Anti-obesity drugs

Anti-obesity drugs include all pharmacological treatments intended to reduce or control weight. Because these drugs are intended to alter one of the fundamental processes of the human body, anti-obesity drugs are medically prescribed only in cases of morbid obesity, where weight loss is life-saving.

A meta-analysis of randomized controlled trials by the international Cochrane Collaboration concluded that in diabetic patients found:
 * "Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 12 to 57 weeks. The magnitude of weight loss is modest, however, and the long-term health benefits remain unclear. The safety of sibutramine is uncertain. There is a paucity of data on other drugs for weight loss or control in persons with type 2 diabetes."

Mechanisms of action
Anti-obesity drugs operate through one or more of the following mechanisms:
 * Suppression of the appetite. Epilepsy medications and catecholamines and their derivatives (such as amphetamine-based drugs) are the main tools used for this.  Drugs blocking the cannabinoid receptors may be a future strategy for appetite suppression.
 * Increase of the body's metabolism.
 * Interference with the body's ability to absorb specific nutrients in food. For example, Orlistat (also known as Xenical and Allī) blocks fat breakdown and thereby prevents fat absorption. The OTC fiber supplements glucomannan and guar gum have been used for the purpose of inhibiting digestion and lowering caloric absorption

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

Available anti-obesity drugs
If diet and exercise are ineffective alone, anti-obesity drugs are a choice for some patients. 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.

Orlistat
Orlistat (Xenical®) reduces intestinal fat absorption by inhibiting pancreatic lipase. Originally available only by prescription, it was approved by the FDA for over-the-counter sale in February of 2007. Orlistat may cause frequent, oily bowel movements, but if fat in the diet is reduced, symptoms often improve.

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

Metformin
In people with Diabetes mellitus type 2, the drug metformin (Glucophage®) can reduce weight.

Byetta
Byetta (Exenatide) 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. 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 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.

Symlin
Symlin (Pramlintide) is a synthetic analogue of the hormone Amylin, which in normal people is secreted by the pancreas in response to eating. Among other effects, Amylin delays gastric emptying and promotes a feeling of satiety. Many diabetics are deficient in Amylin. Currently, Symlin is only approved to be used along with insulin by Type 1 and Type 2 diabetics. However, Symlin is currently being tested in non-diabetics as a treatment for obesity. A drawback is that Symlin must be injected at mealtimes.

Rimonabant
Recent pharmaceutical research has produced potential obesity combating drugs. The discovery of cannabinoid receptors in the brain, liver and muscle has stimulated research in a new class of drugs, namely cannabinoid (CB1) receptor antagonists. These drugs not only causes weight loss, but prevent or reverse the metabolic effects of obesity, such as insulin resistance and hyperlipidemia, and may also decrease the tendency to abuse substances such as alcohol and tobacco.

Sanofi-Aventis has received approval to market Rimonabant as a prescription anti-obesity drug in the European Union, subject to some restrictions. Due to safety concerns, the drug has not received approval in the United States, either as an anti-obesity treatment or as a smoking-cessation drug. Merck has a CB1 inverse agonist, codenamed MK-0364, in Phase IIb/III development for which it hopes to file a New Drug Application in 2008

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. Many of these substances are related to amphetamine.

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, since many of the claims of safety and effectiveness are unsubstantiated. 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. 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.

Side effects
Some anti-obesity drugs have severe and often life-threatening side effects. (See, for example, Fen-phen.) These side effects are often associated with their 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, oily stools, stomach pain, and flatulence. 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.

Limitations of current knowledge
The limitation of 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. Arguably any drug that would abolish appetite may carry a high mortality risk and may be unsuitable for clinical use.

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. Because of this, anti-obesity drugs are not a practical long-term solution for people who are overweight.

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: Qnexa (topiramate + phentermine), Excalia (bupropion + zonisamide) and Contrave (bupropion + naltrexone).

Future developments
Other classes of drugs in development include lipase inhibitors, similar to Xenical (Orlistat). Another lipase inhibitor, called GT 389-255, is being developed by Peptimmune (licensed from Genzyme). This is a novel combination of an inhibitor and a polymer designed to bind the undigested triglycerides therefore allowing increased fat excretion without side effects such as oily stools that occur with Xenical. The development seems to be stalled as Phase 1 trials were conducted in 2004 and there has been no further human clinical development since then.

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 knockout results in the lack of fat accumulation, even when mice are fed a high fat diet. Experiments conducted by Professor Malcolm Parker of Imperial College show that by silencing RIP 140, a nuclear hormone co-repressor which regulates fat accumulation, animal models exhibit a lean profile throughout their life, are resistant to diet-induced obesity, and show an enhanced metabolic rate. CytRx Corporation is developing RNAi therapeutics against this drug target for the treatment of obesity and type 2 diabetes.