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Anti-obesity drugs

Rankin, Waynea,b,c; Wittert, Garya,c

doi: 10.1097/MOL.0000000000000232
THERAPY AND CLINICAL TRIALS: Edited by Erik S.G. Stroes and Gerald F. Watts

Purpose of review The prevalence of obesity across the world continues to climb, bringing with it otherwise preventable obesity-related comorbidities including type 2 diabetes, hypertension and cardiovascular disease. Weight loss is difficult to achieve and maintain through lifestyle interventions alone, leading to intense efforts to develop adjunctive pharmacological approaches. Herein, we examine recent advances in this field and limitations of currently available and emerging agents.

Recent findings Liraglutide, lorcaserin and combination of phentermine–topiramate and bupropion–naltrexone have all been the subject of recent studies examining their efficacy as weight-loss agents. Although each effectively induces weight loss over and above placebo, significant concerns exist regarding side-effect profiles and safety, along with their ability to achieve sustained effects. Dropout rates in all examined studies were up to 50% or more, usually a result of intolerable side-effects. Recruitment of a high proportion of women of European descent also casts doubt on the generalizability of trial data.

Summary Pharmacological interventions for weight loss remain limited, with side-effects often outweighing efficacy. Interestingly, substantial early weight loss was associated with sustained loss, suggesting a responsive phenotype and future trials might best be targeted in identifying responsive subpopulations.

aEndocrine and Metabolic Unit, Royal Adelaide Hospital

bChemical Pathology Directorate, SA Pathology

cDiscipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia

Correspondence to Professor Gary Wittert, Discipline of Medicine, University of Adelaide, Adelaide, 5000 SA, Australia. Tel: +61882225502; fax: +61882233870; e-mail:

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Because weight loss is universally so difficult to achieve, and particularly to maintain, there has been intense effort over many decades to develop adjunctive pharmacological approaches. This is a field of therapeutics with a very large graveyard of stillborn and premature deaths of initially promising therapeutic agents. In general, their effects on weight loss have been modest at best and side-effect profiles have been significant. Moreover, there are no hard outcome data showing benefit. This stands in contrast to the benefits of treating the associated comorbidities with pharmacotherapy, albeit at the cost of polypharmacy and potentially incremental adverse effects.

Perhaps, the problem is not so much with the particular drugs themselves but the drug development process, which fails to take account of a number of significant factors. First, obesity is not a homogeneous condition and it ranges from severe generalized obesity, which is lifelong and associated with clearly defined genetic abnormality to predominantly visceral obesity in middle-aged and older individuals and with a range of phenotypic variations between those extremes. Second, the comorbidities associated with obesity are variable [1 ▪ ,2 ▪ ][1 ▪ ,2 ▪ ], even between individuals with similar distributions of body fat and durations of being obese. Finally, the data on the benefits of intentional diet-induced weight loss are somewhat mixed and accumulating evidence highlights the importance of diet quality in health outcomes, or put another way, eating less of a nutritionally bad diet is not necessarily good for you even if weight is lost [3▪▪].

There have been recent reviews on the pharmacotherapy of obesity [4 ▪ ,5][4 ▪ ,5] as well as the publication of an Endocrine Society clinical practice guideline [6]. This review examines recent data on new and emerging obesity pharmacotherapies with the previously stated considerations in mind.

Box 1

Box 1

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Weight-loss medications, approved by at least some regulatory agencies, target: fat digestion and absorption from the gut, and peripheral, or central appetite regulating mechanisms. Some of the medications exert their effects at a single target. For example, orlistat inhibits pancreatic lipase, lorcaserin is a 5-HT2C receptor agonist and liraglutide is a glucagon-like peptide 1 (GLP-1) agonist. It is likely though that lorcaserin and liraglutide have both peripheral and central effects. Other medications, particularly when used in combination, target multiple appetite regulating systems, for example phentermine and topiramate.

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Orlistat, a pancreatic lipase inhibitor, has widespread approval, and indeed is the only agent approved in the European Union for weight loss. Orlistat achieves weight loss by inducing fat malabsorption, and although its efficacy is limited, it has a well-established long-term safety profile [7].

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Lorcaserin is a centrally acting 5-HT2C receptor agonist. The effect to induce satiety occurs by activating pro-opiomelanocortin (POMC) neurones in the arcuate nucleus [8▪] and by attenuating ghrelin-induced food intake because of cross-talk between the 5-HT2C receptor and the ghrelin receptor growth hormone secretagogue receptor 1A in the hypothalamus and hippocampus [9▪]. In addition, lorcaserin may have peripheral effects resulting from interactions with gastrointestinal cholecystokinin and leptin signaling [10▪].

The ‘Behavioral Modification and Lorcaserin for Overweight and Obesity Management’ (BLOOM) [11] and ‘Behavioral Modification and Lorcaserin Second Study for Obesity Management’ (BLOSSOM) [12] trials examined the weight loss effects of lorcaserin in combination with lifestyle counseling in populations of overweight or obese individuals. Exclusion criteria included diabetes mellitus, hypertension, hypertriglyceridemia and pre-existing cardiac valvulopathy, among others. Individuals were predominantly women (83.5 and 79.8% in BLOOM and BLOSSOM, respectively) and white (70 and 67%). The primary outcome was weight loss at 1 year, with extension to 2 years in the BLOOM trial. The most commonly reported side-effects in the lorcaserin-treated arms were nausea, headache and dizziness and resultant dropout rates were 55–59%. In a pooled analysis of the 52-week outcomes of these two trials, weight loss was 5.8 and 2.5% in the lorcaserin and placebo groups, respectively; 47.1 and 22.4% of the lorcaserin-treated patients achieved a weight loss of at least 5 and at least 10%, respectively, compared with 22.6 and 8.7% in the placebo group. Lipid parameters, glycemic indicators, quality-of-life measures and vital signs improved more in the lorcaserin group compared with placebo. Among those who completed 52 weeks’ treatment, significant changes from baseline concentrations were seen relative to placebo for total cholesterol (–1.2 versus 0.5%), triglycerides (–10.5 versus –3.5%) and HDL-cholesterol (2.8 versus 1.0%) [13▪]. A similarly designed trial that enrolled patients with diabetes mellitus, the BLOOM-DM trial [14], reported similar results. A post hoc analysis of the data showed that those who achieved weight loss of at least 5% from baseline after 12 weeks in both lorcaserin and placebo-treated groups were more likely to maintain or improve that weight loss at 52 weeks [15▪].

The relative specificity for the 5-HT2C receptor predicts that cardiac valvular lesions ought not to occur. However, in an analysis of adverse events in the BLOOM, BLOOM-DM and BLOSSOM trials, DiNicolantonio et al.[16▪▪] demonstrated mitral or aortic regurgitation [odds ratio (OR) 1.88: 95% confidence interval (CI) 1.02–3.47], and a trend to pulmonary hypertension (OR 1.41: 95% CI 0.87–2.27) in the lorcaserin group compared with the placebo group. In addition, there was an increased risk of depression (OR 1.89: 95% CI 1.04–3.44). Accordingly, it is considered, at least by the European Medicines Agency, that lorcaserin requires further investigation [7]. A long-term cardiovascular outcomes study is underway.

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Liraglutide is a long-acting GLP-1 analogue administered by once daily injection. Multiple studies have demonstrated improved glycemic control and weight loss in response to treatment with liraglutide in patients with type 2 diabetes mellitus (T2DM) [17,18 ▪ ][17,18 ▪ ]. Liraglutide treatment is also effective to reduce weight in adults with obesity without T2DM, and these effects appear to be mediated by decreased appetite secondary to delayed gastric emptying with resultant decreased energy intake [19▪]. In addition, animal studies also suggest a role of brainstem or hypothalamic GLP-1 receptor in appetite inhibition [20].

An initial 20-week clinical trial compared once-daily liraglutide (1.2, 2.4 and 3 mg) with placebo and orlistat in 564 patients with a mean BMI of 35 kg/m2. Weight loss in the 2.4 and 3.0 mg liraglutide-dose groups and the orlistat group was 6.3, 7.2 and 4.1 kg, respectively, as compared with 2.8 kg in the placebo group [21]. Extension of this trial to 2 years showed that the weight loss in response to liraglutide was sustained, with the prevalence of prediabetes (measured as impaired fasting glycemia or impaired glucose tolerance) and metabolic syndrome decreasing by 52 and 59%, respectively, in the liraglutide groups [22,23 ▪ ][22,23 ▪ ]. Nausea and vomiting were the most common adverse events, and occurred in a dose-related manner, most often during dose escalation and then abated over time. However, 4% of individuals in the liraglutide groups withdrew because of nausea and vomiting in the first year of the trial compared with none of the other groups. Interestingly, weight loss at 1 year was the greatest among those individuals receiving 3.0 mg of liraglutide daily who experienced nausea and vomiting (9.2 versus 6.3 kg) [23▪]. Because the presence of nausea and vomiting in the liraglutide groups had no influence on assessments of quality-of-life, side-effects of liraglutide were considered well tolerated.

A subsequent 56-week randomized, double-blind, placebo-controlled trial involving 3731 nondiabetic patients, again with a BMI of 30 kg/m2 or greater, or 27 kg/m2 or greater with coexisting risk factors of hypertension and/or dyslipidemia, compared liraglutide at a once daily dose of 3 mg with placebo [24▪▪]. Individuals in the liraglutide group had a mean weight loss of 8.3 kg, versus 2.8 kg in the placebo group: 63 and 33.1% of those in the liraglutide group lost 5% or more, or 10% or more of their body weight, respectively, compared with 27 and 10.6% in the placebo group. Improved lipid parameters were seen in the liraglutide group relative to the placebo group, with a 2.3% decrease seen in total cholesterol, a 3.9% decrease in non-HDL cholesterol and a 1.9% increase in HDL-cholesterol. The number of individuals who progressed from prediabetes to overt diabetes was reduced in the liraglutide group (4/2130) versus placebo (14/813).

The ability of once daily liraglutide to maintain and reinforce weight loss was also examined in a trial in 422 nondiabetic patients, again with an initial BMI of 30 kg/m2 or greater, or 27 kg/m2 or greater with coexisting risk factors of hypertension and/or dyslipidemia, who participated in a 4–12-week pretrial run-in programme of diet and exercise and lost more than 5% of their initial body weight [25]. Randomization occurred after initial weight loss was achieved: liraglutide was administered at a dose of 3 mg daily. Over the 56-week trial period, 81.4% of patients in the liraglutide group maintained weight loss, compared with 48.9% in the placebo group, and 50.5% of those in the liraglutide group achieved further weight loss of 5% of their randomization weight, compared with 21.8%.

Across the liraglutide studies, gastrointestinal effects were common, with nausea and vomiting, although typically transient and usually classified as of mild or moderate severity, contributing to withdrawal from all trials at rates greater than for placebo [22,24 ▪▪ ,25][22,24 ▪▪ ,25][22,24 ▪▪ ,25]. Pi-Sunyer et al.[24▪▪] reported 40.2% experiencing nausea in the liraglutide group, 20.9% experiencing diarrhea and 16.3% experiencing vomiting, compared with 14.7, 9.3, and 4.1% in the placebo group, leading to withdrawal of 159 of 2481 individuals (6.4%) in the liraglutide group versus nine of 1242 (0.7%) in the placebo group. The rates of cholelithiasis, cholecystitis and pancreatitis were also greater in the liraglutide group, with 61 cases of cholelithiasis and cholecystitis in 2481 liraglutide-treated individuals (2.5%), compared with 12 cases in 1242 placebo-treated individuals (1.0%). In addition, 10 cases of pancreatitis were seen in liraglutide-treated individuals, with five of these being gallstone pancreatitis: one case of (gallstone) pancreatitis was seen in the corresponding placebo-treated individuals. Also of note is that episodes of hypoglycemia were reported by both Pi-Sunyer et al.[24▪▪] and Astrup et al.[22] at rates of 11.9 versus 3.3%, and 3.5 versus 1.0%, respectively, although no episodes were rated as severe.

At 56 weeks, 28.1% of liraglutide-treated individuals had withdrawn from the study of Pi-Sunyer et al.[24▪▪]. Although this appears to compare favorably with the rate of withdrawal from the placebo group (35.6%), the number of withdrawals because of adverse events was greater in the treatment group. The 2-year withdrawal rate for those randomized to the 3.0 mg daily liraglutide dose in the NN8022–1807 trial was 49% [23▪]. The overall high withdrawal rate casts doubt on the potential for liraglutide in long-term treatment of obesity outside a closely monitored trial environment. Indeed, a small study of GLP-1 agonists used off-label for weight loss in 43 nondiabetic individuals attending a multidisciplinary weight loss clinic (five men: 38 women), with seven treated with exenatide, 10 μg twice daily and 36 with liraglutide, 1.2 mg daily, showed that after a very short mean treatment follow-up period of 3 months, only 13 of the 43 individuals had continued treatment [26▪▪]. Reasons for ceasing included side-effects (20.9%), which again were predominantly gastrointestinal, minimal weight loss (27.9%) and the important consideration of cost (14%). This outcome is more likely to reflect the real-world situation, where despite good support, in this case a multidisciplinary weight loss clinic, motivation to continue treatment in the face of side-effects, poor efficacy and personal cost is reduced.

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Combination agents

In addition to the above single target agents, two combination drug formulations developed with the aim of improving efficacy and tolerability over single agents have been approved by the United States Food and Drug Administration (FDA): phentermine and extended-release topiramate, and bupropion and naltrexone.

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Phentermine, a centrally acting sympathomimetic agent pharmacologically related to amphetamine, acts as an appetite suppressant. Topiramate is a sulphated monosaccharide with multiple targets including modulation of voltage-activated sodium and calcium channels, interaction with gsamma-amino butyric acid-A and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainite receptors, and inhibition of carbonic anhydrase. The combination of a slow release formulation of phentermine and topiramate decreases energy intake and increases energy expenditure leading to weight loss [27▪]. The concept is to get an augmented weight loss effect by using a lower dose of each drug and accordingly minimize side-effects. The CONQUER trial [28] and subsequent SEQUEL extension trial [29] examined the weight loss effects of phentermine–topiramate over a 108-week period in individuals with a BMI of 27–45 kg/m2 and two or more comorbidities, not excluding T2DM. The similarly designed EQUIP trial enrolled individuals with a BMI greater than or equal to 35 kg/m2[30]. Despite the anticipated weight loss efficacy, neurological and psychiatric/psychological complications were prevalent. Further to this, Neoh et al.[31▪▪] examined its use in the real-world environment of a multidisciplinary weight loss clinic. There was a 40% adverse-event-related cessation rate noted in comparison to the 16% or less seen in clinical trials [29,30][29,30]. Neurological side-effects predominated [31▪▪]. This combination best avoided in patients with cardiovascular disease [32▪]. The high rates of side-effects cast doubt on its safety in real-world prescribing.

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Bupropion, a nonselective inhibitor of dopamine and noradrenaline transporters that also stimulates hypothalamic POMC neurones, inducing satiety, has been used in combination with the opioid antagonist naltrexone, which blocks opioid receptor-mediated POMC neurone inhibition [33,34][33,34]. The weight loss effects of this combination were shown in a phase 3 trial [33] that examined its effects in overweight and obese individuals over a period of 56 weeks. Although weight loss of greater than 5% was seen in approximately 65% of participants with minimal reported side-effects, concerns remain about safety [34]. FDA approval of this combination is contingent on postmarketing evaluation of cardiovascular outcomes and carries risk of suicidal ideation, along with high rates of gastrointestinal side-effects [35].

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All of the major trials examining currently available pharmacological agents for weight loss in nondiabetic obese individuals show significant weight loss effects relative to placebo (Table 1) [11,21,24 ▪▪ ,29–33][11,21,24 ▪▪ ,29–33][11,21,24 ▪▪ ,29–33][11,21,24 ▪▪ ,29–33][11,21,24 ▪▪ ,29–33][11,21,24 ▪▪ ,29–33][11,21,24 ▪▪ ,29–33][11,21,24 ▪▪ ,29–33]; however, all of these trials have a majority of female individuals (approximately 75%), and white individuals of European descent predominate, despite recruitment across multiple sites in multiple countries. Extrapolation of the trial results beyond these groups is, therefore, difficult and although lip service is given to this issue in the discussion relating to several of these trials [28,30,33][28,30,33][28,30,33], no subsequent subgroup analyses or follow-up trials have eventuated.

Table 1

Table 1

In addition, despite attempts to describe effects on body composition from results of dual-energy x-ray absorptiometry and computerized axial tomography [22,28][22,28], the data are presented as if from a homogenous population, again making interpretation and generalizability difficult.

Furthermore, trial design has specifically excluded individuals from particular groups that may show some benefit from pharmacological interventions, for example, those who have had past bariatric surgery and who might benefit from these agents to enhance initial weight loss or to inhibit weight regain.

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Despite the problems encountered in bringing the obesity pharmacological agents to market, the search for effective medications continues, and a number of newly developed agents have recently been examined in preclinical and early phase trials.

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Methionine aminopeptidase 2 inhibitors

Inhibitors of methionine aminopeptidase 2, an enzyme that promotes angiogenesis, have been shown in murine models to have potent antiobesity effects. One such inhibitor, beloranib, has proceeded to phase 1 [36▪] and 2 [37▪] trials, showing weight loss of up to 10%, even in the absence of accompanying lifestyle interventions across a small 12-week, double-blind, randomized study of 147 predominantly white (98%) women (94%), with a BMI between 29.8 and 53.7 kg/m2. Adverse events, in particular gastrointestinal disorders and sleep disturbance, led to the withdrawal of multiple individuals, including 17 of the 35 individuals in the high-dose group. In addition, elevated 3-hydroxybutyrate levels were noted, suggesting that this agent might precipitate ketosis, thus limiting its utility.

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The improved efficacy of combination regimens addressing multiple targets over single-agent therapies has prompted the design of hybrid peptides with multiagonist activity [38,39 ▪ ][38,39 ▪ ], some of which are currently in preclinical assessment. Most recently, Finan et al. described a triple-agonist molecule with potent activity at the GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. In rodent models of diabetes and obesity, this peptide showed synergistic effects on metabolic and glycemic parameters dependent on GLP-1 and GIP receptor signaling along with improved energy metabolism via glucagon receptor signaling, without inducing hypoglycemia or hyperglycemia. Such peptides are yet to be tested in clinical trials.

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Despite the recent flurry of activity and reporting of trials relating to adjunctive pharmacotherapy for obesity, widely applicable agents with acceptable side-effect and safety profiles remain to be described. A recent focus on the GLP-1 agonist liraglutide has revealed that this agent can achieve sustained weight loss in some overweight and obese individuals; however, its general efficacy is limited by its side-effects. Similarly, safety concerns relating to the use of the 5-HT2C receptor agonist lorcaserin have limited its use across the world.

A continued long-term problem in all trials relating to obesity pharmacotherapy is the recruitment of a preponderance of women of European descent, which casts doubt on the generalizability of the reported results. In addition, the high dropout rates seen across examined trials make analysis of endpoints unreliable and might translate to even higher rates of therapy discontinuation in typical clinical use, further limiting efficacy.

Post hoc analysis of trial data has shown that for many weight loss agents, subpopulations exist who have an early response to weight loss agents and it is these individuals who proceed to have the most sustained weight loss across this trial period. Therefore, it is tempting to suggest that reanalysis of trial data with respect to gathered anthropometric data and their relationship to weight loss outcomes might be of use in identifying an individual phenotype for which weight loss medications may be most useful. Similarly, response in the early phases of treatment may be applied to identify nonresponders, consequently limiting unnecessary exposure to these medications.

In addition, we look forward to the reporting of outcomes relating to newly developed agents currently in preclinical or phase I trials.

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Financial support and sponsorship


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Conflicts of interest

W.R. has been a recipient of honoraria and speakers fees from NovoNordisk. G.W. is a member of a Novo Nordisk International Advisory Board. He has been an investigator in clinical trials of liraglutide, lorcaserin and topiramate and has received honoraria for giving talks from Inova (phentermine) and NovoNordisk (liraglutide). He is the independent chair of the Weight Management Council of Australia and has received research funding from Weight Watchers.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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1▪. Martin-Rodriguez E, Guillen-Grima F, Martí A, Brugos-Larumbe A. Comorbidity associated with obesity in a large population: The APNA study. Obes Res Clin Pract 2015; [Epub ahead of print] doi: 10.1016/j.orcp.2015.04.003.

This descriptive cross-sectional study of more than 40000 individuals reinforces the known associations of overweight and obesity with glucose intolerance, dyslipidemia, T2DM, hypertension, osteoarthritis and kidney failure, and reveals an association between high BMI and depression.

2▪. Porter Starr KN, Bales CW. Excessive body weight in older adults. Clin Geriatr Med 2015; 31:311–326.

This article examines interindividual and intraindividual variation in ideal body habitus particularly with respect to ideal body weight with aging and the need to individualize weight loss strategies and targets.

3▪▪. Minihane AM, Vinoy S, Russell WR, et al. Low-grade inflammation, diet composition and health: current research evidence and its translation. Br J Nutr 2015; [Epub ahead of print]. doi:10.1017/S0007114515002093.

This article reviews relationships between obesity and inflammation and the corresponding associations with overall dietary composition and individual dietary components as contributors to and mediators of inflammatory processes.

4▪. Kakkar AK, Dahiya N. Drug treatment of obesity: current status and future prospects. Eur J Intern Med 2015; 26:89–94.

This review addresses the history of development of drug treatments for obesity and the current availability and efficacy of weight loss pharmacotherapies.

5. Kumar RB, Aronne LJ. Efficacy comparison of medications approved for chronic weight management. Obesity (Silver Spring) 2015; 23 (Suppl 1):S4–S7.
6. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015; 100:342–362.
7. Halpern B, Halpern A. Safety assessment of FDA-approved (Orlistat and Lorcaserin) antiobesity medications. Expert Opin Drug Saf 2015; 14:305–315.
8▪. Burke LK, Heisler LK. 5-hydroxytryptamine medications for the treatment of obesity. J Neuroendocrinol 2015; 27:389–398.

This review examines the central 5-hydroxytryptamine system and associated neural circuits and the role of manipulating the system, particularly through targeting the 5-HT2C receptor, in the development of weight loss medications.

9▪. Schellekens H, De Francesco PN, Kandil D, et al. Ghrelin's orexigenic effect is modulated via a serotonin 2c receptor interaction. ACS Chem Neurosci 2015; 6:1186–1197.

The study shows for the first time that interaction between the GHS-R1a and 5-HT2C receptors is able to modulate ghrelin's appetite stimulatory effects, thereby providing insight into the mechanism of action of lorcaserin.

10▪. Voigt JP, Fink H. Serotonin controlling feeding and satiety. Behav Brain Res 2015; 277:14–31.

This review examines hypothalamic 5-hydroxytryptamine signaling the associated interactions as well as peripheral influences on cholecystokinin and leptin signaling.

11. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of Lorcaserin for weight management. N Engl J Med 2010; 363:245–256.
12. Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 2011; 96:3067–3077.
13▪. Aronne L, Shanahan W, Fain R, et al. Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM trials. Postgrad Med 2014; 126:7–18.

This pooled analysis of the BLOOM and BLOSSOM trials showed that lipid parameters, glycemic indicators, quality-of-life measures and vital signs were improved by lorcaserin-related weight loss.

14. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 2012; 20:1426–1436.
15▪. Smith SR, O’Neil PM, Astrup A, et al. Early weight loss while on lorcaserin, diet and exercise as a predictor of week 52 weight-loss outcomes. Obesity (Silver Spring) 2014; 22:2137–2146.

This article re-examines the data from the BLOOM, BLOSSOM and BLOOM-DM trials and showed that individuals who achieved weight loss of at least 5% from baseline within 12 weeks were more likely to maintain or improve that weight loss at 52 weeks, suggesting the presence of the subgroup of medication-responsive individuals.

16▪▪. DiNicolantonio JJ, Chatterjee S, O’Keefe JH, Meier P. Lorcaserin for the treatment of obesity? A closer look at its side effects. Open Heart 2014; 1:e000173.

This article provides an analysis of adverse events in the BLOOM, BLOOM-DM and BLOSSOM trials, and demonstrates the increased risk of mitral or aortic regurgitation and a trend toward development of pulmonary hypertension.

17. Shyangdan DS, Royle P, Clar C, et al. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev 2011; (10):CD006423 doi: 10.1002/14651858.CD006423.pub2.
18▪. Potts JE, Gray LJ, Brady EM, et al. The effect of glucagon-like peptide 1 receptor agonists on weight loss in type 2 diabetes: a systematic review and mixed treatment comparison meta-analysis. PLoS One 2015; 10:e0126769doi: 10.1371/journal.pone.0126769.

This review examines the weight loss effects of GLP-1 receptor agonists in T2DM and shows that exenatide and liraglutide have equivalent effect. It is these data that provided the impetus for the application of this class of medications to weight loss in the nondiabetic population.

19▪. van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, nondiabetic adults. Int J Obes (Lond) 2014; 38:784–793.

This study shows that the effects of liraglutide appear to be mediated by decreased appetite secondary to delayed gastric emptying with resultant decreased energy intake.

20. Jelsing J, Vrang N, Hansen G, et al. Liraglutide: short-lived effect on gastric emptying – long lasting effects on body weight. Diabetes Obes Metab 2012; 14:531–538.
21. Astrup A, Rössner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 374:1606–1616.
22. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012; 36:843–854.
23▪. Lean ME, Carraro R, Finer N, et al. Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, nondiabetic adults. Int J Obes (Lond) 2014; 38:689–697.

This study highlights the high rate of nausea and vomiting seen with liraglutide treatment and draws attention to increased weight loss scene in those who experienced these side-effects.

24▪▪. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of Liraglutide in weight management. N Engl J Med 2015; 373:11–22.

This article describes a large trial involving 3731 individuals treated with liraglutide as an adjunct to diet and exercise over 56 weeks. Liraglutide treatment led to 5.5 kg greater weight loss relative to placebo, associated with improved lipid profiles and decrease progression to overt diabetes.

25. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013; 37:1443–1451.
26▪▪. Sauer N, Reining F, Schulze Zur Wiesch C, et al. Off-label antiobesity treatment in patients without diabetes with GLP-1 agonists in clinical practice. Horm Metab Res 2015; 47:560–564.

This article reveals the potential problems of applying GLP-1 agonists to weight loss outside the trial environment, with high rates of noncompliance seen because of lack of efficacy, side-effects and financial considerations.

27▪. Singh J, Kumar R. Phentermine-topiramate: first combination drug for obesity. Int J Appl Basic Med Res 2015; 5:157–158.

This article reviews the mechanisms of action of phentermine and topiramate and provides insight into the biochemical means by which these two agents act together to induce weight loss.

28. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377:1341–1352.
29. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012; 95:297–308.
30. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012; 20:330–342.
31▪▪. Neoh SL, Sumithran P, Haywood CJ, et al. Combination phentermine and topiramate for weight maintenance: the first Australian experience. Med J Aust 2014; 201:224–226.

This study further highlights problems associated with applying weight loss medication in the real-world environment, revealing a greater than 40% dropout rate in patients treated with combination phentermine and topiramate predominantly as a result of intolerable side-effects.

32▪. Alfaris N, Minnick AM, Hopkins CM, et al. Combination phentermine and topiramate extended release in the management of obesity. Expert Opin Pharmacother 2015; 16:1263–1274.

This paper reviews the evidence base for phentermine and extended release topiramate used in combination as a weight-loss agent. It also addresses safety concerns.

33. Apovian CM, Aronne L, Rubino D, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring) 2013; 21:935–943.
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This article describes the rationale behind the development of methionine aminopeptidase 2 inhibitors as weight loss agents through their action as inhibitors of angiogenesis.

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This is a small phase 1 study examining the weight loss effects of a novel methionine aminopeptidase 2 inhibitor. Weight loss occurred within 12 weeks; however, dropout rates were high because of gastrointestinal side-effects.

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generalizability; individualization; liraglutide; lorcaserin; obesity; side-effects

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