Anti-obesity drug

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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.[1][2]

Meta-analysis of randomized controlled trials are available to guide decisions[3][4], including for patients with hypertension[5], and diabetes mellitus type 2 [6]

Mechanisms of action

Anti-obesity drugs operate through one or more of the following mechanisms:

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. Prescription weight loss drugs 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.[citation needed]

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. [1] 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.[7]

Phentermine monotherapy

Phentermine can help weight loss according to randomized controlled trials[8][9][10] and a meta-analysis[11]; however, there are concerns about its potential for addiction[12] and safety[13].

Liraglutide

Liraglutide as effective in the SCALE randomized controlled trial.[14]

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 onti-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.[citation needed] Pfizer has a CB1 antagonist, codenamed CP-945,598, that it has started Phase III trials for.[citation needed]

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 hemmorhagic stroke due phenylpropanolamine.[15][16] 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,[17] since many of the claims of safety and effectiveness are unsubstantiated.[18] 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.[19] 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.[20]

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. Twenty-five medications for obesity have been withdrawn from the market due to adverse drug reactions.[21]

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[22] (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.

References

  1. ↑ Snow V, Barry P, Fitterman N, Qaseem A, Weiss K (2005). "Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians". Ann. Intern. Med. 142 (7): 525–31. PMID 15809464.
  2. ↑ Cooke D, Bloom S (2006). "The obesity pipeline: current strategies in the development of anti-obesity drugs". Nature reviews. Drug discovery. 5 (11): 919–31. doi:10.1038/nrd2136. PMID 17080028.
  3. ↑ Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ; et al. (2016). "Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis". JAMA. 315 (22): 2424–34. doi:10.1001/jama.2016.7602. PMID 27299618.
  4. ↑ Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR; et al. (2005). "Meta-analysis: pharmacologic treatment of obesity". Ann Intern Med. 142 (7): 532–46. PMID 15809465. Review in: ACP J Club. 2005 Sep-Oct;143(2):50
  5. ↑ Siebenhofer A, Jeitler K, Horvath K, Berghold A, Posch N, Meschik J; et al. (2016). "Long-term effects of weight-reducing drugs in people with hypertension". Cochrane Database Syst Rev. 3: CD007654. doi:10.1002/14651858.CD007654.pub4. PMID 26934640.
  6. ↑ Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Lau J (2005). "Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus". Cochrane database of systematic reviews (Online) (1): CD004096. doi:10.1002/14651858.CD004096.pub2. PMID 15674929.
  7. ↑ George A. Bray and Frank L. Greenway (1999). "Current and Potential Drugs for Treatment of Obesity: Table 19: Clinical trials with metformin for the treatment of obese diabetics". Endocrine Reviews. 20: 805–87. Retrieved 2006-08-07.
  8. ↑ Moldovan CP, Weldon AJ, Daher NS, Schneider LE, Bellinger DL, Berk LS; et al. (2016). "Effects of a meal replacement system alone or in combination with phentermine on weight loss and food cravings". Obesity (Silver Spring). 24 (11): 2344–2350. doi:10.1002/oby.21649. PMID 27664021.
  9. ↑ Campbell CJ, Bhalla IP, Steel JM, Duncan LJ (1977). "A controlled trial of phentermine in obese diabetic patients". Practitioner. 218 (1308): 851–5. PMID 329259.
  10. ↑ Gershberg H, Kane R, Hulse M, Pengsen E. Effects of diet and an anorectic drug (phentermine resin) in obese diabetics. Current Therapeutic Research 1977;22:814–20.
  11. ↑ Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M (2002). "Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials". Int J Obes Relat Metab Disord. 26 (2): 262–73. doi:10.1038/sj.ijo.0801889. PMID 11850760.
  12. ↑ Schoedel KA, Addy C, Chakraborty B, Rosko K, Dunbar S, Maes A; et al. (2012). "Human abuse potential and cognitive effects of taranabant, a cannabinoid 1 receptor inverse agonist: a randomized, double-blind, placebo- and active-controlled, crossover study in recreational polydrug users". J Clin Psychopharmacol. 32 (4): 492–502. doi:10.1097/JCP.0b013e31825d380d. PMID 22722508.
  13. ↑ Woloshin S, Schwartz LM (2014). "The new weight-loss drugs, lorcaserin and phentermine-topiramate: slim pickings?". JAMA Intern Med. 174 (4): 615–9. doi:10.1001/jamainternmed.2013.14629. PMID 24515599.
  14. ↑ Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M; et al. (2015). "A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management". N Engl J Med. 373 (1): 11–22. doi:10.1056/NEJMoa1411892. PMID 26132939. Review in: Evid Based Med. 2015 Dec;20(6):203
  15. ↑ Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. (1996). "Appetite-suppressant drugs and the risk of primary pulmonary hypertension" (Abstract). The New England Journal of Medicine. 29;335(9): 609–616. Retrieved 2006-07-24.
  16. ↑ Alfred P. Fishman, MD (1999). "Aminorex to Fen/Phen: An Epidemic Foretold". Circulation. 99: 156–161. Retrieved 2006-07-24.
  17. ↑ U. S. Food and Drug Administration: The Facts About Weight Loss Products and Programs
  18. ↑ "Prepared Statement of the Federal Trade Commission on the Marketing of Dietary Supplements" (Press release). Committee on Governmental Affairs, United States Senate. 2002-10-08. Retrieved 2006-08-07. Check date values in: |date= (help)
  19. ↑ Malissa Martin, EdD, ATC, Gretchen Schlabach, PhD, ATC, and Kim Shibinski, MS (1998). "The Use of Nonprescription Weight Loss Products Among Female Basketball, Softball, and Volleyball Athletes from NCAA Division I Institutions: Issues and Concerns". Journal of Athletic Training. 33 (1): 41–44. Retrieved 2006-08-07.
  20. ↑ George A. Bray and Frank L. Greenway (1999). "Current and Potential Drugs for Treatment of Obesity: Postabsorptive modifiers of nutrient metabolism". Endocrine Reviews. 20: 805–87. Retrieved 2006-08-07.
  21. ↑ Onakpoya IJ, Heneghan CJ, Aronson JK (2016). "Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review". BMC Med. 14 (1): 191. doi:10.1186/s12916-016-0735-y. PMC 5126837. PMID 27894343.
  22. ↑ Peptimmune homepage

See also

External links

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