Medical Treatment of Obesity: the Past, the Present and the Future

Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684

Contents lists available at ScienceDirect Best Practice & Research Clinical Gastroenterology

11 Medical treatment of obesity: The past, the present and the future

* George A. Bray, MD, MACP, MACE, Boyd Professor

6400 Perkins Road, Baton Rouge, LA 70808, USA

abstract

Keywords: Medications for the treatment of obesity began to appear in the Orlistat late 19th and early 20th century. Amphetamine-addiction led to Serotonergic drugs the search for similar drugs without addictive properties. Four Sympathomimetic drugs sympathomimetic drugs currently approved in the US arose from Glucagon-like peptide-1 agonists this search, but may not be approved elsewhere. When norad- Combination therapy renergic drugs were combined with serotonergic drugs, additional weight loss was induced. At present there are three drugs (orlistat, phentermine/topiramate and lorcaserin) approved for long-term use and four sympathomimetic drugs approved by the US FDA for short-term treatment of obesity. Leptin produced in fat cells and glucagon-like peptide-1, a gastrointestinal hormone, provide a new molecular basis for treatment of obesity. New classes of agents acting on the melanocortin system in the brain or mimicking GLP-1 have been tried with variable success. Combi- nation therapy can substantially increase weight loss; a promising approach for the future. © 2014 Elsevier Ltd. All rights reserved.

Introduction

‘A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals.’

Sir William Osler [1]

* Tel.: þ1 (225) 763 3176; fax: þ1 (225) 763 3045. E-mail addresses: [email protected], [email protected], [email protected].

This chapter will examine the past, present and future of medications to treat obesity. I have divided the ‘past’ into several periods beginning with time before 1892, the year in thyroid hormones was first used to treat obesity. The second period is from 1892 to the beginning of World War II in 1940 when the clinical trials with amphetamine were complete. The third period from 1940 to 1973 is when fenfluramine was approved by the FDA. From 1973 to 1994e96 is the time when leptin was discovered and fenfluramine was withdrawn from the market. The final period is from 1996 to the present.

Medications prior to 1892

Obesity is found in ancient times [2], and monographs on the subject were written from the 18th century onwards [3e5]. Use of medications also has a long history if we include ‘lineaments’ for the skin, ‘cathartics’ to enhance the loss of ‘food stuffs’ through the bowel and ‘emetics’ to lose food stuffs by vomiting [2]. One of the widely used medical texts of the 17the18th century lists a number of preparations used to treat obesity [6]. Among them are vinegar (case 1); purging with a mixture of rheubarb, aloes, agarick, cinnamon and yellow sanders (Case 2); another cathartic mixture that included tartar, cinnamon, ginger and sugar (Case 3). A 4th approach used a purgative with garlick, cresses, leeks, seed of rue and vinegar or squills; the ﬁfth case [5] used tobacco and the ﬁnal treatment was a purgative dating back to the Roman Pliny [6] (Table 1).

Medications between 1892 and World War II

Three major groups of medications came into use between 1887 and 1940.

Thyroid hormone

Patients with hypothyroidism (myxoedema) [7] have a puffy type of weight gain, which is reversed by treatment with thyroid extract. This clinical effect led Baron [see Putnam [8]] to use thyroid extract to treat overweight non-myxoedematous patients. This hormonal preparation has had its subsequent ups and downs [9], but continues to serve as a model for drugs that can increase metabolism and energy expenditure. Clinical use of triiodothyronine, thyroxine and thyroid extract was popular

Table 1 Cases illustrating treatment of obesity in the seventeenth century (Bonet 1684; Bray 2007).

a. Chiapinius Vitellius, Camp Master-General, a middle aged man, grew so fat, that he was forced to sustain his belly by a swath, which came about his neck. On observing that he was every day more unﬁt for the Wars than other, he voluntarily abstained from Wine, and continued to drink vinegar as long as he lived; upon which his belly fell, and his skin hung loose, with which he could wrap himself as with a doublet. It was observed that he lost 87 pounds of weight. b. Lest any great mischief should follow, we must try to subtract by medicine, what a spare diet will not; because it has been observed, that a looseness either natural, or procured by Art, does not a little good. But this must be done by degrees and slowly, since it is not safe to disturb so much matter violently, lest it should come all at once. Therefore the best way of Purging is by Pills, of Rheubarb, Aloes each 2 drachms, Agarick 1 drachm, Cinnamon, yellow Sanders, each half a drachm. Make them up with Syrup of chicory. They must be taken in this manner: First one scruple must be given an hour and a half before meal; then two or three days afterwards, take half a drachm of two scruples before Meal. Thus purging must be often repeated at short intervals, till you think all the cocochymie is removed. c. A certain Goldsmith, who was extremely fat, so that he was ready to be choked, took the following Powder in his Meat, and so he was cured; Take of Tarter two ounces, Cinnamon three ounces, Ginger one ounce, Sugar four ounces. Make a powder. d. Horstius found the things following to take down fat men; especially onions, Garlick, Cresses, Leeks, Seed of Rue, and especially Vinegar or Squills: Let them purge well: Let them Sweat and purge by Urine; Let them use violent exercise before they eat; Let them induce hunger, want of Sleep and Thirst: Let them Sweat in a Stove and continue in the sun. Let them abstain from Drink between Dinner and Supper: for to drink between meals makes men fat. e. I know a Nobleman so fat, that he could scarce sit on Horse-back, but he was asleep; and he could scarce stir a foot. But now he is able to walk, and his body is come to itself, only by chewing Tobacco Leaves, as he afﬁrmed to me. For it is good for Phlegmatick and cold Bodies. f. Let Lingua Avis, or Ash-Keyes be taken constantly about one drachm in Wine. According to Pliny it cures Hydropical persons, and makes fat people lean. G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 667 because the produced rapid weight loss. Unfortunately this weight loss consists of some fat but a larger portion of lean body mass [9].

Dinitrophenol

Dinitrophenol was used to treat obesity after it was noted that factory workers preparing this drug lost weight although it was never ofﬁcially approved for any indication [10]. Although dinitrophenol does produce weight loss, it also produces neuropathy, cataracts and a few deaths and was ﬁnally stopped as a treatment for obesity.

Amphetamine

Amphetamine was synthesized in 1887. It stimulates wakefulness which led to its use in treatment for narcolepsy, a state of increased sleepiness. In 1937, Nathanson [11] noted that ten of his 40 narcoleptic patients had marked loss of appetite and a weight loss of 3.2e9kg(7e20 lbs). The loss of weight was explained by the lessened appetite and increased physical activity. The clinical trial of amphetamine by Lesses and Myerson [12] was one of the ﬁrst clinical trials of a potential weight loss drug. They studied 17 overweight patients who were given a 1400 kcal/d diet and provided with two weeks of medication. Over 6e25 weeks, patients lost an average of 0.66 kg/wk (1.45 lb/wk). It was not long before the abuse potential of amphetamine was recognized [13]. Amphetamine increases norepinephrine and dopamine in the brain. The norepinephrine tells you not to eat [14]. Dopamine may be associated with the risk of habituation.

Medications between 1940 (World War II) and 1973

After World War II, amphetamine and it congener methamphetamine, became street drugs that was widely abused, leading to the search for safe alternatives.

Chemical congeners of amphetamine

® Amphetamine [Benzedrine ], or alpha-methyl-beta-phenethylamine ¼ amphetamine] is a member of the b-phenethylamine chemical series. It resembles norepinephrine an important neurotransmitter. The addictive properties of amphetamine stimulated pharmaceutical chemists to synthesize other drugs that would reduce hunger but not have the abuse potential of amphetamine. [15]. Three different groups of chemical compounds were developed by the organic chemists. The first group was sympathomimetic amines, similar to amphetamine in reducing food intake, but having lower or very much lower abuse potential probably because they released the neurotransmitter norepinephrine, but not dopamine, in the brain. A second group of compounds, typified by mazindol, arose from the observation that a tricyclic inhibitor of norepinephrine reuptake could reduce food intake. Tricyclic drugs provide an important group of drugs to treat depression, and this relationship between depressed mood and weight loss has been observed several times. Fenfluramine provides a third drug which reduces food intake. d,l-Fenfluramine works by releasing serotonin and partially blocking its reuptake into nerve endings [16]. On paper, d,l-fenfluramine is similar to amphetamine, but it is not addictive and d,l-fenfluramine reduces brain serotonin. The concerns that depleting serotonin might have detrimental effects were not born out. Fenfluramine is thus very different in the way it works. This discovery opened a whole new area of research into serotonergic agents as drugs to manage obesity, although it was associated with rare cases of primary pulmonary hypertension.

Drugs developed between 1973 and 1996

Dexfenfluramine and ephedrine were both developed during this period. Dexfluramine is the d- isomer of d,l-fenfluramine and is the isomer responsible for the reduction in appetite and 668 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 dexfenfluramine was pursued as a weight loss drug. The clinical trial by Guy-Grand et al, in 1989 [17] was a year-long double-blind randomized multi-centre trial that demonstrated the effectiveness of dexfenfluramine which was subsequently approved by the US FDA in 1996. Although this drug had a risk for producing primary pulmonary hypertension, it was withdrawn because of cardiac toxicity in Sept 1997, not pulmonary hypertension. Ephedrine is a sympathomimetic used for the treatment of asthma which also increases thermo- genesis and reduces appetite in clinical trials. By itself it has a relatively small effect, but when combined with caffeine it is an effective weight loss drug combination [18].

Combination therapy

An investigator-initiated clinical trial of combination therapy for treatment of obesity was done by Weintraub et al [19] showed that combining a serotonergic drug (d,l-fenfluramine) with an adrenergic drug (phentermine) produced more weight loss with fewer side effects than the individual drugs. Corpulent participants treated with both drugs lost more weight than when treated with either single agent alone, and in many cases were able to keep this weight off for more than three years during this study. When the dramatic weight loss results from combining two FDA approved drugs, d,l-fenfluramine and phentermine, became known, the use of ‘Fen/Phen’, as it was widely called, exploded across the country, even though the combination was not approved. For the first time it appeared that corpulent Americans were winning the battle of the bulge as they had rarely done before. Then came the unintended consequence, or rather calamity. In July 1997 the first cases of valvular heart disease in patients taking Fen/Phen were reported [20]. Urgent meetings by the U.S. Food and Drug Administration assembled enough information to show that up to 30% of the patients treated with Fen/Phen might develop valvular heart disease. On September 15, 1997, fenfluramine and dexfenfluramine were removed from the market worldwide. The Fen/Phen success had been shattered by the ‘law of unintended consequences’ and added another sad ending to a therapy that offered such promise. The combination of ephedrine with caffeine or the herbal combination of ephedra alkaloids with herbal preparations of caffeine became a second effective and popular combination of medications. In clinical trials with ephedrine and caffeine Astrup et al [18] showed clinical effectiveness, but the public enthusiasm for the herbal combinations that were available without prescription led to their wide- spread use and eventually to reports linking them with ‘deaths’ which lead to public uproar and termination of ephedrine for weight loss. These two bad outcomes from treatment of obesity were not the first disasters to befall overweight patients treated for their obesity. Table 2 provides several more examples. We can see that even with thyroid hormone, first used more than 100 years ago, there were unwanted and potentially hazardous

Table 2 Unintended consequences from drug treatment for obesity.

Year Drug Toxic effect

1892 Thyroid Hyperthyroidism 1932 Dinitrophenol Cataracts/Neuropathy 1937 Amphetamine Addiction 1968 Rainbow pillsa Deaths-Arrhythmias 1971 Aminorex Pulmonary hypertension 1985 Gelatin-based VLCD CV deaths (Pointe de Torsade) 1997 Phen/Fenﬂuramineb Valvulopathy 1998 Phenylpropanolamine Strokes/death 2003 Ma Huangc Heart attacks/stroke/death 2007 Ecopipam Depression 2009 Rimonabant Suicidality 2011 Sibutramine Cardiovascular risk

a Mixture in various proportions of digitalis, thyroid and amphetamine. b Fenfluramine and phentermine, but not phentermine removed from the market, September 15, 1997. c Plant extract with Ephedrine isomers. G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 669 problems. This litany of difficulties associated with many treatments should give us pause when new ones are developed. Careful testing is most important to evaluate safety and efficacy for new drugs.

Drug development since 1996

The Year 1996 is a seminal year in obesity research. It was the year dexfenfluramine was approved by the US FDA and two years after leptin has been identified [21] in studies of genetically obese mice. Animals and human beings lacking this molecule are massively obese and treatment with leptin re- verses their obesity. Understanding the mechanism by which leptin from adipose tissue signalled the central nervous system has provided a coherent picture of short and intermediate control of food intake through melanocortin receptors which are modulated by neuropeptide Y, melanocyte stimulating hormone and melanin concentrating hormone. Drugs developed from this knowledge, however, have so far been disappointing. In a clinical trial, injections of leptin into obese patients produced only modest effects on body weight, but it has been approved by the US FDA to treat lipodystrophy [22].A highly selective Neuropeptide Y agonist was similarly unsuccessful in clinical trials [23], as was a melanocortin receptor agonist [23]. Thus two physiologically important pathways controlling food intake has so far not provided new therapies for managing obesity. Dopamine is involved in regulating food intake and modifying behaviour and thus seemed a reasonable target to treat obesity. Dopamine antagonists [24] reduced food intake, but also produced depression and were not further pursued. Dopamine is a central neurotransmitter in the pleasure circuitry which is responsive to many psychoactive drugs, to alcohol, and to food. The mood changes associated with some medications that were tested as potential anti-obesity drugs (ecopipam and rimonabant e see below) is one reason why the central nervous system may be a difficult site for effective treatments. A number of centrally acting drugs were also developed and tested during this period, but only a few approved to treat obesity. There were both inhibitors of monoamine action and several modulators of neuropeptides. Serotonin receptors are involved in both food intake and in mood. Sibutramine is a highly selective inhibitor of the reuptake at nerve endings of the norepinephrine and serotonin, and, to a lesser degree, dopamine. Sibutramine reduced food intake by 23% and seven days and 26% after 14 days and produces weight loss. It is also effective in preventing weight regain as shown in the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) which lasted two years [25]. Sibutramine has a doseeresponse on weight loss, but also increases in blood pressure and heart rate prompting regulatory agencies in Europe to insist on a cardiovascular outcomes trial (SCOUT) [26]. The trial enrolled 10,744 overweight or obese subjects existing CVD, type 2 diabetes or both and were 55 years or older. All participants received sibutramine for six weeks and were then randomized to placebo or sibutramine. The end- point was time to a primary cardiovascular event. Trial lasted an average 3.4 years. Blood pressure declined more in the placebo than in the sibutramine group. A primary event occurred statistically significantly more often in the sibutramine group (11.4%) compared to 10.0% of the placebo group (P ¼ 0.02), leading to withdrawal of this drug from the market shortly after. This was an unusual trial since people for whom the drug was contraindicated were treated with it for up to six years whether or not they lost any weight. Tesofensine, like sibutramine, is a multi-amine reuptake inhibitor. In one six-month clinical trial this drug produced dose-related weight loss with the highest dose producing over 10% weight loss. However, as with sibutramine, there were increases in blood pressure and pulse [27].

Antidepressants

Fenﬂuramine had already shown that serotonin modulation was a target for treating obesity. Fluox- etine, a selective serotonin reuptake inhibitors (SSRI) was evaluated in clinical trials for the treatment of obesity but weight regain during the second six months terminated testing for this drug [28]. Bupropion, another anti-depressant, is a norepinephrine and dopamine reuptake inhibitor which reduces body weight by 6.2% and 7.2% of initial body weight, respectively with doses of 300 and 400 mg/d [29]. 670 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684

Ecopipam is a dopamine 1 and 5 receptor antagonist that was originally studied for the treatment of cocaine addiction. Ecopipam was in development as an obesity drug but its development was recently terminated [24]. Topiramate is an antiepileptic drug that was found to induce weight losses of 3.9% of initial weight at three months and 7.3% of initial weight. In a six-month, placebo-controlled, dose-ranging study [31], 385 subjects were randomized to ﬁve groups: topiramate at 64 mg/d, 96 mg/d, 192 mg/d, or 384 mg/ d or placebo. There was a dose-related weight loss, but there were adverse events including paraesthesias (prickly or itchy skin), somnolence, and difﬁculty with concentration, memory, and attention. Zonisamide is another antiepileptic drug that produces weight loss [30].

Rimonabant

Activation of cannabinoid receptors by one of the two endogenous cannabinoids (anandamide or 2- arachidonoyl-glycerol) or exogenous cannabinoids increases food intake, which is blocked by cannabinoid receptor inhibitors [31]. The CB-1 receptors are found primarily in the brain. Clinical trials of rimonabant showed that it produced weight loss [32,33], but after approval in Europe, concern about suicidality led to withdrawal of licensing approval on October 23, 2008. Further testing of all CB-1 antagonists was terminated although the potential therapeutic advantages might have outweighed the downside if the trials had been continued. In the Stradivarius trial, rimonabant did not significantly reduce the % plaque in coronary arteries, the primary end-point, but did significantly reduce the total atherosclerotic volume, body weight, and triglycerides, and increased HDL-cholesterol. It is possible that in the appropriate patient this drug might have had more benefit than risk, and it is unfortunate that it is not available for any patient [34].

Neuropeptide-Y receptor antagonists

Neuropeptide Y is a widely distributed neuropeptide that acts on five receptors, Y-1, Y-2, Y-4, Y- 5 and Y-6. It stimulates food intake, inhibits energy expenditure and increases body weight by activating Y-1 and Y-5 receptors in the hypothalamus. Several clinical trials with a selective Y-5 receptor antagonist have been completed. In one trial there was a significantly greater weight loss with the antagonist, indicating that NPY is involved in regulation of human body weight. The second trial found a small, but significant effect, which was not large enough to warrant continued pursuit [23]. Leptin is produced almost exclusively in adipose tissue. Absence of leptin produces massive obesity in mice (ob/ob) and in humans, and treatment with this peptide decreases food intake in the ob/ob mouse and the leptin-deficient human. A dose-ranging clinical trial with leptin has been reported. In lean subjects treated for four weeks and in obese subjects treated for 24 weeks there was a modest loss of weight with doses ranging from 0.01 mg/kg to 0.3 mg/kg. The side effects of local irritation at the site of injection limit the use of this preparation. A long-acting leptin preparation may provide an improved way to use this drug [22]. Axokine is a modified form of ciliary neurotrophic factor (CNTF) that acts through the same janus- kinase-signal for transduction and translation (JAK-STAT) system used byleptin. CNTF will reduce food intake in animals that lack leptin or the leptin receptors and in a dose-ranging clinical trial CNTF produced a significant therapeutic response with weight loss of 3e5%. However, about 70% of the CNTF treated patients developed antibodies to the drug that reduced its effect [35]. Cholecystokinin is a peptide that can act on the GI tract and in the central nervous system. Cholecystokinin (CCK) reduces food intake in human beings and in experimental animals [36]. Peptide analogues have been developed and tested experimentally but no clinical data have been published. A second strategy to modify CCK activity is to reduce the degradation of CCK which may be under evaluation. Peptide YY (PYY 3-36) is another gut peptide produced by the L cells. Caloric intake at a lunch buffet was reduced by 30% in 12 obese subjects and by 29% in 12 lean subjects after two hours of PYY 3-36 infused intravenously. Thrice daily nasal administration over six days was well-tolerated and reduced caloric intake by about 30% while giving 0.6 kg weight loss [37]. G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 671

Oxyntomodulin is another GI peptide that like PYY and cholecystokinin, is released from the GI track and can inhibit food intake. In a study of healthy overweight and obese volunteers oxyntomodulin given subcutaneously body weight was reduced by 2.3 ± 0.4 kg in the treatment group compared with 0.5 ± 0.5 kg in the control group (P ¼ 0.0106) and by 250 ± 63 kcal (35 ± 9%) at the ﬁnal study meal (P ¼ 0.0023) [38].

Ghrelin antagonist

Ghrelin is a gastrointestinal peptide that stimulates food intake. No clinical data are yet available.

11-beta-hydroxysteroid dehydrogenase type I inhibitor

Cortisol, the glucocorticoid secreted by the adrenal gland can be inactivated through conversion to cortisone in peripheral tissues and can be reactivated by the enzyme 11-beta-hydroxysteroid dehydrogenase type 1. Mice overexpressing this enzyme have increased amounts of fat in the abdomen, suggesting that modulation of this enzyme could be a target to selectively modulate visceral or central adiposity. No clinically useful drugs acting on this target have yet been approved.

Current drugs approved for treatment of obesity

In this section I will discuss the pharmacological treatment for patients with obesity from two perspectives e use of medications approved for obesity per se and the selection of medications that affect body weight for obese patients who already have complications from their obesity. Although some medications are appropriate for both groups, others are only approved for the obese patients who have co-morbidities, but if they also produce weight loss so much the better for the patient. Not all medications discussed are available in all countries. In general the weight loss at one year canbepredictedfromtherateofweightlossintheﬁrst 1e3 months. If weight loss with any treatment is less than 5% below baseline by six months, the therapeutic plan should be re- evaluated.

Medications approved by the US Food and Drug Administration for the treatment of the patient with obesity

Two groups of medications are shown in Table 3. The ﬁrst are the agents approved for long-term treatment of obesity and include, orlistat, lorcaserin and the combination of phentermine and topiramate as an extended release formulation. The second group is sympathomimetic drugs approved by the US FDA for short-term use e usually considered less than 12 weeks.

Orlistat

Orlistat (tetrahydrolipstatin) is a potent and selective inhibitor of lipases from both the stomach and intestines that reduces intestinal digestion of fat. It is available by prescription in 120 mg pills given three times a day before meals and a non-prescription dose of 60 mg available without prescription. A second lipase inhibitor, cetilstat is currently only available in Japan.

Efﬁcacy of Orlistat A number of long-term clinical trials with orlistat have been published using patients with uncomplicated obesity and patients with obesity and diabetes [39]. The pooled data is summarized in Fig. 1. After one year, the orlistat-treated patients had lost 9% of their body weight compared to about 5.5% in the placebo group. A four-year double-blind, randomized, placebo-controlled trial with orlistat in 3304 overweight patients, 21% of whom had impaired glucose tolerance [40], achieved a weight loss of 11% compared to 6% in the placebo-treated group. There was a subsequent small weight regain, but the orlistat-treated 672 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684

Table 3 Drugs approved by the US Food and Drug Administration that produce weight loss.

Generic name (year of approval) Trade name(s) Dosage DEA schedule

Pancreatic lipase inhibitor approved by FDA for long-term use Orlistat (1999) Xenical 120 mg three times daily before Not meals scheduled Orlistat (2007) Alli (Over-the- 60 mg three times daily before Not Counter) meals scheduled Serotinin-2C receptor agonist approved by FDA for long-term use Lorcaserin (2012) Belviq 10 mg twice daily IV Combination of phentermine-topiramate approved by FDA for long-term use Phentermine-topiramate extended release Qsymia 3.75 mg/23 mg IV (2012) 7.5 mg/46 mg 11.25 mg/69 mg 15 mg/92 mg Noradrenergic drugs approved for short-term use Diethylpropion (1959) Tenuate 25 mg three times a day IV Tenuate dospan 75 mg every morning Phentermine (1959) Adipex and many 15 to 30 mg/d IV others Benzphetamine (1960) Didrex 25 to 50 mg three times/d III Phendimetrazine (1959) Bontril 17.5e70 mg three times daily III Prelu-2 105 mg daily

* ¼ Drug Enforcement Agency Schedule IV. ** ¼ Drug Enforcement Agency Schedule III. Adapted from Bray Guide to Obesity and Metabolic Syndrome 2011. patients remained 6.9% below baseline, compared with 4.1% for those receiving placebo. There was a reduction of 37% in the development of diabetes in patients who had impaired glucose tolerance. Orlistat was studied in 539 adolescents who received 120 mg three times per day [41]. BMI decreased by 0.55 kg/m2 in the drug-treated group compared to an increase of þ0.31 kg/m2 in the placebo-treated group [41]. In a meta-analysis of trials with orlistat, the weighted mean weight loss in the placebo group was 2.40 ± 6.99 kg compared with 5.70 ± 7.28 kg in the orlistat-treated group for a net effect of 2.87 (95% CI 3.21 to 2.53) [42].

Safety proﬁle of Orlistat Orlistat is not absorbed to any signiﬁcant degree, and its side effects relate to blockade of triglyc- eride digestion in the intestine [43]. Fecal fat loss and related GI symptoms are common initially, but

% Change 0 -1

-2

-3

-4 Placebo

-5 60 mg -6

-7 120 mg -8 -9 -10 -40 4 8 12162024283236404448525660646872768084889296100104 Week

Fig. 1. Two year pooled data comparing Orlistat and 120 and 60 mg three times a day and placebo. G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 673 they subside as patients learn to use the drug. Orlistat can cause small but significant decreases in fat- soluble vitamins and a few patients may need vitamin supplementation given at bedtime. Orlistat does not seem to affect the absorption of other drugs, except acyclovir. Rare cases of severe liver injury have been reported with orlistat. Two analyses of orlistat and liver disease, one from published data including a time-to-event analysis for individual patients, and one using 94,695 patients receiving orlistat and registered in the UK Clinical Practice Research Datalink and linked with Hospital Episode Statistics data between 1999 and 2011 have been published. An analysis restricted to definite cases showed no evidence of an increased risk of liver injury during treatment concluded that while idio- syncratic liver injury following exposure to orlistat cannot be excluded, it is likely to be extremely rare. The other concluded that the increased risks of liver injury linked to the start of treatment with orlistat may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug. Patients who take orlistat should contact their health care provider if itching, jaundice, pale colour stools, or anorexia develop [44,45]. A causal relationship has not been established, but patients who take orlistat should contact their health care provider if itching, jaundice, pale colour stools, or anorexia develop [46].

Lorcaserin

Lorcaserin (1R-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-2-benzazepine) selectively targets the serotonin 2c receptors to reduce food intake [47]. It avoids the serotonin-2b receptors on heart valves. ® Lorcaserin is prescribed at 10 mg twice daily (Belviq Prescribing Information).

Efficacy of lorcaserin Three clinical studies provided evidence for approval of lorcaserin [48]. Two of these studies called, BLOOM (Behavioral Modification and Lorcaserin for Overweight and Obesity Management) [49] and BLOSSOM (Behavioral Modification and Lorcaserin Second Study for Obesity) [50], enrolled volunteers who had a BMI 27 kg/m2 with one comorbidity. The third study called BLOOM DM [51], enrolled diabetic patients with haemoglobin A1C between 7 and 10% and a BMI of 27e45 kg/m2.In this study all patients (including the placebo group) received counselling in diet and physical activity. Fig. 2 shows modest weight loss with lorcaserin at one year. There were improvements in cardiovascular risk factors in these studies. In the BLOOM-DM study HbA1c decreased 0.9 ± 0.06 with lorcaserin BID, compared to 0.4 ± 0.06 with placebo (P < 0.001) and fasting glucose decreased 27.4 ± 2.5 mg/dl compared to a decrease of 11.9 ± 2.5 mg/dl for placebo (P < 0.001). Weight maintenance was demonstrated in the BLOOM-DM study with a small amount of regain in the second year.

Effect of Lorcaserin on Body Weight 0

Placebo Lor-Plac -5 Lorcaserin

-10 Weigh (kg) Loss

-15 0 16 32 48 64 80 96 112 Time in Weeks

Fig. 2. Weight loss in a two-year randomized clinical trial with lorcaserin. 674 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684

Safety profile of lorcaserin Lorcaserin is contraindicated in pregnancy. Lorcaserin was scrutinized for potential effects on heart valves during Phase III studies where echocardiograms were done on more than 5,200 subjects. There was no statistically significant increase in FDA-defined valvulopathy with drug treatment as compared to placebo. In the FDA briefing report [48], the relative risk of FDA-defined valvulopathy in lorcaserin- treated participants, as compared with those who received placebo, was 1.16 (95% confidence interval, 0.81e1.67) and was not statistically significant. However, since lorcaserin has much greater selectivity for the 5-HT2c receptor than the 5-HT2b receptor, it is very unlikely that lorcaserin will increase the risk of valvulopathy in humans and routine echocardiography is not needed for prescription of lorcaserin. Another issue with lorcaserin in preclinical toxicology studies was an increased numbers of brain and mammary tumours which on reanalysis were fewer than first thought [48]. Additionally the drug does not reach high levels in the central nervous system of humans, whereas it does in rats [48]. Lorcaserin is well-tolerated. The most common adverse events were headache, nausea, dizziness, fatigue, dry mouth, and constipation which were mild and resolved quickly. However, the drug should not be used with selective serotonin reuptake inhibitors (SSRIs) or with monoamine oxidase inhibitors (MAOIs), because of the risk of serotonin syndrome.

Serotonin syndrome The serotonin syndrome is a potentially life threatening drug reaction that causes the body to have too much serotonin, a chemical produced by nerve cells. Its effects may include headache, agitation, hypomania, mental confusion, hallucinations, and coma. Symptoms of autonomic nervous response such as shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhoea may also be seen as can somatic symptoms of myoclonus (muscle twitching), hyperreﬂexia (manifested by clonus), and tremor. In summary, the value of lorcaserin seems to be in its safety and tolerability not in the magnitude of weight loss. The only issue is the risk of serotonin syndrome and because the background use of SSRI antidepressants is so high, physicians should be watchful and not prescribe in that group of patients.

Phentermine/topiramate extended release (ER)

The combination of phentermine and topiramate, as an extended release (ER) combination (PHEN/ TPM ER), is approved for long-term use. The combination uses lower doses of phentermine (3.75 mg in the starting dose, 7.5 mg in the recommended dose and 15 mg in the full dose) than are usually prescribed when phentermine is used a single agent. Topiramate is used in an extended release formulation, not available other than in this combination. The dose of topiramate in the combination (23 mg in the starting dose, 46 mg in the recommended dose and 92 mg in the full dose) is also lower than when topiramate is used for migraine prophylaxis or to control seizures. In terms of mechanism of action, phentermine acts to reduce appetite through increasing norepinephrine in the hypothalamus and topiramate may reduce appetite through its effect on GABA receptors.

Efficacy of phentermine/topiramate ER Two clinical studies [52,53] provided efficacy and safety data for approval of the medication [54]. The first trial, called EQUIP [52], enrolled subjects 70 years of age with BMI 35 kg/m2 with controlled blood pressure (140/90 mmHg using 0e2 antihypertensive medications), fasting blood glucose 110 mg/dL and triglycerides 200 mg/dL using zero or one lipid lowering medication. The other study called CONQUER [53], enrolled adults 70 years of age with BMI between 27 and 45 kg/ m2, except that patients with type 2 diabetes had no lower BMI limit. The CONQUER study also required patients to have two or more of the following co-morbidities: hypertension, hypertriglyceridemia, dysglycemia (impaired fasting glucose, impaired glucose tolerance or type 2 diabetes) or an elevated waist circumference (40 inches for men or 35 inches for women). The patient population in these two studies represents those with higher risk profiles from the consequences of excess weight. A titration period of two weeks is required for PHEN/TPM ER, starting at 3.75/23 mg dosage. All subjects in these studies received a lifestyle modification program based on the LEARN manual [55]. G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 675

This combination medication produces weight losses approaching 10% which is larger than observed in clinical trials with single drugs [56]. The CONQUER study was extended for a second year of observation with patients keeping their treatment assignment (SEQUEL). At the end of two years, patients completing the trial taking the recommended dose (7.5 mg/46 mg) maintained a weight loss of 9.3% below baseline and those on the top dose maintained a 10.7% weight loss from baseline (Fig. 3) [57]. The weight loss with PHEN/TPM ER is accompanied by improvements in most risk factors. In the CONQUER study [52,53] there were improvements in blood pressure, glycaemic measures, HDL- cholesterol and triglycerides with both the recommended and the top doses of the medication. In the EQUIP, CONQUER and SEQUEL studies improvements in risk factors were related to the amount of weight loss, with greater beneﬁt being observed with greater weight loss. PHEN/TPM ER has also been studied in patients with sleep apnoea and shown to reduce the severity of symptoms from sleep apnoea [57]. Discontinuation of treatment was a problem in these studies as in all drug trials for anti- obesity drugs. Drop-outs were 34e47% in the EQUIP trial and 36e43% in the CONQUER trial.

Safety proﬁle of phentermine/topiramate ER The most commonly observed side effects in these clinical trials were paraesthesias, dizziness, ® dysgeusia (altered taste), insomnia, constipation and dry mouth. (Qsymia Prescribing Information) These side effects are related to the constituents of PHEN/TPM ER or, in the case of constipation, to weight loss per se. Phentermine, as a sympathomimetic agent, causes insomnia and dry mouth, usually early in treatment, which then resolves. Topiramate is a carbonic anhydrase inhibitor that is associated with altered taste for carbonated beverages and tingling in ﬁngers, toes and perioral areas and may lead to mild metabolic acidosis. Safety concerns (Qsymia™ Prescribing Information) with PHEN/TPM ER are seen in several areas. This drug is contraindicated in pregnancy, as are all weight loss medications. Topiramate is associated with oral clefts if used during pregnancy and PHEN/TPM ER is thus pregnancy Category X. Glaucoma is a rare side effect of topiramate, and the drug is contraindicated in glaucoma. PHEN/TPM ER is also contraindicated in hyperthyroidism and within 14 days of treatment with monoamine oxidase inhibitors (MAOIs) and in patients with hypersensitivity to any of the ingredients in the medication. Because of the risk of oral clefts, a negative pregnancy test before treatment and monthly thereafter and use of effective contraception are required. If a patient becomes pregnant while taking PHEN/TPM ER, treatment should be stopped immediately. Other potential issues include warnings about the risks

Fig. 3. Treatment with the combination of phentermine/topiramate (ER) for two years. 676 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 of foetal toxicity, increased heart rate (associated with phentermine), suicide and mood and sleep disorders, acute myopia and glaucoma, cognitive impairment, metabolic acidosis, creatinine elevations, hypoglycemia with diabetes medications and kidney stones (associated with topiramate).

Naltrexone/bupropion (NB) combination, [not yet on the market, but tentatively named CONTRAVE]

Bupropion [±1-(3-Chlorophenyl)-2-[(1,1-dimethylethyl)amino)-1-propanone] reduces food intake by acting on adrenergic and dopaminergic receptors in the hypothalamus. Naltrexone [17-(cyclo- propylmethyl)-4,5-alpha-epoxy-3,14-dihydroxy-morphinan-6-1] is an opioid receptor antagonist with minimal effect on weight loss on its own. Bupropion releases b-endorphin in the hypothalamus which stimulates feeding. This effect is blocked by naltrexone thus allowing the inhibitory effects of a-melanocyte stimulating hormone (a-MSH) to reduce food intake [58].

Efﬁcacy of naltrexone/bupropion Weight loss with the naltrexone/bupropion combination at one year was intermediate between PHEN/TPM ER and lorcaserin, and was associated with improvement in risk factors [58,59]. However, the decline in blood pressure is not as great as one would expect from the weight loss in the Phase III trials of naltrexone/bupropion [COR [59] and COR BMOD trials [5]].

Safety proﬁle of naltrexone/bupropion Because bupropion increases pulse and both bupropion and naltrexone increase blood pressure in the phase III studies, the FDA has required a pre-marketing study of the combination drug with assessment of cardiovascular outcomes. If the cardiovascular outcome trial shows no increased risk for cardiovascular events with naltrexone/bupropion, this drug could be a valuable addition to the therapeutic toolbox in obesity. There are some tolerability issues, chieﬂy nausea on initiating the drug [60], and potential issues with SSRIs or MAOIs.

Drugs approved by the US Food and Drug Administration for short-term use in treating the patient with obesity

The sympathomimetic drugs, benzphetamine, diethylpropion, phendimetrazine, and phentermine are grouped together because they act like norepinephrine and were tested before 1973. Phentermine and diethylpropion are classiﬁed by the U.S. Drug Enforcement Agency as schedule IV drugs; benzphetamine and phendimetrazine are schedule III drugs. This regulatory classiﬁcation indicates the government's belief that these drugs have the potential for abuse, although this potential appears to be very low [43]. These drugs are approved for only a ‘few weeks,’ which usually is interpreted as up to 12 weeks.

Phentermine

Efficacy of phentermine. Phentermine, as a single agent, was approved by the US FDA in 1959 and re- mains the most often prescribed drug for weight loss in the United States [61]. Because phentermine was approved in 1959 for short-term use for weight loss, there is little current data to evaluate its long- term efficacy. A six month study in the FDA briefing document for topiramate/phentermine combination had four treatment arms and 200 subjects with 158 subjects completing six months [62]. Weight loss at six months with phentermine 15 mg daily was 4.6%, compared with 2.1% for placebo. In another six month study of phentermine/topiramate there were seven treatment arms among 756 subjects, i.e., >100 subjects per dose. At 28 weeks the completion rate was 65% and weight loss for the placebo group was 1.7% from baseline compared to 5.5% for phentermine 7.5 mg/d and 6.1% for phentermine 15 mg/d. Finally, a report from Korea [63] evaluated a diffuse, controlled release form of phentermine at 30 mg (n ¼ 37) versus placebo (n ¼ 37). At 12 weeks, mean weight loss was 8.1 ± 3.9 kg for drug-treated G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 677 patients versus 1.7 ± 2.9 kg for placebo patients. These trials suggest that weight loss with phentermine is dose-related.

Safety of phentermine. The sympathomimetic drugs produce central excitation, manifested as dry mouth, insomnia or nervousness. This effect is most obvious shortly after the drug is started and wanes substantially with continued use. Sympathomimetic drugs may also increase heart rate and blood pressure. The prescribing information usually recommends that the drugs not be given to individuals with a history of cardiovascular disease. There is little evidence of quantitative effects on blood pressure and pulse, especially after six months or more of treatment. A short-term study evaluating phentermine and taranabant (a cannabinoid receptor antagonist) [64] showed that there were no significant differences in blood pressure and heart rate versus placebo. In a 12 week study in 68 obese Koreans [65] there were no significant differences in mean blood pressure changes between groups at 12 weeks with 37.5 mg/d of phentermine, but the phentermine group lost significantly more weight (7.2 ± 2.7 kg vs. 1.9 ± 2.7 kg, P < 0.001). In another Korean study [63] with a diffuse controlled release formulation (not marketed in the US), at twelve weeks, mean weight loss was significantly greater in the phentermine group (8.1 ± 3.9 vs. 1.7 ± 2.9 kg, P < 0.001), and there were no significant differences in systolic and diastolic blood pressure. However, despite clinically significant weight loss, one does not observe the expected decreases in blood pressure and the phentermine group actually had a mean increase in heart rate of 2.7 ± 11.4 beats/min, compared to a decrease of 4.3 ± 12.5 in the placebo- treated subjects. Lacking good quantitative measures of the effects of sympathomimetics on heart rate and pulse, we recommend caution in prescribing drugs in this group. They should not be prescribed to persons with a history of cardiovascular disease and blood pressure and pulse should be monitored. Although there is no convincing evidence of mean blood pressure increases, the lack of the expected reductions in blood pressure with weight loss suggests that these drugs do have some stimulatory effect on blood pressure. Prescribers should be aware of the local and federal regulations governing prescribing limits and the lack of long-term clinical trial data for sympathomimetics.

Treatment of the overweight or obese patient who has diabetes, depression or epilepsy

Weight gain or weight loss are side effects of many drugs. If there is a reasonable choice when selecting medications for the patient with obesity, good clinical practice would be to choose the drug that produces weight loss [66].

Treatment of the obese patient with diabetes

The epidemic of diabetes follows closely on the heels of the obesity epidemic. Table 4 lists the drugs that are available to treat diabetes categorized by their effect on body weight. Insulin produces a weight gain that ranges from 1.8 to 6.6 kg [66]. Two widely used sulfonylurea drugs (glipizide and glibenclamide) also produce weight gain in most studies which ranges from 0.3e4.0 kg [67], and this is also true for the thiazolidinediones, rosiglitazone and pioglitazone, which produce weight gains of 0.18e1.5 kg or more [67]. Other drugs are weight neutral or can cause weight loss.

Metformin Metformin is a biguanide that is approved by the US Food and Drug Administration for the treatment of diabetes mellitus, and has a good safety proﬁle. This drug reduces hepatic glucose production, decreases intestinal glucose absorption from the gastrointestinal tract and enhances insulin sensitivity. The longest and best study of metformin on body weight comes from the Diabetes Prevention Program [68]. During the ﬁrst 2.8 years of the double-blind, placebo-controlled trial, the metformin- treated group lost 2.9 kg (2.5%) versus 1.04 kg in the placebo group (P < 0.001). Weight loss was related to the adherence to metformin, with the most adherent participants losing 3.5 kg at two years, compared with a small weight gain of 0.5 kg in those who were least adherent. This differential weight loss persisted throughout the eight years of follow-up with highly adherent patients remaining 3e4kg 678 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684

Table 4 Effect on body weight of medications used to treat diabetes mellitus, depression, epilepsy and psychosis.

Drug class Produce Are weight neutral Produce weight gain weight loss

Antidiabetic Metformin Dipeptidyl peptidase-4 (DPP-4) Insulin Pramlintide inhibitors Sulfonylureasa Exenatide Acarbose Glitinides Liraglutide Miglitol Thiazolidinedionesb Bromocriptine Neurobehavioral Bupropion Haloperidol Tricyclic antidepressantsc Venlafaxine Aripiprazole Monoamine oxidase inhibitors Desvenlafaxine Paroxetine Topiramate Escitalopram Zonisamide Lithium Lamotrigine Olanzapine Ziprasidone Clozapine Risperidone Carbamazepine Valproate Divalproex Mirtazapine

Hypertension/Cholesterol Selective b1-receptor agonists Atenolol, metoprolol, propranolol d Angiotensin converting enzyme Some b1-receptor agonists inhibitors Some ɑ2-receptor antagonists Angiotensin receptor blockers Nicotinic acid Statins

a Glipizide, glimepiride, glibenclamide, chlorpropamide. b Pioglitazone, rosiglitazone. c Nortriptyline, amitriptyline, doxepin. d Atenolol, metoprolol, propranolol. Bray G. A Guide to Obesity and the Metabolic Syndrome. Boca Raton: CRC Press, Taylor and Francis Group; 2011. below baseline and the non-adherent participants being no different from placebo [68]. A systematic review found that metformin reduced or prevented weight gain during treatment with anti-psychotic medications [69].

Pramlintide Pramlintide is a modiﬁed form of amylin, a peptide secreted, along with insulin, from the beta-cell of the pancreas. Pramlintide, which has been approved by the FDA to treat diabetes, also produces weight loss. The combination of phentermine with pramlintide produced additive weight loss in a six- month clinical trial in the patient with diabetes [70].

Glucagon-like peptide-1 (GLP-1) Glucagon-like pepetide-1 is a naturally occurring peptide that is released by the GI tract in response to food and is a suppressor of food intake. Two GLP-1 receptor agonists may be of value in treating the diabetic patient with obesity.

Exenatide. Exenatide (Exendin-4) is a 39 amino acid peptide that is produced in the salivary gland of the Gila monster lizard. It has 53% homology with GLP-1, but it has a much longer half-life. Exenatide has been approved by the US Food and Drug Administration for treatment of type 2 diabetics who are inadequately controlled with either metformin or sulfonylureas. In human beings, exenatide reduces fasting and post-prandial glucose levels, slows gastric emptying and decreases food intake by 19% [71]. A systematic review of incretin therapy in type 2 diabetes [72] showed a weight loss of 2.37 kg for all GLP-1 analogues. The effect was 1.44 kg for exenatide versus placebo injection and 4.76 kg for exenatide vs insulin. The side effects of exenatide in humans are headache, nausea and vomiting that are lessened by gradual dose escalation [73]. Weight loss with exenatide occurred without prescribing G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 679 lifestyle modiﬁcation, diet or exercise. A 26 week randomized control trial of exenatide produced a weight loss of 2.3 kg compared to a gain of 1.8 kg in the group receiving the glargine insulin [74].

Liraglutide. Liraglutide is another GLP-1 receptor agonist that has a 97% homology to GLP-1. This molecular change extends the circulating half-life from 1e2 min to 13 h. In a 20 week multi-centre Eu- ropean clinical trial daily injections of liraglutide (1.2, 1.8, 2.4 or 3.0 mg) produced weight losses of 4.8, 5.5, 6.3 and 7.2 kg respectively, compared to a loss of 2.8 kg in the placebo-treated group and 4.1 kg in the orlistat-treated comparator group [75]. In the group treated with 3.0 mg/d 76% achieved a >5% weight loss compared to 30% in the placebo group. Blood pressure was signiﬁcantly reduced, but there were no changes in lipids. The prevalence of prediabetes was reduced by liraglutide. Liraglutide has been approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of diabetes at a dose up to 1.8 mg/d. Although this dose is lower than the top dose of 3.0 mg/ d in clinical trials [75] it would be a good choice for the diabetic patient with obesity.

Treatment of the patient with obesity and neurobehavioural disorders such as depression, epilepsy and migraine

This category includes patients with obesity who are depressed, those with migraine symptoms and those needing anti-psychotic drugs. Some of the approved drugs in this class produce weight gain, and others are associated with weight loss (Table 4). The magnitude of weight gain ranges from 1.2 to 5.8 kg for valproate, 4.0 kg for lithium, 2.1e2.3 kg for risperidone, 2.8e7.1 kg for olanzapine and 4.2e9.9 kg for clozapine [67]. This degree of weight gain can make continuation of treatment more difﬁcult, and switching to alternative medication that is weight neutral or produces weight loss would be good clinical practice.

Bupropion Bupropion is an approved drug for treatment of depression and as an aid in smoking cessation. It reduces food intake by acting on adrenergic and dopaminergic receptors in the hypothalamus. A study with uncomplicated and non-depressed obese patients, 327 subjects were randomized equally to bupropion 300 mg/d, bupropion 400 mg/d, or placebo. They were prescribed a hypocaloric diet and used liquid meal replacements. At 24 weeks body weight was reduced by 5.0%, 7.2%, and 10.1% for the placebo, bupropion 300 mg, and bupropion 400 mg groups, respectively (p < 0.0001) in the 69% who remained in the study. At 24 weeks the placebo group was randomized to the 300-mg or 400-mg group and the trial was extended to week 48. The weight losses with 300 mg or 400 mg of bupropion were 6.2% and 7.2% of initial body weight, respectively in the 41% who completed the trial [29].

Topiramate Topiramate is an anticonvulsant drug approved for certain types of epilepsy and for the prophylaxis of migraine headache. Topiramate induced weight loss of 3.9% of initial weight at three months and 7.3% of initial weight at one year in clinical trials for epilepsy. In a six-month, placebo-controlled, dose-ranging study [76], 385 subjects were randomized to five groups: topiramate at 64 mg/d, 96 mg/d, 192 mg/d, or 384 mg/d or placebo. Doses were gradually increased over 12 weeks to assigned levels and were tapered off in a similar manner at the end of the trial. Weight loss from baseline to 24 weeks was 5.0%, 4.8%, 6.3%, 6.3%, and 2.6%, in the five groups, respectively. The most frequent adverse events were paraesthesias (tingling or prickly feelings in skin), somnolence, and difficulty with concentration, memory, and attention. Response to medication varies; some people will respond well, others will have little response and some may even gain weight. A 5% weight loss criterion provides a useful basis for separating responders from non-responders. Individuals losing <5% of their body weight by three months should have their treatment programs re-evaluated, since individuals with <5% weight loss after three months of treatment are significantly less likely to weigh less at 12 months than those with greater initial weight loss. For lorcaserin, for example, mean weight loss is just over 5% in the randomized clinical registration trials, but that means that half of them lose more and some may lose considerably more. It is this latter group who will get the most benefit from this drug. 680 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684

Future of drug development

The third part of this chapter looks brieﬂy at the future of drug development. It is hazardous to look into the crystal ball to guess the future. During his Presidential Address to the Royal Society in 1897e1899 Lord Kelvin, one of the world's greatest physicists is alleged to have made the following comments:

‘Radio has no future’ ‘X-rays are clearly a hoax’ ‘The aeroplane is scientiﬁcally impossible’

We have made great strides in understanding of mechanism for the short-term control of food intake. Using this information, however, has not yet led to significant new drugs. Failures at the clinical level of leptin, a neuropeptide Y agonist, and a melanocortin receptor agonist have occurred either because of the unwanted side effects or lack of efficacy. With this said, however, a few mechanisms seem promising. The first mechanism is agents acting on the GI tract. In addition to its enter-endocrine system we know that there are taste and smell receptors in the GI tract that could potentially be tapped to control food intake. Some have drawn an analogy between obesity and hypertension. Treatment for hypertension has a robust armamentarium of agents which work through a variety of mechanisms. Monotherapy for hypertension often fails to produce the desired reduction in blood pressure, so combination therapy is used. This strategy has been applied to obesity, initially with phentermine/fenfluramine (now withdrawn) and more recently with phentermine/topiramate. This strategy requires that there are several therapeutic agents acting on different mechanisms. So far, monotherapy for obesity has been limited to a few agents. This analogy with hypertension breaks down with specific drugs is considered. For example two approved drugs, phentermine, and topiramate/phentermine, increase blood pressure. Sibutramine, a serotonin-norepinephrine reuptake inhibitor that was an approved drug was withdrawn because of increased cardiovascular risk and high blood pressure [26]. Finally, tesofensine which produced over 10% weight loss in a clinical trial also increased blood pressure [27] and has not yet been pursued further. Understanding this close relation between blood pressure and weight loss might provide insight into future potential therapies. The fact that treatment of leptin deficient individuals, rare as they may be, with leptin can completely reverse their obesity suggests that new strategies to harness the effects of leptin might be developed. From this perspective, the future looks bright. A recent report of a four week trial in patients with PradereWilli Syndrome, a rare form of syndromic obesity found that a new agent, beloranib produced a decrease in fat of 8.1% compared to control, a promising new approach.

Conclusions

Medications are useful in treatment of the patient with obesity because they can reinforce behavioural intentions that lead to lifestyle change. The current approach to medicating the patient with obesity is often to wait until a comorbidity has developed and to medicate for control of the comorbidity. However, weight loss alone can mitigate many of these co-morbidities. There are now three medications approved by the US FDA for long-term weight loss. This offers hope that we may be able to use weight management to prevent or delay the development of co- morbidities. The future points to the use of more combination medications for weight management and evaluation of anti-diabetic drugs for weight loss indications. The lessons of the past are several. First, we learned that prescribing for obesity, like prescribing for hypertension, is a chronic disease management paradigm. Drugs must be prescribed and used over an extended period since they don't produce permanent weight loss. Second, we learned the importance of understanding the mechanism by which drugs produce weight loss, so that the medication can be prescribed along with appropriate instruction in diet and physical activity. Third, safety and tolerability G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 681 are key factors. By increasing doses of a single agent to maximize weight loss, adverse consequences may arise. Thus, combination therapy using lower drug doses may be a better approach. Lastly, we've learned the hard lessons of unintended consequences. Because it is difﬁcult to predict the future, the current trend is to prescribe for patients with unhealthy weight, who will beneﬁt from weight loss. Prescribing for cosmetic weight loss would require a much higher margin of safety that we have today.

Conﬂicts of interest

None.

Practice points

Obesity is associated with health risks. Weight loss can reduce these risks and reduce need for other therapies. All drugs have potential side effects AND only work when taken. Thus evaluation prior to therapy is a ﬁrst requirement. Re-evaluation of response to treatment is important to reduce risk to drugs that don't work’ for an individual patient and allow them to try others.

Research agenda How important is obesity in the development of non-alcoholic fatty liver disease?

Are there medications that can speciﬁcally reduce visceral fat? Regional fat? Does inhibiting fat storage prevent obesity? What are the mechanism(s) for the plateau in body weight with weight loss? Are there strategies to make lifestyle’ in obesity? What is the CNS connection between depression and obesity? What is the CNS connection between blood pressure and obesity? How do we reduce the supply of food without impairing the quality of nutrition? Why don't the regulatory agencies have a single set of criteria for anti-obesity drugs?

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