Significant Visceral Fat Loss Seen Within 12 Weeks With Orlistat
Martha Kerr

February 3, 2010 — A randomized placebo controlled trial of orlistat (Alli, GlaxoSmithKline) 60 mg daily for overweight to obese but otherwise healthy subjects showed that the weight-loss agent was not only associated with greater overall weight loss than placebo, but that there was a greater loss of visceral fat with active treatment.

Furthermore, effects were seen within 3 months, investigator Rex Newbould, PhD, head of the Clinical Imaging Center at Hammersmith Hospital in London, United Kingdom, reported at the first International Congress on Abdominal Obesity (ICAO) underway in Hong Kong.

Of the 26 overweight and obese subjects (body mass index [BMI], 25.0 to 35.0 kg/m2; waist circumference >88 cm for women and >102 cm for men) enrolled, 24 completed the 12-week study.

Subjects took orlistat 60 mg 3 times a day and ate a hypocaloric (reduced by 500 kcal) low-fat diet. Subjects received a single dietary counseling session, and an abdominal magnetic resonance imaging (MRI) scan was performed to measure visceral adipose tissue (VAT) at baseline. Body weight and waist circumference were measured at weeks 4, 8, and 12, and a repeat abdominal MRI scan was performed at week 12.

After 12 weeks, orlistat was associated with a significant reduction in body weight, waist circumference, and VAT, according to MRI.

"MRI measures fat more accurately than weight or waist measurement," Dr. Newbould told Medscape Medical News. "It measures the fat inside the fat, and has less 'noise' than other measurements. It measures only fat, whereas weight is a measure of fat, fluid, and other factors."

The change in VAT was correlated with the change in weight (P < .0001) but not waist circumference (P = .35). The mean change in weight was –5.24 kg (–5.6%), in waist circumference was –4.54 cm (–4.3%), and in VAT was –0.60 L (–10.6%).

"Visceral fat is the metabolically active type of fat that is associated with adverse outcomes," Dr. Newbould explained. "We would expect [a loss of VAT] to be associated with improved outcomes."

A similar study was presented by Kaj Stenlöf, MD, executive director of the Clinical Trial Center at Sahlgrenska Academy in Göteborg, Sweden.

He and his colleagues randomized 131 overweight and obese subjects (BMI, 25 to 35 kg/m2; waist circumference >88 cm for women and >102 cm for men) to orlistat 60 mg or placebo 3 times a day plus a hypocaloric low-fat diet for 24 weeks. Subjects were "encouraged to exercise," but were not on a prescribed exercise regimen.

Treatment was well tolerated, Dr. Stenlöf said, and 107 subjects completed the study. The primary adverse effects were gastrointestinal.

Mean change in VAT after 24 weeks of orlistat treatment was –9.39% in the placebo group (P < .0001) and –15.66% in the orlistat group (P < .0001). The percent change difference from baseline to week 24 between the placebo and orlistat groups was 0.227 (P < .0244).

In addition, there was a significant reduction in mean body weight from baseline to week 24 in both groups, with a loss of 5.96 kg in the orlistat group and 3.91 kg in the placebo group (P < .05).

Although only data on VAT were presented at the meeting, Dr. Stenlöf told Medscape Medical News that they are calculating cardiac muscle fat and fat in other muscles, and are computing other parameters, such as blood pressure and blood glucose. These data will be presented this summer at the International Conference on Obesity in Stockholm, Sweden.

"With the over-the-counter formulation of orlistat, there has been a conceptual shift in the treatment of obesity," Jean-Pierre Després, PhD, director of research in cardiology at the Quebec Heart and Lung Institute at Laval University in Quebec City, told Medscape Medical News.

"Instead of overall weight loss, we are now focusing on this high-risk form of obesity, with loss of the more metabolically active visceral fat — the fat that carries a high risk of heart disease."

"We don't know if orlistat induces a preferential loss of visceral fat. Those data are just now coming in, and we heard some new data here," said Dr. Després, who is chair of the ICAO. "We don't know if the loss of visceral fat is part of overall weight loss. The key point is that there has been a paradigm shift to focus on the reduction of this most dangerous form of obesity."

"Orlistat is very safe and is an effective therapy in motivated patients," said Christie M. Ballantyne, MD, professor of medicine at Baylor College of Medicine and director of the Center for Cardiovascular Disease Prevention at Methodist DeBakey Heart Center in Houston, Texas, in an interview with Medscape Medical News. He was not involved in either study.

"I think it has been underutilized because of [gastrointestinal] side effects, but the data are very clear that this provides additional weight loss to a program of lifestyle modification. It has clearly been shown to have favorable effects on metabolism, and the newer data on visceral fat are also encouraging."

"This therapy should be discussed as an option, particularly in patients with comorbidities, because both the efficacy and safety are proven," Dr. Ballantyne asserted.

First International Congress on Abdominal Obesity (ICAO). Presented January 28, 2010.

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Monogenic forms of obesity, although very rare, have helped delineate some of the central pathways involved in appetite regulation. For example, humans with homozygous deficiency of POMC or the melanocortin-4 receptor (which is the receptor for a-MSH from anorexigenic neurones) develop severe, early onset obesity.[17] Interestingly, NPY knockout mouse models do not exhibit a lean phenotype as expected, but do display normal food intake[18] – most likely owing to the activation of numerous compensatory pathways protecting against starvation. These findings lend support to the generally held view that organisms possess an evolutionarily programmed tendency to protect against weight loss more than weight gain.

Understanding the genetic contribution of more common forms of obesity is an area of intense recent research, with the hope that this may help to identify novel pharmacological approaches. Observationally, it is clear that some people are protected more than others against the obesogenic effects of our modern lifestyles. In fact, twin studies suggest that 70% of variation in adiposity within the population is due to genetic factors.[19] Thus, the commonly held view that obesity is simply a consequence of the individual's decision to eat too much and exercise too little is an oversimplification. The salient question that remains largely unanswered is: what biologically determined factors make it difficult for some more than others to maintain a normal bodyweight? We are a long way from explaining the high heritability of the condition and, as is true of many common and complex diseases, a large number of genetic factors are likely to be interplaying. The advent of high-powered genome-wide association studies is helping to pave the way to identifying new candidate genes, with the FTO gene in obesity as a recent example.[20] The obesity high-risk FTO allele is common in Caucasians, and homozygous adults are 2–3 kg heavier, with higher BMI and reduced satiety observable from childhood. FTO codes for the enzyme 2-oxoglutarate-dependent nucleic acid demethylase,[21] which is particularly highly expressed in the hypothalamus, although the exact molecular mechanism underlying the FTO association with obesity remains to be elucidated.

What are the Current Treatment Options?

Lifestyle
Although not yet matched by a robust evidence base, many government policy-makers support the introduction of societal interventions as a means of encouraging people away from obesogenic environments and behavior patterns. Such efforts are important, but seem largely impractical as an immediate means of tackling the obesity crisis as it stands. Dietary and exercise advice remains the mainstay of the medical management of obesity and should be encouraged alongside all other treatment adjuncts. Sustained caloric restriction (to 1500 kcal/day for women and 1800 for men), regardless of dietary macronutrient composition or regimen,[22] has fairly similar effects on weight loss, ranging from 3–5 kg over 2 years.[23] The addition of physical exercise facilitates weight loss by increasing energy expenditure and increasing basal metabolic rate through an increase in muscle mass. Unfortunately, lifestyle interventions alone rarely result in long-term weight loss and the majority of dieters return to baseline weight within 3–5 years. This even holds true for participants in weight-loss trials who are offered education and intensive support to help prevent weight regain,[24,25] and adds support to the concept that appetite may be consciously overridden in the short-term but in the longer term this is superseded by a biologically determined 'set-point'.

Pharmacotherapy
In the midst of the obesity-related health crisis, the case for safe and efficacious pharmacotherapies is clear. Unfortunately, drugs currently available for long-term weight management are limited in number and efficacy. There are many more examples of drugs used historically for weight loss that have been removed owing to significant side effects, including hypertension, severe mood disturbance, serious cardiac pathology and increased mortality. This has often been due to the use of centrally acting adrenergic stimulants, which suppress appetite and increase energy expenditure though generalized sympathetic activation. At present, there remain three sympathomimetic amphetamine-like drugs still approved by the US FDA as weight-loss adjuncts; phentermine, diethylpropion and phendimetrazine. This drug class has been associated with side effects including systemic and pulmonary hypertension, as well as the obvious potential for abuse and addiction. They are approved for short-term use only and so they have limited use in the long-term management of obesity.[26] FDA guidance for the approval of weight-loss therapies intended for long-term use recommends a 5% placebo-corrected weight reduction that should be maintained for at least 12 months after treatment initiation. Small, sustained reductions in weight can significantly improve cardiovascular risk factors, particularly glucose tolerance, in overweight and obese individuals. The target adult population for drug therapy is set at BMI above 30 (or >27 with comorbidities). This opens up a potentially huge market for weight-loss drugs. However, there are currently only two drugs licensed in the USA for the long-term treatment of obesity. The first is orlistat (Xenical; Roche) and the second sibutramine (Meridia/Reductil; Abbott). Orlistat irreversibly inhibits intestinal lipases by covalently binding to a serine residue on the active site. Lipases are required to hydrolyze dietary triglycerides into absorbable FFAs. With orlistat, up to 30% of ingested fat is not absorbed. This is the reason for the most common adverse events reported with the drug–gastrointestinal discomfort and fecal urgency. In fact, some claim that the benefit of the drug is best seen in patients who learn to switch to a low-fat diet in order to avoid such side effects. In the longer term, there is also the risk of deficiency of fat-soluble vitamins. Between 1999 and 2008, six cases of liver failure in patients taking orlistat were reported to the FDA's Adverse Event Reporting System. Analysis of these and other reports of liver injury associated with orlistat use is being undertaken by the agency, although as yet no clear link has been identified.[203] In terms of efficacy, meta-analysis of clinical trials indicate a mean weight loss for orlistat-treated patients of 2.89 kg compared with placebo-treated patients over 12 months.[27] This mix of modest weight loss and often intolerable side effects leads to high attrition rates in users. One survey of 17,000 orlistat users in Canada reported rates of ongoing use of less than 10% at 1 year and 2% at 2 years.[28] In 2007, GlaxoSmithKline (GSK) under licence from Roche released a low-dose, over-the-counter formulation of orlistat (Alli). Initial US sales in that year reached $119.6 million but fell to $76.7 million in 2008. European trends are following a similar pattern.[202] Sibutramine belongs to the class of selective serotonin and noradrenaline reuptake inhibitors that elevate synaptic concentrations of 5-hydroxytriptamine (5-HT).[29] It may also increase energy expenditure through sympathetic activation[30] and the elevated heart rate and blood pressure seen with the drug may be a cause for concern. Analysis from the ongoing Sibutramine Cardiovascular Outcomes (SCOUT) trial, which is a prospective randomized, double-blind, placebo controlled trial in cardiovascular high-risk, overweight and obese subjects, has raised some concerns about a possible increased incidence of cardiovascular events in such patients taking the drug. Further FDA guidance is awaited.[204] Meta-analysis of earlier clinical trials reveals that after 1 year, an average of 4.2 kg more weight is lost by patients taking sibutramine, with an associated 20–30% increased probability of losing at least 5% of their bodyweight.[27]

Surgery
At present, the most effective means of significant and sustained weight loss for obese patients is bariatric surgery. Gastric banding is a restrictive procedure that involves the insertion of an adjustable band around the upper portion of the stomach to limit the amount of food that can be ingested. Roux-en-Y gastric bypass involves the formation of a small stomach pouch and bypass of the proximal small bowel. Although malabsorption is not a major feature of modern gastric bypass surgery,[31] patients undergoing this type of procedure lose much more weight (in the order of 30%) than those undergoing gastric banding alone (20% loss).[32] They also experience a prompt reduction in appetite and improvement in glucose metabolism, well before the advantages of weight loss through restricted intake have had time to accrue. These added advantages of bypass surgery are thought to be due to an alteration in the release profile of gut hormones. Postprandial levels of glucagon-like peptide (GLP-)1 and peptide tyrosine tyrosine (PYY), which are appetite-inhibiting gut hormones, are elevated following gastric bypass surgery but not after gastric banding. GLP-1 also acts at pancreatic β-cells to augment glucose-dependent insulin release,[32–35] referred to as the incretin effect. However, bypass surgery is costly, in many cases irreversible and associated with significant risks, including a 0.5% mortality rate.[36] There is, therefore, a huge incentive to provide safe pharmacological alternatives.

Expert Commentary

Gut Hormones in the Treatment of Obesity

The discovery of leptin and gut hormones as major neuroendocrine regulators of bodyweight is leading the way to the development of attractive therapeutic approaches to the long-term manipulation of energy homeostasis in favor of appetite reduction and weight loss. It is hoped that this may be associated with a relative paucity of central or unexpected side effects. The rest of this article will concentrate on these therapeutic strategies.

Leptin

Leptin is a circulating 167-amino acid peptide that is the product of the ob gene that is exclusively expressed in adipose tissue. Plasma leptin concentrations are highly correlated with adipose tissue mass.[51] Peripheral and intracerebroventricular injections of leptin reduce food intake and bodyweight in both wildtype and leptin-deficient (ob) mice, but not in leptin-receptor-deficient (db) mice.[52–54] The leptin receptor is expressed throughout the CNS, particularly in the hypothalamus.[55] It is now understood that by modulating neural activity in hypothalamic neurones that regulate energy balance, leptin acts in an important negative feedback loop to homeostatically maintain adiposity. Congenital leptin deficiency in humans is associated with massive early-onset obesity which is reversible with leptin replacement treatment.[56] However, the majority of cases of human obesity are associated with elevated circulating leptin levels and hence leptin-resistance, such that the utility of leptin as monotherapy for the treatment of obesity is limited.[57] More recent studies have investigated the synergistic use of leptin alongside other antiobesity agents to induce clinically significant weight loss in obese individuals.[58] Understanding the molecular mechanisms underpinning leptin resistance may open the way to other potential anti-obesity treatments. The leptin receptor signals via the JAK-kinase signal transducers and activators of transcription (JAK-STAT) pathway.[59] This type of signaling is limited by the activation of suppression of cytokine signaling (SOCS) proteins, which inhibit JAK kinase. Mice deficient in SOCS3 are resistant to diet-induced obesity and remain leptin sensitive[60] and in the future, chemical inhibitors of these proteins may have potential as anti-obesity drugs.

Peptide Tyrosine Tyrosine

Along with pancreatic polypeptide (PP) and NPY, PYY is a member of the PP-fold family of peptides – so named due to a common hair-pin fold motif necessary for receptor binding. PP-fold proteins mediate their effects through a set of G-protein coupled Y receptors – Y1, Y2, Y4, Y5 and Y6. The receptors are distributed widely in the periphery as well as the CNS, and there is a degree of cross-reactivity between all of the PP peptides at each of the receptors, producing an overlapping system that is difficult to untangle. However, there is evidence that each of the PP-fold peptides bind more selectively to specific receptor subtypes and have distinct effects on energy homeostasis.[61] PYY is released from L-cells of the gastrointestinal tract, in proportion to the number of calories ingested. Circulating levels rise approximately 15 min after a meal has been ingested and remain elevated for 2 h.[62] Fasted humans infused intravenously with PYY3–36 to mimic postprandial concentrations consume 35% fewer calories at a subsequent buffet meal.[63] Importantly, in contrast to the problem of leptin resistance, obese subjects remain just as sensitive to the anorectic effects of the hormone.[64] The prospective finding of a negative correlation between peak postprandial PYY concentrations and bodyweight suggests that altered PYY physiology has a role to play in the pathogenesis of obesity.[65,66] Furthermore, fasting levels of PYY are chronically elevated in a number of anorexia-driven weight-losing enteropathies in humans.[67,68] PYY knockout mice display hyperphagia and increased adiposity, which is reversed upon exogenous replacement of PYY3–36.[69] Some of the satiety effects of PYY are because it slows gastric emptying, the 'ileal brake' effect, leading to a more prolonged feeling of fullness. However, PYY released into the bloodstream more importantly exerts its appetite-regulatory effects in a neurohumoral manner along the gut–brain axis. The major site of action of circulating PYY3–36 is most likely to be the hypothalamus via the nearby median eminence. Studies reveal that c-fos expression (a marker of neuronal activation) is increased in the hypothalamus following the peripheral administration of PYY, which increases POMC and decreases NPY mRNA expression in the ARC.[64,70,71] Acute stress induces anorexia by downregulating arcuate NPYergic activity in a very similar manner.[72] Exploiting the anorectic action of PYY3–36 still holds promise for the development of novel anti-obesity therapies. Similar to the other satiety-inducing gut hormones, the most commonly reported adverse effect with PYY, which is dose related, is nausea. This probably represents part of the spectrum of the expected effects of these hormones, from a pleasant sensation of fullness through to feeling 'overfull' and eventually nauseous. Phase II clinical trials of nasal PYY (Nastech/Merck) taken with each meal were terminated after 24 weeks since it was no better than currently available sibutramine at reducing weight, and because there were significant problems with nausea.[208] However, in this study the maximum plasma PYY concentrations achieved of 105 pmol/l were much higher than normal postprandial levels of 50 pmol/l. Furthermore, the time taken to reach peak levels of 18–26 min was greatly shorter than the more gentle and sustained natural post-prandial rise.[73] Thus the high incidence of nausea and failure of nasal PYY to induce longer-term appetite reduction and weight loss may possibly have been due to the pharmacokinetics of this mode of delivery. Future studies investigating the chronic use of steady-state preparations of PYY are warranted. A more detailed understanding of the Y-receptor system and the highly complicated neuronal circuitry involved in the appetite regulatory effects of PYY is vital for the development of optimally targeted antiobesity drugs of this nature. At physiologic concentrations, PYY activates hypothalamic presynaptic (autoinhibitory) Y2 receptors, as evidenced by the lack of anorectic effect of PYY in Y2 receptor knockout mice, and the attenuation of the anorectic effect of peripherally administered PYY when a Y2 receptor antagonist is concomitantly given.[63] Recent functional magnetic resonance imaging studies in humans point to the fact that PYY may also interact with even higher brain centers, such as those involved in the reward processing of food, to alter meal preference and palatability.[74] In B6.V- Lepob/J obese mice under chronic stress (who have very high circulating NPY levels), there is evidence that pharmacological inhibition or fat-targeted knockdown of peripheral Y2 receptors is anti-adipogenic, reducing abdominal obesity and metabolic abnormalities,[75] highlighting the complicated interplay between the Y-receptor superfamily and the PP-fold peptides.

Pancreatic Polypeptide

Pancreatic polypeptide is synthesized and secreted from PP cells within the islets of Langerhans in the pancreas. PP is released postprandially largely under vagal control in proportion to calories ingested and levels remain elevated for 6 h.[76] Chronic administration of PP to rodents reduces food intake, increases energy expenditure and results in a loss of bodyweight.[77–79] PP-overexpressing mice display a lean and hypophagic phenotype, reversible with the administration of antibodies against PP.[80] In fasted healthy lean human volunteers, an infusion of PP mimicking normal postprandial levels reduces caloric intake over the subsequent 24 h period by 25%.[81] PP probably acts both via the vagus nerve and directly at the brainstem to produce its appetite regulatory effects via the Y4 receptor, for which it shows particularly high affinity.[61] The anorexigenic effect of intra-peritoneally administered PP in rodents is abolished by vagotomy.[78] Direct injection of PP into the dorsal vagal complex (DVC) of rats stimulates efferent vagal activity, suggesting that circulating PP also acts directly on the brainstem.[82] This occurs via the nearby area AP, which is rich in Y4 receptors.[83] The hypothalamus has also been demonstrated to play a role in PP's appetite-modulatory effects. The Y4 receptor is expressed in both the ARC and PVN of the hypothalamus. Peripheral injection of PP results in a downregulation of hypothalamic NPY expression.[78] This may occur in direct response to circulating PP or secondary to incoming nervous signals from the brainstem. These initial insights into the satiety-inducing affects of PP and PYY have driven the development of synthetic analogs as potential anti-obesity agents. 7TM Pharmaceuticals (Copenhagen) have developed two such analogs. TM-30339 is a selective Y4-receptor agonist which demonstrated significant weight loss when administered chronically to diet-induced obese mice. Phase I/IIa trials are currently underway in healthy obese individuals over a 28 day study period to assess safety, tolerability and the effective dose to induce weight loss.[209] TM-30338, named Obinepitide, is a dual Y2-Y4 receptor agonist already shown to be safe and well tolerated in humans during Phase I/II clinical trials. In obese volunteers given once daily subcutaneous injections, the compound significantly reduced food intake for up to 9 h after dosing and is scheduled for further Phase II testing.[210]

Glucagon-like Peptide-1

Glucagon-like peptide-1 is secreted from intestinal L-cells along with PYY and oxyntomodulin (OXM). It is rapidly released postprandially and levels remain elevated for several hours. Alongside OXM and glucose-dependent insulinotropic polypeptide (GIP), it is an incretin hormone which stimulates postprandial insulin release. In addition to its pancreatic glucoregulatory effects, the active form of GLP-1, GLP7–36amide, also inhibits food intake in a number of species when given centrally or peripherally. Chronic peripheral administration causes significant weight loss in mice, which is inhibited by the coadministration of the specific GLP-1 receptor antagonist exendin9–39.[93] Unexpectedly, the GLP-1 receptor knockout mouse displays normal food intake and bodyweight (although it is glucose intolerant).[94] However, as is true of many neuropeptide and receptor knockout strains, the lack of an obese phenotype is probably owing to developmental compensatory mechanisms. In fasted wild-type rats, direct intracerebroventricular (ICV) administration of GLP-1 strongly inhibits feeding, an effect that is abolished by the coadministration of exendin9–39. Furthermore, ICV exendin9–39 on its own doubles food intake in satiated rats, suggesting that endogenous GLP-1 physiologically regulates appetite.[95] In normal-weight humans, GLP-1 dose-dependently reduces appetite and acutely reduces food intake by 12%. These appetite inhibitory effects are preserved in obese and diabetic human studies.[96,97] Circulating GLP-1 is likely to exert its appetite regulatory effects both via vagal afferents and direct interaction with the brainstem and hypothalamus. GLP-1 administered either directly into the CNS or peripherally strongly induces c-fos expression in the PVN.[93,98] Peripheral administration in addition activates the brainstem. GLP-1 receptor mRNA is found in high levels in the hypothalamic ARC, PVN and supraoptic nuclei. A further observation is that vagotomy and lesioning to disconnect the brainstem from the hypothalamus attenuates peripherally delivered GLP-1's anorectic effects.[99] Short plasma half-life is a feature shared by all peptide gut hormones. In the case of GLP-1, the half-life is 2 min. Complete deactivation occurs following N-terminal cleavage by the enzyme dipeptidyl-peptidase (DPP)-IV.[100] Exendin1–39amide, a peptide purified from the saliva of the Gila monster Heloderma suspectum, was developed by Amylin Pharmaceuticals, in conjunction with Eli Lilly, into the drug exenatide. Better known by its trade name Byetta, exenatide is a long-acting GLP-1 agonist licensed as an adjunct to oral treatments for Type 2 diabetes. In addition to improved glycemic control, meta-analysis of clinical trials reveals an average weight loss of 2.13 kg in exenatide treated groups above placebo, and a 4.76-kg weight loss compared with insulin.[101] Eli Lilly have reported results from a 24-week, double-blinded, randomized, control trial of high-dose exenatide in obese, nondiabetic subjects as an adjunct to dietary and exercise intervention. Individuals who received exenatide lost 5.06 kg compared with a 1.61-kg loss in the placebo group. Only exenatide-treated subjects (9.6%) lost more than 10% of their bodyweight. As with other peptide hormone treatments, Byetta needs to be delivered by twice-daily subcutaneous injection, a mode that will be unfamiliar and unattractive to many. Amylin and Eli Lilly are seeking approval for their once-weekly formulation of exenatide LAR, which was demonstrated to produce significantly improved glycemic control compared with the twice daily version with similar weight-loss effects in the long term.[102] In early 2009, Alta Therapeutics Corp granted Amylin and Eli Lilly exclusive worldwide rights to develop transdermal exenatide using its Passport Transdermal Delivery System. A once-daily transdermal exenatide patch is now in Phase I testing for Type 2 diabetes. The most common side effect with exenatide is nausea. In comparative studies, the incidence ranged from 33 to 57% in exenatide groups compared with 0.4–9% in patients treated with insulin analogs.[103] In general, this side effect can be ameliorated by early dose titration and eventually mitigates with continued use. There is evidence to support the notion that the drug continues to exert its therapeutic benefits on both glycaemic control and bodyweight after side effects have subsided.[104] In October 2007, the FDA issued an alert that acute pancreatitis should be included on exenatide's product label precautions section. This followed 30 postmarketing reports of acute pancreatitis in patients taking Byetta. Among these were 22 examples of symptomatic improvement following discontinuation of the drug, six cases where the symptoms started at the point of dose escalation, and three examples of a resurgence of symptoms after the drug was reintroduced. It has been noted that the obese, Type 2 diabetic population is at an already increased risk of developing gallstone or hypertriglyceridemia-related pancreatitis. In fact, the drug's manufacturers have reported retrospective data negating an increased incidence of pancreatitis in patients taking Byetta.[212]

A second GLP-1 analog has recently been introduced: liraglutide (Victoza; Novo Nordisk). Liraglutide is 97% identical to the native human peptide. It is coupled to a 16-carbon fatty acid side chain, which promotes binding to albumin, thereby lengthening its half-life in a similar fashion to insulin detemir. It is argued that its 97% homology to the native human peptide reduces the drug's immunogenicity (around 40% of patients taking exenatide produce antibodies to it, although in practice this is rarely of clinical consequence). Victoza is already approved in the EU for the treatment of Type 2 diabetes, with evidence of improved glycemic control compared with exenatide and a similar weight loss profile.[105] NovoNordisk have reported results from their 32-week open-label extension study of liraglutide in obese non-diabetic subjects following on from the 20-week, double-blind, placebo-controlled Phase II study comparing liraglutide with open-label orlistat. At 52 weeks, high-dose liraglutide led to a 5.5–6.0-kg placebo-adjusted weight loss. A total of 75% of subjects receiving high-dose liraglutide lost greater than 5% bodyweight, and 35% lost over 10%. A 10% drop-out rate owing to side effects, largely nausea, is comparable to that seen with exenatide.[213] There was no increased incidence of pancreatitis in trial participants compared with controls. However, a slightly increased incidence of medullary thyroid tumors has been reported in two nonhuman species in clinically relevant liraglutide doses, which is worrisome.[214]

Other long-acting GLP-1 analogs in the pipeline include lixisenatide by Zealand Pharma(currently undergoing Phase III testing[215]); CJC-1134-PC from ConjuChem Biotechnologies Inc., which is a conjugate of exendin-4 and recombinant human albumin; albiglutide by GSK and taspoglutide by Roche. In a separate development, Emisphere have formulated orally administered PYY and GLP-1 using a sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) carrier. Early studies revealed that peptides delivered orally in this way are rapidly absorbed from the gastrointestinal tract and reach concentrations several-fold higher than those seen naturally postprandially. Oral GLP-1 (2-mg tablet) alone and the combination of oral GLP-1 (2-mg tablet) plus PYY3–36 (1-mg tablet) induced a significant reduction in calorie intake.[216]

Five Year View

The stage is set for the continued rise in the prevalence of obesity and its associated morbidities. While lifestyle interventions at personal and societal levels are of the utmost importance, the need for better tolerated and more efficacious pharmacotherapies is undoubted. Important historical lessons have been learned from drugs designed to interact with receptors and neurotransmitters involved in the complicated circuitry of energy homeostasis and appetitive behavior, which overlap with several other higher functions, resulting in unwanted effects such as mood disturbance. A more detailed understanding of the physiological control of energy balance and the pathophysiology of obesity will continue to inform the development of highly selective, better targeted compounds. Energy homeostasis is of such critical physiological importance that there exists much redundancy and compensatory mechanisms within the system. This is compounded by the tendency to protect against weight loss much more avidly than weight gain. As more drugs become available, a polypharmacy approach, possibly alongside shifting dosing schedules, will develop to overcome these problems. This may be further aided by the greater understanding of the genetic influences on obesity, such as receptor polymorphisms, which would allow for individually tailored combinations. As natural activators of satiety circuits on a daily basis, gut hormones are likely to be an ongoing area of intense research in the field of anti-obesity drug development. There is impetus towards the realistic goal of using combination gut hormone therapy to produce a 'medical bypass' – achieving the outstanding weight loss and health benefits of gastric bypass surgery without its associated risks. Future advances in this field will include the development of long acting peptide hormone analogs to overcome the problem of the very short plasma half-life of endogenous peptide hormones, and the introduction of new forms of delivery: slow-release injectable depots, protease-resistant oral formulations, inhalation devices and transdermal patches.

Key Issues

    * Obesity is a global health crisis associated with multiple morbidities and early mortality. There is evidence to show that weight loss will reverse such consequences and prolong life.
    * A better understanding of the complex physiological systems regulating energy homeostasis is crucial for the production of more efficacious and better tolerated weight-loss drugs.
    * Currently approved drugs for the long-term treatment of obesity, orlistat and sibutramine, produce only modest weight loss and a series of side effects that result in high attrition rates.
    * Qnexa, Contrave and lorcaserin, all of which interact with appetitive neurotransmission in the CNS, are anti-obesity drugs currently in late-stage clinical trials.
    * Gastric bypass surgery is currently the most effective long-term treatment for obesity but is risk-laden and costly. Many of the weight-loss effects of bypass have been shown to be mediated via postoperative elevations in appetite-inhibitory gut hormones. Combination therapy with anorexigenic gut hormones or their analogs in an attempt to mimic the effects of surgery is a promising approach.

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