http://informahealthcare.com/pgm ISSN: 0032-5481 (print), 1941-9260 (electronic) Postgrad Med, 2015; 127(5): 494–502 DOI: 10.1080/00325481.2015.1048181

CLINICAL FOCUS: DIABETES REVIEW

Obesity: Lifestyle management, bariatric surgery, drugs, and the therapeutic exploitation of gut hormones Preeshila Behary, Jaimini Cegla, Tricia M. Tan and Stephen R. Bloom Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 06/05/15 For personal use only.

Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, Du Cane Road, London, UK

Abstract

Keywords

Obesity is on the rise and the pursuit of efficient and safe treatment is ongoing. Available antiobesity medical therapies have so far proved to be disappointing, whereas bariatric surgery is leading the way and offers long-term health benefits. Part of the success of bariatric surgery is thought to be mediated by gut hormones. A better understanding of the role of gut hormones within the gut-brain signaling pathway in the control of hunger, satiety, and energy homeostasis, has led to their therapeutic exploitation as possible anti-obesity drugs. In this review, we provide a summary of currently available treatment options for obesity from simple lifestyle modifications and bariatric surgery to traditional and novel medical therapies.

Obesity, lifestyle management, bariatric surgery, drugs, gut hormones

Introduction Obesity is a growing global epidemic. The World Health Organization estimates that over 1 billion adults and over 42 million children under the age of 5 are overweight worldwide [1,2]. In the UK, a quarter of adults are obese [3] and 30% of children are classified as overweight or obese [4], whereas in the US, a third of the adult population and ~ 17% of children are obese [5,6]. Obesity is recognized as an important risk factor for the development of diabetes, cardiovascular disease, and certain types of cancer, all contributing to significant morbidity, mortality, and financial burden. This has driven considerable interest in understanding the pathophysiology of this condition, the ultimate aim being to devise innovative ways to tackle obesity [5,6]. Food intake is closely regulated to match energy intake to the metabolic demands of the body. This “homeostatic control” dictates our eating behavior and is believed to have played a critical role in human evolutionary self-preservation. The problem arises when this homeostatic system becomes overwhelmed, resulting in an imbalance between energy intake and energy expenditure, hence weight gain. There is no doubt that the food industry and modern technology promoting a sedentary lifestyle have been key factors in exacerbating this imbalance especially in the developed world. Accessibility, availability, and the appeal of convenient and energy dense foods have contributed to the disruption of the homeostatic control of eating behavior. Worryingly, obesity is no longer confined to the developed world but is also affecting many low and middle income

History Received 5 February 2015 Accepted 1 May 2015

countries [7,8]. Therefore, there is a drive to find solutions to this emerging problem. In this review, we will provide an overview of the treatments available for obesity, from conventional lifestyle management to emerging pharmaceutical and innovative surgical options. We will discuss the potential mechanisms being targeted in each therapy and their limitations.

Lifestyle management Reducing energy intake while maximizing energy expenditure appears to be the ideal solution to restore balance in body weight. For this reason, exercise and diet remain cornerstone treatments for obesity. Restricting calorie intake through dieting is an effective way to lose weight, with numerous weight loss diet plans to choose from. Some of the popular ones include the low and very low calorie diet, low glycemic, low carbohydrate, low fat, and high protein content diets. There is an ongoing debate in regard to the most effective weight loss diet and concern has been expressed over longterm safety, benefits, and sustainability of numerous diets [9-12]. Unsurprisingly, the prospective patient can get easily confused by the marketing of companies that claim the superiority of their weight loss diet plans. The available clinical evidence is not always helpful as robust long-term data directly comparing different weight loss dietary profiles are limited and contradictory. For example, a recent study advocates the superiority of low-carbohydrate content diets over low-fat diets on both weight loss and cardiovascular factor

Correspondence: Preeshila Behary, Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, 6th Floor Commonwealth Building, Du Cane Road, London W12 0NN, UK. E-mail: [email protected]  2015 Informa UK Ltd.

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DOI: 10.1080/00325481.2015.1048181

Obesity: Lifestyle management, bariatric surgery, drugs, and gut hormones

risk reduction [13]. Others have shown that, irrespective of the macronutrient content of the designated weight loss diet, as long as they are consistent with a reduction in overall calorie content, people do lose clinically meaningful amounts of weight [14]. A recent meta-analysis showed that significant weight loss was observed with any low-carbohydrate or low-fat diet and weight loss differences between individual named diets were negligible [15]. Modest weight loss of 5% is associated with clinical improvement in cardiovascular risk factors including type 2 diabetes, with greater benefits derived from more substantial weight loss [16]. In fact, “reversal” of type 2 diabetes is possible following a short-term very low calorie diet of 600 kcal (2511 KJ) a day [17]. A very low calorie diet is a drastic short-term diet, potentially leading to weight loss of 15–25% over 3- to 4-month period when coupled with lifestyle modification [10]. Although effective for weight loss, there is a small increased risk of complications such as gallstones and micronutrient deficiency [9,18]. Irrespective of the diet plan, there is a high relapse rate of obesity. Weight regain of 50% by 1 year has been reported and net weight loss of 40 kg/m2) obesity (Table 1) [33,36,38]. However, there is now emerging evidence to validate its use in some patients with class I obesity (BMI = 30.0–34.9 kg/m2) as well [39,40]. The most commonly performed bariatric procedures worldwide, in order of popularity, are the Roux-en-Y gastric

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Postgrad Med, 2015; 127(5):494–502

Table 1. Classification of obesity by body mass index. 2

Body mass index (kg/m ) Overweight Class 1 obesity Class 2 obesity Class 3 obesity

25.0–29.9 30.0–34.9 35.0–39.9 ‡40.0

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Data taken from [38].

bypass (RYGB), the sleeve gastrectomy (SG), and laparoscopic gastric banding (LGB) (Figure 2). However, in the US, Canada, and countries of the Asia-Pacific region, more SG surgeries are being performed compared to RYGB, whereas LGB is declining in popularity globally [41]. The biliopancreatic diversion is another surgical procedure which is rarely performed nowadays due to its association with profound malabsorption and nutritional deficits [42,43]. LGB is a minimally invasive and technically easy procedure where a band is placed around the stomach just inferior to the gastroesophageal junction, to restrict gastric volume and regulate how much the patient can eat. One specific shortcoming of this procedure is that it requires repeated follow up for adjustment of the pressure in the band to achieve the desired level of restriction. SG involves a longitudinal resection of the stomach leading to the formation of a tube-like structure called the “sleeve”. This procedure is irreversible. RYGB involves the creation of a small gastric pouch of ~ 30 ml in volume, which is then anastomosed to a divided section of the distal small intestine. This is referred to as the Roux limb. The majority of the stomach and the proximal small intestine are bypassed. The bypassed bowel, known as the biliopancreatic limb, is then connected further down the Roux limb to allow the flow of pancreatic secretions and bile. This procedure combines restriction of food intake with some degree of malabsorption to induce weight loss. RYGB typically causes up to 30% body weight loss and a remission rate of diabetes of between 40 and 80%, depending on the criteria used to define remission [44-46]. Furthermore, long-term data suggest that bariatric surgery confers sustained weight loss of up to 20 years and reduction in cardiovascular death and all causes of mortality. This is despite a gradual weight regain observed after 2–3 years post surgery which subsequently appears to level off by 8–10 years [47]. These expert center trials can, however, be misleadingly optimistic with high attrition rates. SG performed in centers with the surgical expertise can also produce comparable weight loss and improvement in obesity related comorbidities, although long-term data to

challenge the RYGB procedure are not yet available [48-50]. Data available indicate that weight loss through SG is less than with RYGB; in addition, even if improvement in glycemic control in type 2 diabetes patients may not be significantly different between the two procedures, more antidiabetic medications need to be used in patients who undergo the SG [51]. However, compared to conventional nonsurgical management of obesity such as lifestyle modification, all three types of bariatric surgery are superior in achieving significant and sustained weight loss [47,51]. The beneficial metabolic effects of RYGB are thought to be mediated beyond the simplistic restrictive and malabsorption mechanisms. Compared to LGB, RYGB leads to additional weight loss and induce diabetes remission. The diabetes improves or “remits” within days of the RYGB surgery, before substantial weight loss has occurred, suggestive of weight-independent mechanisms [52,53]. The gut hormones GLP-1, OXM, and PYY are elevated early after RYGB and stay elevated for years, whereas ghrelin levels tends to be reduced [54-58]. It is thought that the rapid delivery of nutrients to the lower gut enhances the nutrient sensing ability of L cells which promote secretion of GLP-1, PYY, and OXM after eating [52]. These hormones have been shown to induce satiety, promote insulin release, and increase energy expenditure in humans [59-63]. Hence they have the potential to be the key mediators of weight loss and diabetes remission post-RYGB. In fact, Roux et al. showed that blocking the action of PYY in rats post-jejuno-intestinal bypass led to an increase in ad libitum food intake comparable to sham-operated animals; whereas exogenous injection of PYY in sham-operated rats led to a decrease in ad libitum food intake [57]. The same group also showed that inhibiting PYY and GLP-1 with octreotide post-RYGB resulted in an increase in appetite and food intake in both human and animal studies [56,64]. In other studies, satiety increases dramatically post-RYGB and has been associated with a rise in gut hormones [55,65]. In further support of the “gut hormone hypothesis”, it has been shown that patients who successfully lose weight post-RYGB “responders” have higher circulating GLP-1 and PYY compared to “non-responders” [66]”. In opposition to the “gut hormone hypothesis”, some studies observed significant weight loss and improvement in glycemia post-RYGB in both humans and animals, despite abolishing the effect of GLP-1 [67-69]. GLP-1 blockage was achieved by either an intravenous infusion of exendin-9 to -39), a potent GLP-1 antagonist, or by using a GLP-1R knocked-out mouse model. The authors therefore concluded

Figure 2. Illustrations showing common bariatric procedures: a) laparoscopic gastric banding; b) Roux-en-Y gastric bypass; c) sleeve gastrectomy.

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DOI: 10.1080/00325481.2015.1048181

Obesity: Lifestyle management, bariatric surgery, drugs, and gut hormones

that GLP-1 was unlikely to mediate the beneficial metabolic effects of RYGB and other factors are important. Besides gut hormones, other mechanisms have also been postulated to contribute toward the observed weight loss after RYGB. The vagus nerve represents an important relay system by which gut hormones exert their effect on the brain [70]. Therefore, it is feasible that disruption of vagal innervation to the gastrointestinal tract following surgery could modulate appetite and satiety toward weight loss [71-73]. Other implicated mechanisms involve a change in the composition and levels of bile acids, fibroblast growth factor 19 (FGF-19) and FGF-21 post-RYGB. These have been reported to be elevated post-RYGB and there is increasing evidence to suggest that these molecules act as regulators of glucose and energy metabolism [74-76]. Furthermore, a shift in gut microbiota composition has been observed after RYGB which favors an environment promoting glucose and energy metabolism possibly through short-chain free fatty acids production by colonic bacteria [77,78]. It is also believed there is an interplay between the microbiome post-RYGB and bile acids in regard to altering their absorption and deconjugation and enhancing overall enterohepatic recycling [79]. In comparison to the hormonal changes observed postRYGB, GLP-1, OXM, and PYY levels are unchanged or decreased following calorie restriction-induced weight loss and unchanged following LGB [80,81]. This may explain the superiority of RYGB over LGB and calorie restriction in inducing weight loss. The success of RYGB in inducing weight loss could also relate to the changes in food preferences post-surgery. There is some evidence to suggest that post-RYGB, healthier food options have a greater appeal to patients compared to high fat, high sugar food [82]. This is consistent with fMRI findings of decreased brain activation within the hedonic regions to high fat food but not low fat food after RYGB surgery [83]. Bariatric surgery is a life-changing procedure and, as with any surgery, carries risks and complications. The 30-day mortality of RYGB is estimated at 0.1% to 0.3%, comparable to a laparoscopic cholecystectomy, and hence considered a relatively “low risk” procedure [84]. Common short-term complications are bleeding, anastomotic leaks, wound infections, and thromboembolic events. Long-term complications may include nutritional deficiencies, weight regain, or hyperinsulinemic hypoglycemia. However, these are uncommon and the key factors impacting on surgical risk profile are experience of the surgeon, center’s volume, patient’s comorbidities, and complexity of surgery among others [85]. There is no doubt that bariatric surgery is currently the best ammunition we have to battle obesity but it does come with financial implications and resource limitations [86]. Furthermore, bariatric surgery is not always readily accessible to everyone, especially to those who are more likely to benefit such as individuals from lower socioeconomic background [86,87].

Pharmacotherapy There is an urgent need for noninvasive, simpler, and more accessible treatment options for obesity. The development of

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anti-obesity drugs represents a major research area and has been the focus of reputable pharmaceutical companies for many years. The drug regulatory agencies, the FDA in the US, and the European Medicines Agency (EMA) in Europe, considers a mean weight loss of at least 5% from baseline to be a valid primary efficacy point for approving a weight loss drug [88,89] Rimonabant, a cannabinoid CB1 receptor antagonist, and sibutramine, a serotonin and noradrenaline reuptake inhibitor, initially showed promise when they were first launched. However, they were both withdrawn from the market because of the increased risk of depression and suicidal ideation in the case of rimonabant and cardiovascular disease with sibutramine in 2008 and 2010, respectively [90,91]. Orlistat, a potent selective pancreatic lipase inhibitor, was, until recently, the only licensed anti-obesity drug in Europe and is also approved by the FDA for long-term use. Orlistat can be purchased over the counter in some countries. An average weight loss of 3 kg is typically seen following a year’s treatment on orlistat [92,93]. However, its gastrointestinal side effects such as steatorrhea mean that orlistat is poorly tolerated and therefore limits its use. Two newer agents, lorcaserin and phentermine/topiramate have been approved by the FDA for the US market 2 years ago [94]. Lorcaserin is a selective serotonin 2C receptor agonist, which promotes satiety via stimulation of proopiomelanocortin (POMC) neurons. Clinical studies involving overweight and obese individuals with one obesity-related comorbidity have shown modest weight reduction of ~ 5% [95]. On the up side, the drug has shown a relatively good tolerability profile and the increased incidence of valvulopathy observed in rodents has not been borne out in humans thus far [94]. Phentermine, a central noradrenaline releasing drug and topiramate, is a licensed antiepileptic drug. The combination of both has been shown in clinical trials to induce average weight loss of 10% in around half of the study subjects when given the higher dose of the drug and most importantly, weight loss was sustained up to 56 weeks [96]. Despite phentermine’s long-established use as an appetite suppressant, the mechanism by which it suppresses appetite is unclear. Major safety concerns such as the risk of teratogenicity remain and therefore this drug may not be the ideal choice for women of childbearing age. As from September 2014, two anti-obesity agents have been approved by the FDA in the US. They are liraglutide 3mg (Saxenda), a GLP-1 agonist, and the combination drug naltrexone/bupropion [97,98]. In January 2015, the EMA also voted in favor of Saxenda to be brought to the European market [99]. This is discussed later in the review. Naltrexone is an opioid antagonist, which can be used for treating opioid and alcohol addiction, whereas bupropion is an antidepressant, which inhibits noradrenaline and dopamine re-uptake. It is believed that the combination drug works by promoting satiety via the activation of POMC neurons and modulation of the mesolimbic pathways [100]. In separate double-blinded, randomized clinical trials (RCTs) of 56 weeks duration, between 44% and 55% of study participants lost at least 5% of their body weight following treatment with

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naltrexone/bupropion. In subjects with type 2 diabetes, mean placebo-subtracted weight loss of 3.2% was seen [101-103]. The most common reported side effect from the RCTs was nausea with no difference observed in the incidence of psychiatric symptoms between the treatment group and placebo. In summary, there are limited pharmacotherapeutic options which are deemed safe and efficient in achieving clinically meaningful weight loss. Furthermore, long-term safety data is limited and therefore caution should be exercised with newer agents.

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Gut hormones Exploiting the gut–brain axis by taking advantage of the properties of gut hormones is the focus of intensive research looking for a new therapeutic approach for obesity. However, most gut hormones are rapidly broken down by peptidases in the circulation, and oral therapies are unable to withstand the harsh gastric environment. Therefore, injectable therapy remains the main form of administration. We have summarized below past and current manipulation of gut hormones in designing novel anti-obesity agents resistant to degradation. We chose to discuss these gut hormones specifically as they are the main ones implicated in mediating the beneficial metabolic effects of RYGB and are being investigated in current human clinical trials. GLP-1 GLP-1 has been the most therapeutically exploited gut hormone to date. It is secreted from the L cells of the ileum in response to oral nutrients. It is also a potent incretin, augmenting glucose-dependent insulin release from the pancreatic b cells. The biological active forms are GLP-1 (7–37) amide and GLP-1 (7–36) amide, although the latter is more prevalent in the circulation. Central and peripheral administration of GLP-1 has shown reduction in food intake and weight in rodents. Peripheral administration in both lean and overweight humans produces a reduction in ad libitum food intake [60,104]. It is believed that GLP-1 acts centrally on the hypothalamus and brainstem to inhibit appetite [105,106]. GLP-1 is broken down rapidly by the enzyme dipeptidyl peptidase-4 (DPP-4) and has a half-life of 2 minutes in the circulation. Manipulation of the peptide to extend its life is therefore necessary. Exenatide (Byetta) was the first GLP-1 analog to be marketed for the treatment of type 2 diabetes in 2005. This was originally based on exendin-4, which was isolated from the saliva of the Gila monster and is more robust to DPP-4 degradation. Further GLP-1 analogs then followed: liraglutide (Victoza), a GLP-1 analog engineered to bind to albumin and therefore to persist in circulation and exenatide LAR (Bydureon), a weekly preparation of exenatide in slowdissolving microspheres. Other GLP-1 mimetics currently on the market for the treatment of type 2 diabetes are albiglutide, dulaglutide, and lixisenatide [107]. Liraglutide is the analog that has seen most application in obesity. At a dose of 1.2 and 1.8 mg/day, liraglutide was initially approved for patients with type 2 diabetes and has been shown to cause a sustained weight loss of ~ 3 kg in clinical

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trials [108]. This is indeed modest but still useful for treating the obese patient with diabetes as several current glucoselowering therapies, including insulin as well as sulfonylureas, are associated with further weight gain. More exciting data from the Phase IIIa SCALE Diabetes trial were recently revealed which showed that liraglutide 3 mg/day achieved a placebo-subtracted weight loss difference of 5.9 kg over 56 weeks. Furthermore, it was also demonstrated that >80% of subjects treated with a 12-week run-in period of low calorie diet followed with liraglutide 3mg, maintained a weight loss of >5% for the study duration [109]. These results are in agreement with a previous study showing significant weight loss with liraglutide in a dose-dependent manner compared to both placebo and orlistat [110]. Weight loss was sustained for over 2 years and a good tolerability profile was observed with liraglutide given up to 3 mg/day [111]. Liraglutide 3 mg/day (Saxenda), as mentioned earlier, has now been approved both in the US and the UK as monotherapy for obesity in patients without diabetes. A common side effect of GLP-1 analogs is nausea. Nausea is likely to reflect the extreme end of the spectrum of GLP-1’s anorectic effects, with a gray zone in between where satiety is achieved without inducing nausea. However, nausea appears to subside with long-term therapy in the majority of patients [112]. Recently, concerns have been raised regarding the increased risks of pancreatitis, pancreatic and medullary thyroid cancer related to the long-term use of GLP-1 analogs [113]. This has fuelled much debate; however, the overall consensus is that the benefits far outweigh the risks and although caution needs to be exercised, there is insufficient evidence to firmly link GLP-1 analogs to the above mentioned adverse effects [114,115]. Pancreatic polypeptide PP is a 36 amino acid peptide secreted from the Islets of Langerhans in response to eating. It is believed to preferentially act on neuropeptide Y4 receptors within the hypothalamus and brain stem to promote satiety, although there is also some evidence for its anorectic action to be mediated via the vagus [116]. Intravenous infusion of PP has been shown to achieve food intake reduction of 25% over 24 hours in lean healthy volunteers [117]. Furthermore, a Phase Ia clinical trial of PP1420, a long-acting potent PP analog, showed promise in terms of safety and tolerability profile when given as a subcutaneous injection [118]. Phase Ib and Ic studies, which will focus on further safety and efficacy parameters such as food intake, at various ascending doses, are currently in progress (ClinicalTrials.gov identifier: NCT01052493). Peptide YY PYY is also a 36 amino acid peptide belonging to the same “PP fold” family as PP. It is secreted from the L cells in response to eating and exerts anorectic effects by preferentially acting on neuropeptide Y2 receptors, mostly situated in the arcuate nucleus of the hypothalamus. Batterham et al. demonstrated a reduction in food intake following PYY infusion in obese subjects and a reduction in weight following

DOI: 10.1080/00325481.2015.1048181

Obesity: Lifestyle management, bariatric surgery, drugs, and gut hormones

chronic PYY administration in rodents. They also showed significantly lower basal and postprandial rise in PYY levels in the obese compared to lean control which may suggest a role for PYY in the pathogenesis of obesity [62,119]. Currently, several novel long-acting injectable PYY analogs are under investigation in first-in-human studies (ClinicalTrials.gov identifier: NCT01515319).

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Oxyntomodulin OXM is a 37 amino acid peptide co-secreted with GLP-1 from L cells of the distal gut following a meal. OXM binds to both GLP-1 and glucagon receptors although with lower affinity compared to the individual peptides. Therefore, OXM represents an attractive possibility to exploit dual receptors and augment weight loss. This approach combines the appetite suppressive effects of GLP-1 and glucagon, with the energy expenditure increasing effects of glucagon [120,121]. In fact, peripheral infusion and chronic subcutaneous injection of OXM resulted in reduction of food intake, weight loss, and increase in activity-related energy expenditure in humans [61,63]. The concept of dual receptor agonism at both the GLP-1 and glucagon receptors is an exciting prospect and analogs such as ZP2929 by Zealand Pharma combining these properties are under development [122].

Conclusion There is no doubt that gut hormones have a key role in the regulation of appetite and weight and we have come a long way in both our understanding of this intricate neuroendocrine system as well as in using this knowledge to advance anti-obesity drug development. Bariatric surgery has set the benchmark and neither gut hormone analogs nor any of the current medical therapies can rival its dramatic effects on weight. In attempting to understand the mechanisms by which bariatric surgery exerts its effects, a novel therapeutic approach to the treatment of obesity has been uncovered. Perhaps the secret of its success lies in the changes of gut hormone profiles observed post-surgery. The elevations of at least three different anorexic gut hormones after RYGB may give rise to an additive or even synergistic effect on inducing and maintaining weight loss. It might also explain why single gut hormone agonists such as liraglutide do not achieve weight loss on the same scale as RYGB surgery. Our best chances of unraveling a “medical bypass” may be to mimic the changes seen in the post-RYGB hormonal milieu with combination drug therapy or designing dual or even triple receptor gut hormone agonists.

Declaration of interest The section is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology Capacity Building Award, an FP7- HEALTH- 2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the

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subject matter or materials discussed in the manuscript apart from those disclosed.

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