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

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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]. http://dx.doi.org/10.1016/j.bpg.2014.07.015 1521-6918/© 2014 Elsevier Ltd. All rights reserved. 666 G.A. Bray / Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 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 fen- fluramine 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.
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