View source for Anti-obesity medication/en

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{{Short description|Class of pharmacological agents}}
{{Human body weight}}
[[File:Obesity Med2008.JPG|thumb|alt=The cardboard packaging of two medications used to treat obesity.|right|[[Orlistat]] (Xenical), the most commonly used medication to treat obesity and [[sibutramine]] (Meridia), a medication that was withdrawn due to cardiovascular side effects]]

'''Anti-obesity medication''' or '''weight loss medications''' are [[pharmacological]] agents that reduce or control excess [[body fat]]. These [[medication]]s alter one of the fundamental processes of the [[human anatomy|human body]], [[body weight|weight]] regulation, by: [[anorectic|reducing appetite]] and consequently [[energy intake]], increasing [[energy expenditure]], redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

Weight loss drugs have been developed since the early twentieth century, and many have been banned or withdrawn from the market due to adverse effects, including deaths; other drugs proved ineffective. Although many earlier drugs were [[stimulants]] such as [[amphetamines]], in the early 2020s, [[GLP-1 receptor agonist]]s became popular for weight loss.

The medications [[liraglutide]], [[orlistat]], [[semaglutide]], and [[tirzepatide]] are approved by the US [[Food and Drug Administration]] (FDA) for weight management in combination with reduced-calorie diet and increased physical activity. As of 2022, no medication has been shown to be as effective at long-term weight reduction as [[bariatric surgery]]. The main treatment modalities for obesity remain [[dieting]] ([[healthy diet]] and [[caloric restriction]]) and [[physical exercise]].

==Mechanisms of action==
===Energy intake===
* [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] agonists reduce appetite by working on [[serotonin receptor]]s in a region of the brain called the [[hypothalamus]]. [[Lorcaserin]] (Belviq) was FDA approved for weight loss but was withdrawn from the market because a safety clinical trial shows an increased occurrence of cancer.
*[[Cannabinoid receptor antagonist]]s were developed to treat obesity because researchers noticed that cannabinoid agonists (such as [[THC]], the main pharmacologically active component of [[cannabis]]), increased appetite. However, some drugs in this class such as [[rimonabant]] were withdrawn or ceased development to concerns about mental health and suicide. More selective drugs—some are in development that act only in peripheral tissues, not the brain—may be able to achieve this result with fewer adverse effects.
* [[GLP-1 agonist]]s such as tirzepatide, semaglutide, and liraglutide slow gastric emptying and also have neurologically driven effects on appetite. It is unknown if GLP-1 agonists or dual/triple agonists of GLP-1 and/or the [[glucagon receptor|glucagon]] or [[Gastric inhibitory polypeptide receptor|GIP receptors]] act solely by reducing energy intake or if they also increase energy expenditure.
*[[Setmelanotide]] is an agonist of the [[melanocortin 4 receptor]] and is used in people with certain rare genetic conditions that cause obesity. It is less effective and not approved for general obesity.
*Some weight loss drugs act on the neurotransmitters [[serotonin]], [[dopamine]], and [[norepinephrine]] to reduce appetite.

===Energy expenditure===

*[[Adrenergic agonists]] that work on the [[beta-2 adrenergic receptor]] increase energy expenditure. Although some such as [[clenbuterol]] are used without medical approval for weight loss, none have achieved approval for this indication due to cardiac risks. The anti-obesity effects of [[amphetamines]], besides acting on the brain to reduce energy intake, are also mediated by the beta-2 adrenergic receptor. [[Ephedrine]] (and related compounds that are also active ingredients in [[Ephedra (medicine)|ephedra]] preparations) exert their effects by acting directly and indirectly as adrenergic agonists.
*The discontinued drug [[2,4-dinitrophenol]] works by increasing energy expenditure by decreasing the efficiency of mitochondria ([[uncoupling agent]]). A [[prodrug]] of DNP, [[HU6]], has been tested in clinical trials for weight loss and [[fatty liver disease]].
*[[FGF21|Fibroblast growth factor-21]] receptor agonists and drugs increasing FGF-21 activity are being investigated for obesity-related diseases; they can increase energy expenditure and several have been tested in humans.
*[[Thyroid hormone]]s, another early weight loss drug, also raised energy expenditure but ceased to be used for weight loss due to cardiac risks and other adverse effects. Selective [[thyromimetic]]s that work on the [[thyroid hormone receptor beta]] may be able to exert some of the beneficial [[thermogenic]] effects of thyroid hormones with fewer adverse effects, but none have received approval as of 2023.

===Both===
*[[Amylin]] analogues can both reduce energy intake and increase expenditure and can usefully be combined with [[leptin]] analogues for synergistic effect. The [[dual amylin and calcitonin receptor agonist]] [[cagrilintide]], [[cagrilintide/semaglutide|in combination with semaglutide]], was more effective than semaglutide alone in promoting weight loss in clinical trials.
*[[Glucagon receptor agonist]]s both reduce energy intake and increase energy expenditure in humans. They can cause hyperglycemia so it is recommended to combine them with a hypoglycemic drug, such as a GLP-1 or GIP receptor agonist.

===Other mechanisms===
*[[Bimagrumab]], an experimental drug, works by inhibiting the action of [[myostatin]], which limits the size of [[skeletal muscle]]. The drug has shown the ability to increase lean mass simultaneously to decreasing fat mass in obese humans, which is beneficial because it preserves or increases energy expenditure while reducing risks associated with excess fat.
*[[Orlistat]] (Xenical) and [[cetilistat]] reduce intestinal fat absorption by inhibiting [[pancreatic lipase]], an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. Frequent oily bowel movements [[steatorrhea]] is a possible side effect of using Orlistat. Originally available only by prescription, it was approved by the FDA for over-the-counter sale in February 2007. In May 2010, the U.S. Food and Drug Administration (FDA) approved a revised label for Xenical to include new safety information about rare cases of severe liver injury that have been reported with the use of this medication. A 2010 phase 2 trial found cetilistat significantly reduced weight and was better tolerated than orlistat.
*[[SGLT2 inhibitor]]s cause the loss of {{convert|60–100|g}} [[glucose]] in the urine each day and are associated with a modest, sustained weight loss of {{convert|1.5-2|kg}} in people with type 2 diabetes. The weight loss is less than expected due to compensatory increases in energy intake, but is additive when combined with [[GLP-1 receptor agonist]]s.

==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 [[laxative]]s 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 [[palpitation]]s and [[insomnia|difficulty sleeping]]. [[2,4-Dinitrophenol]] (DNP) was introduced in 1933; this worked by [[Uncoupler|uncoupling]] the biological process of [[oxidative phosphorylation]] in [[mitochondria]], causing them to produce heat instead of [[Adenosine triphosphate|ATP]]. Overdose caused fatal [[hyperthermia]] and DNP also caused [[cataracts]] in some users. After the passage of the [[Food, Drug, and Cosmetic Act]] in 1938, the FDA banned DNP for human consumption.

[[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 diet 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, [[diuretic]]s, [[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. While rainbow diet pills were banned in the US in the late 1960s, they reappeared in South America and Europe in the 1980s. In 1959, phentermine had been FDA approved and [[fenfluramine]] in 1973. In the early 1990s two studies found that a combination of the drugs was more effective than either on its own; ''[[fen-phen]]'' became popular in the United States and had more than 18 million prescriptions in 1996. Evidence mounted that the combination could cause [[valvular heart disease]] in up to 30 percent of those who had taken it, leading to withdrawal of fen-phen and [[dexfenfluramine]] from the market in September 1997.
In the early 2020s, [[GLP-1 receptor agonist]]s such as [[semaglutide]] or tirzepatide became popular for weight loss because they are more effective than earlier drugs, causing a shortage for patients prescribed these medications for [[type 2 diabetes]], their original indication.

==Patient population==
The United States [[Food and Drug Administration]] and the [[European Medicines Agency]] have approved weight loss medications for adults with either a [[body-mass index]] (BMI) of at least 30, or a body-mass index of at least 27 with at least one weight-related comorbidity. This patient population is considered to have sufficiently high baseline health risks to justify the use of anti-obesity medication.

The [[American Academy of Pediatrics]] had not previously supported the use of weight loss medication in adolescents but issued new guidelines in 2023. It now recommends considering the use of weight loss medication in some overweight children aged 12 or older. The [[European Medicines Agency]] has approved semaglutide for children aged 12 or older who have a BMI in the 95 percentile for their age and a weight of at least {{convert|60|kg}}. However, GLP-1 agonists may not be cost effective in this population.

==Medication==

=== US FDA approved ===
The US [[Food and Drug Administration]] (FDA) approves anti-obesity medications as an adjunctive therapy to diet and exercise for people for whom lifestyle changes do not result in sufficient weight loss. In the United States, semaglutide (Wegovy) is approved by the FDA for chronic weight management. The FDA guidelines say that a therapy may be approved if it results in weight loss that is statistically significant greater than placebo and generally at least five percent of body weight over six months that comes predominantly from fat mass. Some other prescription weight loss medications are stimulants, which are recommended only for short-term use, and thus are of limited usefulness for patients who may need to reduce weight over months or years. As of 2022, there is no pathway for approval for drugs that reduce fat mass without 5 percent overall weight loss, even if they significantly improve metabolic health; neither is there one for drugs that help patients maintain weight loss although this can be more challenging than losing weight.

As of 2022, no medication has been discovered that would equal the effectiveness of [[bariatric surgery]] for long-term weight loss and improved health outcomes.
{| class="wikitable"
|+
!Medication Name
!Trade name(s)
!Mechanism of action
!Current FDA Status
!placebo-adjusted percent bodyweight lost (highest dose studied)
|-
|[[Semaglutide]]
|Wegovy
|[[GLP-1 receptor agonist]]
|Approved for weight management (chronic)
|12%
|-
|[[Phentermine/topiramate]]
|Qsymia
|Phentermine is a [[substituted amphetamine]] and topiramate has an unknown mechanism of action
|Approved for weight management (short-term) by the FDA but not the European Medicines Agency
|10% or {{convert|8.25| kg}}
|-
|[[Naltrexone/bupropion]]
|Contrave
|
|Approved for weight management (chronic) in the US and EU
|5 percent
|-
|[[Liraglutide]]
|Saxenda
|[[GLP-1 receptor agonist]]
|Approved for weight management (chronic)
|4 percent
|-
|[[Gelesis100]]
|Plenity
|Oral hydrogel
|FDA approved for weight management (chronic) but the American Gastroenterology Association recommends that its use be limited to [[clinical trials]] due to lack of evidence.
|2%
|-
|[[Orlistat]]
|Xenical
|Absorption inhibitor
|Approved for weight management (chronic)
|{{convert|3|kg}}; percentage not provided
|-
|[[Phentermine]]
|
|[[Substituted amphetamine]]
|Approved for weight management (short-term)
|{{convert|5|kg}}
|-
|[[Methamphetamine]]
|Desoxyn
|[[Substituted amphetamine]]
|Approved for weight management (short-term)
|
|-
|[[Tirzepatide]]
|Zepbound
|Dual [[GLP-1 receptor agonist]] and [[Glucose-dependent insulinotropic polypeptide|GIP agonist]]
|FDA approved for weight management (chronic); EMA approval for weight loss is pending
|{{convert|10.91|kg}}
|}

===Withdrawn===

{| class="wikitable"
|+
!Medication Name
!Trade name(s)
!Mechanism of action
!Current FDA Status
!placebo-adjusted percent bodyweight lost (highest dose studied)
|-
|[[Lorcaserin]]
|Belviq
|[[5-HT2C receptor]] agonist
|Withdrawn for safety reasons
| 6.25 percent
|-
|[[Sibutramine]]
|Meridia
|[[Serotonin–norepinephrine reuptake inhibitor]]
|Withdrawn due to cardiovascular risks
| 19.7 percent
|-
|[[Rimonabant]]
|Acomplia, Zimbutli
|[[Cannabinoid receptor antagonist]]
|Withdrawn for safety reasons
| {{convert|2.6 to 6.3|kg}}
|-
|[[Fenfluramine]]
|
|[[Serotonin releasing agent]]
|Withdrawn for safety reasons
| -
|-
|[[Fenfluramine/phentermine]] (fen-phen)
|Pondimin
|
|Withdrawn for safety reasons
|13.9 percent
|-
|[[Dexfenfluramine]]
|Redux
|[[Serotonin releasing agent]]
|Withdrawn for safety reasons
|{{convert|3.5|kg}}
|-
|[[2,4-Dinitrophenol]]
|
|[[Uncoupling agent]]
|Withdrawn for safety reasons
|{{convert|17.1|lb}} per patient on average (uncontrolled study)

|-
| [[Ephedrine]]
|
| [[Adrenergic agonist]]
| Approved for [[asthma]]
|Average of {{convert|1.9|kg}} in a meta-analysis (all dosages)
|-
|[[ECA stack]]
|
|Combination of ephedrine and [[caffeine]], sometimes adding [[aspirin]]
|
|Around {{convert|4-6|kg}}
|-
|[[Ephedra (medicine)|Ephedra]]
|Plant extract sold as a [[dietary supplement]]
|Contains [[ephedrine]], an [[adrenergic agonist]]
|Banned in 2004 for safety reasons
|{{convert|0.9|kg}} per month more than placebo
|-
|[[Amphetamine salts]]
|[[Obetrol]]
|
|Approved 1960, withdrawn 1973; [[Adderall]] was later approved for [[ADHD]] and [[narcolepsy]] and is still used for those purposes
|
|-
|[[Phenylpropanolamine]]
|Was an over-the-counter medication ingredient
|
|Withdrawn in 2005 due to risk of [[hemorragic stroke]]
|{{convert|1.5|kg}}
|}

===Never approved===

{| class="wikitable"
|+
!Medication Name
!Trade name(s)
!Mechanism of action
!Current FDA Status
!placebo-adjusted percent bodyweight lost (highest dose studied)
|-
|[[Retatrutide]]
|
|GLP-1, [[GIP receptor|GIP]], and [[glucagon receptor]] triple agonist
|In clinical trials
|24 percent in a Phase II trial
|-
|[[Exenatide]]
|Byetta
|[[GLP-1 receptor agonist]]
|Approved for type 2 diabetes
|{{convert|2.5|kg}}
|-
|[[Cetilistat]]
|
|Absorption inhibitor
|Not approved
| {{convert|1.5|kg}}
|-
| [[Tesofensine]] (NS2330)
|
|[[Serotonin–norepinephrine–dopamine reuptake inhibitor]]
|Not FDA approved
|10.6 percent

|-
|[[Metformin]]
|Glucophage
|Unknown
|Approved for type 2 diabetes
|5.6 percent
|-
|[[Cagrilintide]]
|
|[[Dual amylin and calcitonin receptor agonist]] (DACRA)
|Not approved
|7.8 percent
|-
|[[Cagrilintide/semaglutide]]
|CagriSema
|DACRA/GLP-1 agonist combination
|Not approved
|15.4 percent after 32 weeks
|}

==Safety and side effects==
Some anti-obesity medications 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. Out of 25 anti-obesity medications withdrawn from the market between 1964 and 2009, 23 acted by altering the functions of chemical [[neurotransmitters]] in the brain. The most common side effects of these drugs that led to withdrawals were mental disturbances, cardiac side effects, and [[Substance abuse|drug abuse]] or [[drug dependence]]. Deaths were associated with seven products. [[Ephedra (medicine)|Ephedra]] was removed from the US market in 2004 over concerns that it raises blood pressure and could lead to strokes and death.


== External links ==
* {{Commons category-inline}}
* [https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity Prescription Medications to Treat Overweight & Obesity] US National Institute of Diabetes and Digestive and Kidney Diseases

{{Obesity}}
{{Antiobesity preparations}}
{{Major drug groups}}
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{{二次利用|date= 7 March 2024}}
{{DEFAULTSORT:Anti-Obesity Medication}}
[[Category:Anti-obesity drugs| ]]