implicated in roles as diverse as learning and memory[51] and excitation–contraction coupling in cardiomyocytes;[52] thus, any drugs targeting this system could prove to have unwanted side effects.
Glucagon-like Peptide-1 Receptor Agonists
Centrally, the glucagon-like peptide (GLP)-1 receptor is expressed in the paraventricular, arcuate and dorsomedial nuclei in the hypothalamus and the nucleus tractus solitarius, area postrema and parabrachial nucleus in the brainstem.[53] GLP-1 is an agonist at this receptor and is released postprandially from intestinal L cells, as well as from preproglucagon neurons in the nucleus tractus solitarius, and has been shown to inhibit food intake when administered peripherally or centrally. [54–56] GLP-1 also acts as an incretin, increasing glucose-stimulated insulin release and inhibits glucagon release and gastric emptying. Chronic subcutaneous infusion of GLP-1 to patients with Type 2 diabetes mellitus can induce weight loss and improved glucose homeostasis, [57] making the GLP-1 receptor an attractive target for anti-obesity agents. As GLP-1 itself is rapidly cleared from the circulation, analogs of this hormone have been developed that are resistant to dipeptidyl peptidase-IV, the primary enzyme responsible for GLP-1 degredation. The first available mimetics were exenatide (Byetta®; Lilly)[58–61] and liraglutide (Victoza®; Novo Nordisk), which caused improved glycemic control and dose-dependent weight loss in Phase III clinical trials in patients with Type 2 diabetes.[62–64] These agents have been approved for the treatment of Type 2 diabetes but are not currently licensed to treat obesity itself.
A once-weekly suspension of exenatide as a poly-lactide-glycolide microsphere suspension with 3% peptide content has recently been developed, aiming at sustained glycemic control along with a more comfortable standard once-weekly dosing.[65] In the first 30-week randomized trial, long-acting exenatide led to slightly greater improvements in fasting blood glucose and HbA1C than did exenatide given twice daily.[65] Similar benefits with long-acting compared with twice-daily exenatide were shown on bodyweight (3.7 ± 0.5 kg weight loss in 30 weeks [65]and 2.6 ± 0.2 kg weight loss in 26 weeks[66]), blood pressure and triglycerides.[65,67,68]
Another GLP-1 receptor agonist, taspoglutide (Roche), was also designed for once weekly administration. Despite its initially promising results in preclinical and clinical trials,[69,70] Roche discontinued Phase III trials in September 2010 due to diverse gastrointestinal events and hypersensitivity issues. It is not yet known whether these are indicative of the entire class of GLP-1 receptor agonists. Whether long-acting exenatide may succeed twice-daily exenatide as a treatment for type II diabetes will depend on the results of specifically designed trials for accrual of valid safety data.
The most common side effects observed with all GLP-1 mimetics are nausea and vomiting at high doses.[71,72] Thyroid C-cell abnormalities have been reported in preclinical studies for exenatide and liraglutide. Exenatide showed an increased incidence of benign C-cell adenomas, while liraglutide was associated with an increase in C-cell carcinomas in rats and female mice administered the highest liraglutide dose tested.[73] These findings could not be verified in nonhuman primates at an exposure up to 60-fold that of the maximum recommended human dose.[74]
In order to assess the potential role of liraglutide on C-cell function in humans, calcitonin levels were monitored among patients enrolled in liraglutide clinical trials. These data showed no differences in calcitonin levels between liraglutide-treated patients and control groups.[75] The discrepancy between rodent and human data may be due to a species differences in the sensitivity of rodent C cells versus primate C cells to activation by GLP-1 agonists or due to higher dose levels used in the preclinical studies. In view of the rodent data, liraglutide is contraindicated in patients with a history of medullary thyroid carcinoma or multiple neoplasia Type 2.[76]
Oxyntomodulin is also an endogenous GLP-1 receptor agonist. Like GLP-1, oxyntomodulin reduced food intake in rats when administered centrally or peripherally but, unlike GLP-1, oxyntomodulin also increases energy expenditure.[77–80] This is thought to be because oxyntomodulin is also a glucagon receptor agonist. In humans, intravenous infusion of oxyntomodulin reduces food intake, [81] while repeated subcutaneous injection increases energy expenditure and causes weight loss in obese volunteers.[82,83] A peptide analog of oxyntomodulin (PF-05212389) was developed by Thiakis and bought by Wyeth/Pfizer in 2008 who are putting this agent through Phase I trials. A pegylatedoxyntomodulin analog has also been produced, which has caused weight loss and improved glucose tolerance in preclinical studies.[84] As GLP-1 receptor agonists, it is possible that oxyntomodulin analogs will prove to have the same propensity to induce nausea and vomiting as the currently available GLP-1 receptor agonists.
Centrally Acting Agents Affecting the Hedonic Control of Food IntakeA second approach to reducing food intake is to target the brain's reward pathways. The reward systems are activated in response to the intake of high-calorie palatable foods and are thought to stimulate intake of these foods even in the absence of nutrient deficit or weight loss.[85] Pharmacological interventions that alter the reward value of food might therefore be useful in controlling food intake. However, the same systems are thought to be involved in addictive behavior and motivation more generally, and thus drugs targeted at these systems may have profound emotional and behavioral consequences. Physiologically, a single neurotransmitter will usually mediate several different actions or systems but these are physically separated, such as in different neural pathways, which prevents functional overlap. A chemical mimic of the neurotransmitter will necessarily activate all the pathways it participates in and thus obligatorily have several different actions, some of which may be unwanted therapeutically.
Cannabinoid Receptor (CB1) Antagonists
The endocannabinoids are endogenous lipids derived from arachidonic acid, which activate G-protein-coupled cannabinoid receptors (CB). Endocannabinoid signaling within the hypothalamus and mesolimbic system affects food intake. Administration of an endocannabinoid into the ventromedial hypothalamus or the nucleus accumbens of rats causes increased food intake, an effect blocked by a CB1 receptor antagonist.[86,87] Antagonists of the CB1 receptor have been developed as potential treatments for obesity and several clinical trials using these agents have been carried out.[88–90]
The first selective CB1 receptor antagonist to be approved to treat obesity was rimonabant (Acomplia®, Sanofi-Aventis). Weight loss of approximately 7% was achieved over a 1-year period in patients treated with this drug.[88] Reduction in food intake, premeal hunger and desire to eat, with only little effect on satiety, suggested that the CB1 blockade specifically suppressed the motivation to eat.[91,92] A significant improvement in metabolic comorbidities was also reported. However, shortly after its introduction to the European market, independent reports suggested that other effects of blocking the CB1 system were closely associated with this drug, including depression and suicidal thoughts. Subsequently, when the drug came before the FDA committee in 2007,[209] the panel voted
against its approval, and in January 2009, rimonabant was officially withdrawn from the European market.
A second CB1 antagonist, taranabant, revealed similar efficacy and side effects to rimonabant. [93–97] Attempts to reduce the drug doses in favor of better tolerability failed.[98] The psychiatric side effects seen with both drugs were therefore assumed be indicative of the entire class of CB1 antagonists and the development of other advanced CB1 antagonist programs was temporarily suspended by pharmaceutical companies (including the Pfizer CB1 antagonist, otenabant [CP-945,598] and the Bristol Myers Squibb compound, SLV-319).
Cannabinoid receptor antagonists continue to be developed, with the aim of stimulating weight loss by peripheral mechanisms (see the section entitled 'Peripherally acting agents modifying food intake and energy expenditure').
Combination Approaches to Obesity TreatmentMonotherapies that selectively target one specific system in the CNS have rarely achieved greater than 5% weight loss; hence, the concept of tackling multiple targets in the regulatory pathways of energy balance has become more popular as a potentially safer and more efficient strategy for obesity treatment. Many of these combination treatments target the brain's reward circuitry. The first drug combinations have now reached Phase III clinical trials, including the phentermine–topiramate (Qnexa), the bupropion–zonisamide (Empatic®, Orexigen Therapeutics) and the bupropion–naltrexone (Contrave) combinations.
Qnexa has been presented as an effective combination therapy involving low doses of the amphetamine derivate, phentermine, and the anticonvulsant agent, topiramate. The mechanisms of action for both topiramate and zonisamide have not been fully characterized; however, they have demonstrated biphasic dopaminergic and serotinergic activity.[99–101] At least three Phase III studies have been completed, testing three different dose combinations of phentermine and topiramate. The EQUATE (756 obese subjects comparing mid- and full-dose Qnexa with the individual components and a placebo over 28 weeks), the EQUIP (1267 morbidly obese patients treated with low- or full-dose Qnexa or placebo over 52 weeks) and the CONQUER (2487 overweight and obese patients with high blood pressure, high cholesterol or Type 2 diabetes receiving mid- or full-dose Qnexa or a placebo over 52 weeks) trials assessed the effect of mid- and full-dose combinations, in which treatment caused a major weight loss of approximately 8.3 (8.5%) and 9.0 kg (9.2%) after 28 weeks[210] and of 8.6 kg (8.4%) and 10.7 kg (10.4%) after 56 weeks.[211,212] Psychiatric mood assessments were carried out during the trials and did not show evidence of increased depression or suicidal thoughts.
However, 18% of participants on high-dose treatment were withdrawn from the trials after experiencing mild side effects (such as tingling of the hands and feet, headache and constipation) and approximately 40% of all participants did not complete the study for various reasons. In fact, the rate of withdrawal of patients on the highest dose for depression, anxiety and sleep disorders was sevenfold higher than in the placebo group. The highest dose combination was also associated with an increased heart rate of 1.5 bpm, which was not seen with the mid-dose combination, and slightly more disturbances in attention, amnesia and memory impairment. Owing to these reports, the FDA committee expressed concerns over the risk of psychiatric and cognitive dysfunction and cardiovascular issues, prompting the agency to finally vote against Qnexa in July 2010. However, in November 2010, the FDA issued a letter to Vivus asking them to provide data on any birth defects or cardiovascular adverse events that may be associated with Qnexa, suggesting that approval might be granted at a later time if they are able to provide satisfactory safety data.
Empatic is another combination that has already been evaluated in a few Phase II clinical trials and includes bupropion and the anticonvulsant zonisamide. Bupropion, a dopamine and norepinephrine-reuptake inhibitor approved for the treatment of depression and smoking cessation, was consistently related to significant weight reduction in obese patients with or without depression compared with placebo. As an antidepressant, bupropion has proved to be both clinically effective and well tolerated, without the potential for abuse associated with more efficacious stimulators of dopamine function.[102] The underlying mechanism of zonisamide-induced bodyweight loss has not been fully characterized; however, it has been shown to have dopaminergic [103] and serotoninergic[104] activity and is likely to act through these systems.
In a pilot study of 18 obese women conducted over 12 weeks, subjects were treated with either zonisamide alone or a combination of zonisamide (100 mg rising to 400 mg over 4 weeks) and bupropion (100 mg rising to 200 mg after 2 weeks). Bodyweight loss was 2.9 kg (3.1%) in the zonisamide group compared with 7.2 kg (7.5%) in the combination-therapy group. [213] Zonisamide alone was relatively poorly tolerated, with a 44% drop-out rate due to fatigue, speech difficulties, drowsiness, nausea and diarrhea, while the combination appeared to be better tolerated, with a 22% drop-out rate.
In a subsequent double-blind placebo-controlled Phase IIb trial over 24 weeks, two doses of zonisamide were administered alone (120 and 360 mg) and the same doses were combined with bupropion 360 mg together with additional placebo and buproprion monotherapy controls. [105] Zonisamide 120 mg and 360 mg alone gave a 3.2 and 5.3% weight loss, while bupropion 360 mg gave a 2.3% weight loss and placebo a 1.4% weight loss. Empatic, containing 120 mg zonisamide, resulted in a 6.1% weight loss, while the 360 mg zonisamide administration gave a 7.5% weight loss. Overall, 60.4% of high-dose Empatic and 46.9% of lower-dose Empatic-treated subjects achieved more than 5% weight loss and the corresponding figures for more than 10% weight loss were 32.3 and 24.7%, respectively. The doses of zonisamide and bupropion tested here for weight-loss therapy were comparable to those used in other indications. Discontinuation rates were 34% for high-dose Empatic and 29% for placebo. The main adverse events were headache, drowsiness, insomnia and nausea, which conform to the typical side-effect profile of bupropion and zonisamide.
It should be noted that the bupropion prescribing information notes that severe hypertension has occasionally been observed in patients with and without pre-existing hypertension. [214] High doses of bupropion (400–500 mg) caused a rise in supine blood pressure in cardiac patients but had no effect on pulse rate,[106] while no changes in blood pressure or heart rate occurred at a lower dose of 300 mg/day.[107] Although the cardiovascular side effects of bupropion appear to be mild, it cannot be recommended for patients with heart disease. In previous analyses, zonisamide has been associated with cognitive impairment,[108] mood disorders[108] and teratogenicity.[109] These concerns need to be addressed in more detail in upcoming Phase III studies for Empatic before firm conclusions about its safety profile can be drawn.
Expectations were high for a third combination therapy, which was the first weight-loss drug in over a decade to gain FDA recommendation for approval. Contrave combines bupropion and naltrexone, a centrally active opioid receptor antagonist. Both agents stimulate the firing of anorexigenic POMC neurons. Naltrexone is hypothesized to block the opioid-mediated negative feedback that suppresses POMC firing.[110] Several Phase III trials have been completed in diabetic and nondiabetic patients (Contrave Obesity Research [COR]-I, COR-II, COR-Intensive Behavior Modification [BMOD] and COR-Diabetes trials),[111–113] demonstrating that patients on Contrave had an average placebo-subtracted weight loss of 4.2%. Although these results did not meet the 5% or more weight loss criterion for approval, the total number of patients reaching 5% or more weight loss was promising (44.5% on treatment vs 18.9% on placebo).
A note of caution should also be expressed regarding the cardiovascular profile of Contrave, where the anticipated benefits of weight loss on cardiovascular function have not been observed to date but, indeed, a small increase in blood pressure and heart rate have been demonstrated when compared with placebo.[215]
This uncertainty of the cardiovascular safety profile was also the main reason for the negative FDA expert vote on Contrave in February 2011. Before approval, the panel demanded a randomized double-blind placebo-controlled trial to investigate whether there is a risk of major adverse cardiovascular events in obese patients.[216]
Peripherally Acting AgentsGut-related Peptides Affecting Obesity
Several anorectic peptides are released from the gut postprandially and there has been interest in developing therapeutics to mimic this effect. Investment in gut hormone research as effectors of appetite regulation and also energy expenditure has been encouraged by the recent success of bariatric surgery. Certain evidence suggests that surgically induced weight loss, seen particularly after gastric bypass surgery, might be, at least in part, the result of an increased postprandial gut hormone response of several gut peptides, including GLP-1, PYY and oxyntomodulin. [82–84] Analogs of these hormones were discussed in the section on centrally acting agents, but it is important to remember that they are also likely to have peripheral effects.
CB1 Antagonists
A new generation of antagonists have been designed to antagonize peripherally expressed CB1 receptors but not to penetrate the blood–brain barrier and thus to avoid the behavioral effects of centrally active agents. Peripheral CB1 receptor antagonists may be useful for inducing weight loss as peripheral CB1 agonism increases food intake.[114] Peripheral CB1 antagonism is also thought to have beneficial effects on energy expenditure.[115] This approach has been pursued by 7TM Pharma, whose TM38837 has been shown to be a peripherally restricted CB1 antagonist and has completed a Phase I clinical trial.[217] Other similar agents such as Northeastern University's AM6545 are also in development and have shown promising results in preclinical studies. [116] It remains to be shown if clinically relevant weight loss can be achieved without the central appetite-suppressant effects of blood–brain barrier-penetrant CB1 antagonists.
Gut-related Peptides to Treat Obesity & the Metabolic Syndrome
Similarly to the GLP-1R agonists, other new agents, which not only affect weight control but also improve metabolic and cardiovascular disorders, are attracting growing interest. The critical therapeutic end point in the treatment of obesity is not only the reduction in bodyweight, but the reduction in morbidity and mortality from associated comorbidities.
Pramlintide (Symlin®; Amylin Pharmaceuticals), an analog of the pancreatic hormone amylin, is one of these drugs. The agent has been approved as an adjunct to mealtime insulin in patients with Type 1 and 2 diabetes mellitus, but is also associated with a reduction in appetite and food intake through a delayed gastrointestinal motility. In a first dose-escalation randomized trial testing pramlintide for obesity treatment, a mean weight loss of 3.7% was reported after 16 weeks (with a dose of 240 μg) and at least 31% of participants achieved a 5% or greater weight loss.[117] A subsequent dose-escalation study (with 120, 240 and 360 μg administered two-to-three-times daily) showed a progressive weight reduction at 12 months, with a placebo-subtracted weight loss of 6.1 kg (120 μg) and 7.2 kg (360 μg), respectively.[118] Two amylin-based analogs are currently undergoing development for obesity treatments: a second-generation amylin analog davalintide [119] and a combination of pramlintide and metreleptin (a recombinant human leptin). [120] The combination of the
leptin recombinant with pramlintide was expected to restore the leptin sensitivity in obese patients. Indeed, the combined treatment over 20 weeks has been demonstrated to produce greater weight loss than pramlintide or metreleptin administered alone.[120]
The most common pramlintide-related adverse events are hypoglycemia and nausea, followed by anorexia and vomiting.[121]
Pramlintide did not show an increase in the overall event rate of severe hypoglycemia in long-term placebo-controlled studies. However, during the first 4 weeks of pramlintide therapy, there was an increase in severe hypoglycemia, particularly in patients with Type 1 diabetes, [122–125] where the event rate per patient-year ranged between 2.0 and 4.0. As demonstrated in subsequent studies, titrating pramlintide and initially reducing mealtime insulin minimizes the risks of insulin-induced severe hypoglycemia, with improved HbA1C and weight loss.[126,127] That way, the event rate per patient year for severe hypoglycemia for the first 3-month period of the open-label clinical practice study could be reduced to 0.29 for patients with Type 1 diabetes and to 0.05 for patients with Type 2 diabetes.
AMP-activated Protein Kinase & Peroxisome Proliferator-activated Receptor Modulators
AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of energy metabolism that has pleiotropic effects in multiple tissues. AMPK is activated under fasting conditions and causes increased fatty acid oxidation, glucose uptake and glycolysis, and the inhibition of fatty acid and glycogen synthesis. Recently, AMPK has also emerged as a regulator of appetite, contributing to the control of energy metabolism at both the cell and whole-body levels.[128] 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide (AICAR), a cell-permeable adenosine analog that can be phosphorylated to form 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl-5'-monophosphate, stimulates AMPK activity and glucose uptake in both muscle and adipose tissues. [129–131] AMPK activation by AICAR administration into the third ventricle or directly into the paraventricular nucleus of the hypothalamus has been shown to significantly increase food intake.[132] By contrast, the expression of dominant negative AMPK in the hypothalamus was sufficient to reduce food intake and bodyweight, whereas constitutively active AMPK increased both.[128] These experimental studies suggest that while activation of AMPK in the periphery may be beneficial to obese patients by increasing energy expenditure, in the brain, suppression of AMPK would be desirable to inhibit appetite. Peroxisome proliferator-activated receptor (PPAR)-γ antagonism has also been considered as a possible target for obesity treatment, even though the concept is relatively new. [133] PPAR-γ is known to regulate fatty acid storage and glucose metabolism. The genes activated by PPAR-γ stimulate lipid uptake and adipogenesis by fatty cells, while PPAR-γ-knockout mice fail to generate adipose tissue when fed a high-fat diet.[134] Treatment for 10 weeks with SR-202, a PPAR-γ antagonist, has been shown to reduce weight gain, white adipose tissue accumulation and brown fat mass in a mouse model.[135] Several other PPAR-γ antagonists have recently been reported including GW-0072 (GlaxoSmithKline Pharmaceuticals) and LG-100641 (Ligand Pharmaceuticals, Inc), which antagonize thiazolidinedione-induced adipocyte differentiation.[136,137] These early results suggest that PPAR-γ antagonists may have clinical potential for obesity treatment.
G-protein-coupled Receptor 119
The success of GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in diabetes treatment[138] has also awakened interest in G-protein-coupled receptor 119 (GPR119) as another target for the treatment of diabetes and obesity. GPR119 or glucose-dependent insulinotropic receptors are predominantly expressed in the islet β-cells and the GI tract. Ethanolamides are proposed to be the endogenous ligands for GPR119, with oleoylethanolamide as the most potent endogenous GPR119 agonist identified to date. Stimulation of GPR119 receptors is an attractive target for treating Type 2 diabetes as they have been shown to play a role in glucose homeostasis through modulation of insulin secretion[139–143] and direct stimulation of GLP-1 and glucose-dependent
insulinotropic peptide secretion.[144,145] These endogenous antidiabetic hormones stimulate glucose-dependent insulin secretion and improve glycemic control. Stimulation of GPR119 has the benefit of stimulating a multihormonal response, which mimics the physiological response to elevated glucose. In addition to its antidiabetic control, GPR119 agonists also seem to provide a major beneficial effect on bodyweight.[146] However, the mechanisms underlying these effects on energy homeostasis remain to be demonstrated.
Sodium–Glucose Transporter 2 Inhibitors
Another new class of antidiabetic drugs with potential impact on bodyweight involves the sodium–glucose cotransporter (SGLT2) inhibitors. Glucose is reabsorbed from primary urine via the high-capacity, low-affinity SGLT2 on the luminal surface of the renal cells in the proximal tubules. Selective inhibitors of SGLT2 reduce glucose reabsorption, causing excess glucose to be eliminated in the urine, which results in a decrease in plasma glucose levels. The glucosuria produced by SGLT2 inhibitors is associated with weight loss and reduced blood pressure.
Orally active SGLT2 inhibitors currently in clinical development include BI 10733, canagliflozin (TA7284)[147] and dapagliflozin.[148,149] It has been reported that in obese diabetic rodents, these agents induced significant urinary glucose excretion, and reduced blood glucose and bodyweight. To date, clinical data have only been published for dapagliflozin as monotherapy [150,151] and for combination therapy with metformin,[152] glimepiride[153] and insulin plus oral antidiabetic agents.[154] In a randomized placebo-controlled trial over 12 weeks, dapagliflozin (dosed at 2.5–50 mg/day) produced a 1.3–2.0 kg higher weight loss compared with metformin (1500 mg/day) alone.[151] Long-term weight loss is consistent with the calories lost due to ongoing glucose elimination in the urine. A common side effect seen in this class of drugs is an increased risk of genitourinary infections. In summary, SGLT2 inhibitors illustrate a novel and interesting class of antidiabetic and anti-obesity drug, but long-term clinical trials are needed to confirm their safety in patients with diabetes. SGLT1 inhibitors (e.g., LX4211 [Lexicon Pharmaceuticals]) block glucose absorption in the gut and increase the release of the satiety-inducing gut hormones GLP1 and PYY.
Expert Commentary & Five-year ViewGiven that obesity is the greatest epidemic in human existence (based upon the number of lives affected[155]), it is perhaps surprising that no efficacious pharmacotherapies currently exist. Safety issues with previous weight-loss drugs that led to the discontinuation of fenfluramine, rimonabant and sibutramine may have tempered and perhaps even jaded the enthusiasm for future therapeutics. Because relatively healthy people would need chronic treatment, safety is a leading concern of regulators. However, in the majority of cases, improving the safety margin leads to a reduction in drug efficacy. Thus, what can we expect from this field in the next few years?
In December 2010, a FDA panel approved laparoscopic gastric banding for individuals with a BMI of 35–40 kg/m2 without comorbidities and a BMI of 30–35 kg/m2 with comorbidities. This expansion of the indication for gastric banding may indicate a turning point and the recognition of obesity as a serious chronic disease that is a burden to the healthcare system. Indeed, bariatric surgery is currently the predominant approach to obesity treatment, with the gastric bypass as the most effective procedure available for sustained weight loss and mortality benefit.[156] However, the surgical treatment is limited due to its invasive nature and the high risk of peri- and post-operative complications. Although the mechanisms of long-term weight loss following bariatric surgery are yet to be determined, evidence suggests that the surgical manipulations (the small gastric pouch and exclusion of the duodenum and proximal jejunum) are insufficient to account for the resulting bodyweight loss alone.[157–159] In fact, postoperative changes in eating behavior and appetite have been demonstrated to be related to altered responses of several gut hormones. [46,160]
Therefore, tackling obesity in the future will most likely involve the elucidation of the mechanisms that underlie surgically induced weight loss and the mimicry of the changes in gut hormone profile and neuroendocrine signaling associated with gastric bypass surgery, using pharmacological intervention.
The 'medical bypass' is still a long way off and its achievement will require hard work from both researchers and pharmaceutical industries in the field. The authors are confident that this is a challenge that can, and will, be dealt with successfully in the next decade. We appreciate the surgical option for now, but without a new generation of obesity drugs, a meaningful strike against the obesity epidemic and its associated healthcare costs will prove difficult to achieve.
SidebarKey Issues
Obesity has reached epidemic levels, with a total of 500 million adults classed as obese globally in 2008, which is expected to rise to 700 million by 2015 (WHO).
A number of new centrally, peripherally or even combinative acting drugs are in development, but no efficacious pharmacotherapies for obesity currently exist.
Increasingly stringent efficacy and safety requirements have led to the rejection of many weight-loss drugs by the US FDA.
Bariatric surgery is currently the main approach to obesity treatment, with the gastric bypass being the most effective procedure available for sustained weight loss and decreased mortality risk. However, the invasive nature of this treatment and the risk of peri- and post-operative complications must not be underestimated.
Elucidating and utilizing the underlying mechanisms of surgically induced weight loss for the effective and safe treatment of obesity will represent a major area of research in the coming years.
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