Anti-obesity medication/ja

肥満症の治療薬として最も一般的に使用されているオルリスタット（ゼニカル）と、心血管への副作用のため発売中止となったシブトラミン（メリディア）である。

抗肥満薬または減量薬とは、過剰な体脂肪を減少させる、またはコントロールする薬理学的薬剤である。これらの医薬品は人体の基本的なプロセスの1つである体重調節を変化させる： 食欲減退およびその結果としてのエネルギー摂取量の減少、エネルギー消費量の増加、脂肪組織から除脂肪組織への栄養素の方向転換、またはカロリーの吸収の妨害である。

減量薬は20世紀初頭から開発されており、その多くは死亡例を含む副作用のために禁止または市場から撤退している。初期の薬剤の多くはアンフェタミンなどの覚せい剤であったが、2020年代初頭にはGLP-1受容体作動薬が減量薬として普及した。

リラグルチド、オルリスタット、セマグルチド、ティルゼパチドの各薬剤は、カロリーを抑えた食事と身体活動の増加との併用による体重管理薬として、米国食品医薬品局（FDA）により承認されている。2022年現在、肥満手術ほど長期的な体重減少に有効であることが示されている薬剤はない。肥満に対する主な治療法は、依然として食事療法（健康的な食事とカロリー制限）と身体運動である。

作用機序

エネルギー摂取

• 5-HT_2C受容体作動薬は、脳の視床下部と呼ばれる部位にあるセロトニン受容体に作用して食欲を減退させる。ロルカセリン（ベルビック）は減量薬としてFDAに承認されたが、安全性に関する臨床試験でがんの発生が増加したため、市場から取り下げられた。
• カンナビノイド受容体拮抗薬が肥満治療のために開発されたのは、カンナビノイド作動薬（大麻の主薬理学的活性成分であるTHCなど）が食欲を増進させることに研究者が気づいたからである。しかし、リモナバントのようなこのクラスの薬物のいくつかは、精神衛生や自殺に関する懸念のために撤回されたり、開発が中止されたりした。より選択性の高い薬物-脳ではなく末梢組織のみに作用するものも開発中である-は、より少ない副作用でこの結果を達成できるかもしれない。
• ティルゼパチド、セマグルチド、リラグルチドなどのGLP-1アゴニストは、胃排出を遅らせ、食欲に対する神経学的な作用も有する。GLP-1アゴニストまたはGLP-1および/またはグルカゴンまたはGIP受容体の二重/三重アゴニストが、エネルギー摂取を減少させることによってのみ作用するのか、あるいはエネルギー消費も増加させるのかは不明である。
• セトメラノチドはメラノコルチン4受容体の作動薬であり、肥満を引き起こす特定のまれな遺伝的疾患を持つ人に使用される。効果は低く、一般的な肥満には承認されていない。
• 一部の減量薬は、神経伝達物質であるセロトニン、ドーパミン、ノルエピネフリンに作用して食欲を減退させる。

エネルギー消費

• 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 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.
• 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 hormones, 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 thyromimetics 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, in combination with semaglutide, was more effective than semaglutide alone in promoting weight loss in clinical trials.
• Glucagon receptor agonists 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 inhibitors cause the loss of 60–100 grams (2.1–3.5 oz) glucose in the urine each day and are associated with a modest, sustained weight loss of 1.5–2 kilograms (3.3–4.4 lb) 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 agonists.

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. 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, 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. 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 agonists 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 60 kilograms (130 lb). 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.

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 8.25 kilograms (18.2 lb)
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)	3 kilograms (6.6 lb); percentage not provided
Phentermine		Substituted amphetamine	Approved for weight management (short-term)	5 kilograms (11 lb)
Methamphetamine	Desoxyn	Substituted amphetamine	Approved for weight management (short-term)
Tirzepatide	Zepbound	Dual GLP-1 receptor agonist and GIP agonist	FDA approved for weight management (chronic); EMA approval for weight loss is pending	10.91 kilograms (24.1 lb)

Withdrawn

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	2.6 to 6.3 kilograms (5.7 to 13.9 lb)
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	3.5 kilograms (7.7 lb)
2,4-Dinitrophenol		Uncoupling agent	Withdrawn for safety reasons	17.1 pounds (7.8 kg) per patient on average (uncontrolled study)
Ephedrine		Adrenergic agonist	Approved for asthma	Average of 1.9 kilograms (4.2 lb) in a meta-analysis (all dosages)
ECA stack		Combination of ephedrine and caffeine, sometimes adding aspirin		Around 4–6 kilograms (8.8–13.2 lb)
Ephedra	Plant extract sold as a dietary supplement	Contains ephedrine, an adrenergic agonist	Banned in 2004 for safety reasons	0.9 kilograms (2.0 lb) 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	1.5 kilograms (3.3 lb)

未承認

医薬品名	商品名	作用機序	現在のFDAステータス	プラセボ調整による体重減少率（最高用量試験）
Retatrutide/ja		GLP-1, GIP, glucagon receptor/jaトリプルアゴニスト	臨床試験中	第II相試験では24％であった
Exenatide/ja	バイエッタ	GLP-1受容体作動薬	2型糖尿病治療薬として承認されている	2.5 kilograms (5.5 lb)
Cetilistat/ja		吸収阻害剤	未承認	1.5 kilograms (3.3 lb)
Tesofensine/ja (NS2330)		Serotonin–norepinephrine–dopamine reuptake inhibitor/ja	未承認	10.6%
メトホルミン	グルコファージ	不明	2型糖尿病治療薬として承認されている	5.6%
Cagrilintide/ja		Dual amylin and calcitonin receptor agonist/ja (DACRA)	未承認	7.8%
Cagrilintide/semaglutide/ja	カグリセマ	DACRA/GLP-1作動薬配合剤	未承認	32週後に15.4%

安全性と副作用

抗肥満薬のなかには、重篤な、場合によっては致死的な副作用をもたらすものもあり、フェンフェンはその有名な例である。フェンフェンはFDAを通じて、心エコー異常、心臓弁障害、まれな弁膜症などを引き起こすことが報告された。1964年から2009年の間に市場から撤退した25の抗肥満薬のうち、23は脳内の化学物質神経伝達物質の機能を変化させることによって作用した。これらの薬剤の最も一般的な副作用は、精神障害、心臓の副作用、および薬物乱用または薬物依存であった。死亡は7つの製品に関連していた。エフェドラは、血圧を上昇させ、脳卒中や死につながる可能性があるという懸念から、2004年に米国市場から削除された。

外部リンク

• Media related to Anti-obesity medication at Wikimedia Commons
• 過体重・肥満治療のための処方薬 米国国立糖尿病・消化器・腎臓病研究所