Anti-obesity medication

The cardboard packaging of two medications used to treat obesity. Orlistat is shown understanding under the brand name Xenical in a white package with the Roche logo in the bottom right corner ( the Roche name within a hexagon). Sibutramine is below under the brand name Meridia. The package is white on the top and blue on the bottom separated by a measuring tape. The A of the Abbott Laboratories logo is on the bottom half of the package.
Orlistat (Xenical) the most commonly used medication to treat obesity and sibutramine (Meridia) a medication that was recently withdrawn due to cardiovascular side effects

Anti-obesity medication or weight loss drugs are pharmacological agents that reduce or control weight. These drugs alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absorption of calories.[1] The main treatment modalities for overweight and obese individuals remain dieting and physical exercise.

In the United States orlistat (Xenical) is currently approved by the FDA for long-term use.[2][3] It reduces intestinal fat absorption by inhibiting pancreatic lipase. Rimonabant (Acomplia), a second drug, works via a specific blockade of the endocannabinoid system. It has been developed from the knowledge that cannabis smokers often experience hunger, which is often referred to as "the munchies". It had been approved in Europe for the treatment of obesity but has not received approval in the United States or Canada due to safety concerns.[4][5] The European Medicines Agency in October 2008 recommended the suspension of the sale of rimonabant as the risks seem to be greater than the benefits.[6] Sibutramine (Meridia), which acts in the brain to inhibit deactivation of the neurotransmitters, thereby decreasing appetite was withdrawn from the United States and Canadian markets in October 2010 due to cardiovascular concerns.[3][7]

Because of potential side effects, and limited evidence of small benefits in weight reduction especially in obese children and adolescents,[8] it is recommended that anti-obesity drugs only be prescribed for obesity where it is hoped that the benefits of the treatment outweigh its risks.[9][10]

Mechanisms of action

Current and potential anti-obesity drugs may operate through one or more of the following mechanisms:

Anorectics are primarily intended to suppress the appetite, but most of the drugs in this class also act as stimulants (e.g., dexedrine), and patients have abused drugs "off label" to suppress appetite (e.g. digoxin).

History

The first described attempts at producing weight loss are those of Soranus of Ephesus, a Greek physician, in the second century AD. He prescribed elixirs of laxatives and purgatives, as well as heat, massage, and exercise. This remained the mainstay of treatment for well over a thousand years. It was not until the 1920s and 1930s that new treatments began to appear. Based on its effectiveness for hypothyroidism, thyroid hormone became a popular treatment for obesity in euthyroid people. It had a modest effect but produced the symptoms of hyperthyroidism as a side effect, such as palpitations and difficulty sleeping. 2,4-Dinitrophenol (DNP) was introduced in 1933; this worked by uncoupling the biological process of oxidative phosphorylation in mitochondria, causing them to produce heat instead of ATP. The most significant side effect was a sensation of warmth, frequently with sweating. Overdose, although rare, lead to a rise in body temperature and, ultimately, fatal hyperthermia. By the end of 1938 DNP had fallen out of use because the FDA had become empowered to put pressure on manufacturers, who voluntarily withdrew it from the market.[12]

Amphetamines (marketed as Benzedrine) became popular for weight loss during the late 1930s. They worked primarily by suppressing appetite, and had other beneficial effects such as increased alertness. Use of amphetamines increased over the subsequent decades, including Obetrol and culminating in the "rainbow pill" regime. This was a combination of multiple pills, all thought to help with weight loss, taken throughout the day. Typical regimens included stimulants, such as amphetamines, as well as thyroid hormone, diuretics, digitalis, laxatives, and often a barbiturate to suppress the side effects of the stimulants. In 1967/1968 a number of deaths attributed to diet pills triggered a Senate investigation and the gradual implementation of greater restrictions on the market.[13]

Meanwhile, phentermine had been FDA approved in 1959 and fenfluramine in 1973. The two were no more popular than other drugs until in 1992 a researcher reported that when combined the two caused a 10% weight loss which was maintained for more than two years.[14] Fen-phen was born and rapidly became the most commonly prescribed diet medication. Dexfenfluramine (Redux) was developed in the mid-1990s as an alternative to fenfluramine with fewer side-effects, and received regulatory approval in 1996. However, this coincided with mounting evidence that the combination could cause valvular heart disease in up to 30% of those who had taken it, leading to withdrawal of Fen-phen and dexfenfluramine from the market in September 1997.[13]

Ephedra was removed from the US market in 2004 over concerns that it raises blood pressure and could lead to strokes and death.[15]

Medication

Some patients find that diet and exercise is not a viable option; for these patients, anti-obesity drugs can be a last resort. Some prescription weight loss drugs are stimulants, which are recommended only for short-term use, and thus are of limited usefulness for extremely obese patients, who may need to reduce weight over months or years.[16]

Orlistat

Orlistat (Xenical) reduces intestinal fat absorption by inhibiting pancreatic lipase. Some side-effects of using Orlistat include frequent, oily bowel movements (steatorrhea). But if fat in the diet is reduced, symptoms often improve. Originally available only by prescription, it was approved by the FDA for over-the-counter sale in February 2007.[17] On 26 May 2010, the U.S. Food and Drug Administration (FDA) has approved a revised label for Xenical to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication.[18] Of the 40 million users of Orlistat worldwide, 13 cases of severe liver damage have been reported.[19]

Lorcaserin

Lorcaserin (Belviq) was approved June 28, 2012 for obesity with other co-morbidities. The average weight loss by study participants was modest, but the most common side effects of the medication are considered benign.[20]

Sibutramine

Sibutramine (Reductil or Meridia) is an anorectic or appetite suppressant, reducing the desire to eat. Sibutramine may increase blood pressure and may cause dry mouth, constipation, headache, and insomnia.

In the past, it was noted by the US that Meridia was a harmless drug for fighting obesity. The US District Court of the Northern District of Ohio rejected 113 cases complaining about the negative effects of the drug, stating that the clients lacked supporting facts and that the representatives involved were not qualified enough.[21]

Sibutramine has been withdrawn from the market in the United States,[22] the UK,[23] the EU,[24] Australia,[25] Canada,[26] Hong Kong[27] and Colombia.[28] Its risks (non-life-threatening myocardial infarction and stroke) have been shown to outweigh the benefits.

Rimonabant

Rimonabant (also known as SR141716; trade names Acomplia and Zimulti)[29] was an anorectic antiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States.[30][31] Rimonabant is an inverse agonist for the cannabinoid receptor CB1 and was the first drug approved in that class.[32][33]

Metformin

In people with Diabetes mellitus type 2, the drug metformin (Glucophage) can reduce weight.[34] Metformin limits the amount of glucose that is produced by the liver as well as increases muscle consumption of glucose. It also helps in increasing the body's response to insulin.[35]

Exenatide / Liraglutide

Exenatide (Byetta) is a long-acting analogue of the hormone GLP-1, which the intestines secrete in response to the presence of food. Among other effects, GLP-1 delays gastric emptying and promotes a feeling of satiety. Some obese people are deficient in GLP-1, and dieting reduces GLP-1 further.[36] Byetta is currently available as a treatment for Diabetes mellitus type 2. Some, but not all, patients find that they lose substantial weight when taking Byetta. Drawbacks of Byetta include that it must be injected subcutaneously twice daily, and that it causes severe nausea in some patients, especially when therapy is initiated. Byetta is recommended only for patients with Type 2 Diabetes. A somewhat similar drug, Symlin, is currently available for treating diabetes and is in testing for treating obesity in non-diabetics.[37]

Liraglutide (Saxenda) is another GLP-1 analogue.

Phentermine/topiramate

The combination of phentermine and topiramate, brand name Qsymia (formerly Qnexa) was approved by the U.S. FDA on July 17, 2012, as an obesity treatment complementary to a diet and exercise regimen.[38] The European Medicines Agency, by contrast, rejected the combination as a treatment for obesity, citing concerns about long-term effects on the heart and blood vessels, mental health and cognitive side-effects.

Other drugs

Other weight loss drugs have also been associated with medical complications, such as fatal pulmonary hypertension and heart valve damage due to Redux and Fen-phen, and hemorrhagic stroke due phenylpropanolamine.[39][40] Many of these substances are related to amphetamine.

Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity.[41] Tesofensine was originally developed by a Danish biotechnology company, NeuroSearch, who transferred the rights to Saniona in 2014.[42] Tesofensine has been evaluated in Phase 1 and Phase 2 human clinical studies with the aim of investigating treatment potential with regards to obesity.

Unresearched nonprescription products or programs for weight loss are heavily promoted by mail and print advertising and on the internet. The US Food and Drug Administration recommends caution with use of these products,[43] since many of the claims of safety and effectiveness are unsubstantiated.[44] Individuals with anorexia nervosa and some athletes try to control body weight with laxatives, diet pills or diuretic drugs, although these generally have no impact on body fat.[45] Products that work as a laxative can cause the blood's potassium level to drop, which may cause heart and/or muscle problems. Pyruvate is a popular product that may result in a small amount of weight loss. However, pyruvate, which is found in red apples, cheese, and red wine, has not been thoroughly studied and its weight loss potential has not been scientifically established.[46]

Alternative medicine

Recommendations for medicinal plants for weight loss target five basic bodily mechanisms: managing or controlling appetite, stimulating thermogenesis and lipid metabolism, inhibiting pancreatic lipase activity, preventing adipogenesis, and promoting lipolysis.

However, some currently available supplements and alternative medicine have insufficient evidence to support or oppose their use.[47]

Conjugated linoleic acid is claimed to helps reduce obesity but it is ineffective for this use.[48]

The ECA Stack cannot be marketed in most developed countries but used to be marketed as a weight loss; it provided modest short term weight loss but was ineffective in the long term and had adverse effects on the cardiovascular, mental, digestive, and nervous systems.[49]

Side effects

Some anti-obesity drugs can have severe, even, lethal side effects, fen-phen being a famous example. Fen-phen was reported through the FDA to cause abnormal echocardiograms, heart valve problems, and rare valvular diseases.[50] One of, if not the first, to sound alarms was Sir Arthur MacNalty, Chief Medical Officer (United Kingdom). As early as the 1930s, he warned against the use of dinitrophenol as an anti-obesity medication and the injudicious and/or medically unsupervised use of thyroid hormone to achieve weight reduction.[51][52] The side effects are often associated with the medication's mechanism of action. In general, stimulants carry a risk of high blood pressure, faster heart rate, palpitations, closed-angle glaucoma, drug addiction, restlessness, agitation, and insomnia.

Another drug, orlistat, blocks absorption of dietary fats, and as a result may cause oily spotting bowel movements (steatorrhea), oily stools, stomach pain, and flatulence.[53] A similar medication designed for patients with Type 2 diabetes is Acarbose; which partially blocks absorption of carbohydrates in the small intestine, and produces similar side effects including stomach pain and flatulence.[54]

Limitations of current knowledge

The limitation of - or knowledge gap concerning - drugs for obesity is that we do not fully understand the neural basis of appetite and how to modulate it. Appetite is clearly a very important instinct to promote survival.

Because the human body uses various chemicals and hormones to protect its stores of fat (a reaction probably useful to our ancestors when food was scarce in the past,) there has not yet been found a 'silver bullet', or a way to completely circumvent this natural habit of protecting excess food stores.

In order to circumvent the number of feedback mechanisms that prevent most monotherapies from producing sustained large amounts of weight loss, it has been hypothesized that combinations of drugs may be more effective by targeting multiple pathways and possibly inhibiting feedback pathways that work to cause a plateau in weight loss. This was evidenced by the success of the combination of phentermine and fenfluramine or dexfenfluramine, popularly referred to phen-fen, in producing significant weight loss but fenfluramine and dexfenfluramine were pulled from the market due to safety fears regarding a potential link to heart valve damage. The damage was found to be a result of activity of fenfluramine and dexfenfluramine at the 5-HT2B serotonin receptor in heart valves. Newer combinations of SSRIs and phentermine, known as phenpro, have been used with equal efficiency as fenphen with no known heart valve damage due to lack of activity at this particular serotonin receptor due to SSRIs. There has been a recent resurgence in combination therapy clinical development with the development of 3 combinations: Qsymia (topiramate + phentermine), Empatic (bupropion + zonisamide) and Contrave (bupropion + naltrexone).

Future developments

Other classes of drugs in development include lipase inhibitors, similar to orlistat. Another lipase inhibitor, called GT 389-255, was being developed by Peptimmune[55] (licensed from Genzyme). This was a novel combination of an inhibitor and a polymer designed to bind the undigested triglycerides therefore allowing increased fat expulsion without side effects such as oily stools that occur with orlistat. The development stalled as Phase 1 trials were conducted in 2004 and there was no further human clinical development afterward. In 2011, Peptimmune filed for Chapter 7 Liquidation.[56]

Another potential long-term approach to anti-obesity medication is through the development of ribonucleic acid interference (RNAi). Animal studies have illustrated that the deletion of the RIP140 gene in mice by genetic knockdown results in the lack of fat accumulation, even when mice are fed a high fat diet.[57] Similarly, another nuclear hormone receptor co-repressor, SMRT, has demonstrated an opposing effect in genetically engineered mice. Dr. Russell Nofsinger and Dr. Ronald Evans of the Salk Institute showed that disruption of the molecular interaction between SMRT and their nuclear hormone receptor partners leads to increased adiposity and a decreased metabolic rate.[58] These studies suggest that new drugs targeting the molecular interaction between nuclear hormone receptors and their regulatory cofactors could provide a useful new category of therapeutic targets to be developed in an effort to control obesity.

Another approach is to induce a sense of satiety by occupying space in the gastric and intestinal cavities. One clinical trial involves a hydrogel (Gelesis) made of indigestible, food-grade materials.[59] Another pilot study uses pseudobezoars.[60]

Other drugs in clinical trials as of October 2009 include Cetilistat and TM38837.

See also

References

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  51. ↑ , Launceston, Tasmania, Australia, Examiner, Friday, January 21, 1938, p 14, which states in postscript "However, the sex which for many years injured its health by tight lacing is not likely to be deterred from slimming by such considerations, The dictates of fashion will be paramount." Sir Arthur was particularly concerned with the neurological side effects of the then popular practice of dosing with thyroid extract to lose weight and, also, use of the then much vaunted weight loss drug dinitrophenol, which his report found killed as many patients as it reduced in girth, as well as, the compromise of the malnourished’s immune system and their consequent, often, inability to resist infectious diseases like the then endemic tuberculosis (archaic "epidemics of consumption").
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Further reading

Boss, Olivier; Karl G. Hofbauer (2004). Pharmacotherapy of obesity: options and alternatives. Boca Raton: CRC Press. ISBN 0-415-30321-4. 

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