View source for GLP-1 receptor agonist/ja

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'''グルカゴン様ペプチド-1（GLP-1）受容体作動薬'''は、'''GLP-1アナログ'''、'''GLP-1DA'''または'''インクレチン模倣薬'''としても知られており、[[glucagon-like peptide 1 receptor/ja|GLP-1受容体]]を活性化することによって血糖値と[[energy intake/ja|エネルギー摂取量]]を減少させる薬物の一種である。食後に腸から分泌される内因性の[[incretin/ja|インクレチン]]ホルモン[[GLP-1/ja|GLP-1]]の作用を模倣する。 

GLP-1作動薬は当初[[type 2 diabetes/ja|2型糖尿病]]のために開発された。
2022年の[[American Diabetes Association/ja|米国糖尿病学会]]の医療標準では、GLP-1作動薬は2型糖尿病の第一選択薬として、特に[[atherosclerotic cardiovascular disease/ja|動脈硬化性心血管病]]または[[obesity/ja|肥満]]を有する患者に推奨されている。
また、GLP-1作動薬は食事摂取量と体重を有意に減少させることが指摘されており、糖尿病を伴わない肥満の治療薬としても承認されているものもある。
また、[[non-alcoholic fatty liver disease/ja|非アルコール性脂肪肝疾患]]、[[polycystic ovary syndrome/ja|多嚢胞性卵巣症候群]]、依存症などの[[reward system/ja|報酬系]]の疾患など、他の適応症についても開発が進められている。

==作用機序==
{{Anchor|Mechanism of action}}
GLP-1作動薬は、[[GLP-1 receptor/ja|GLP-1受容体]]を活性化することによって作用する。GLP-1作動薬は、[[gastric emptying/ja|胃排出]]を遅らせ、[[glucagon/ja|グルカゴン]]の放出を阻害し、[[insulin/ja|インスリン]]産生を刺激するため、[[type 2 diabetes/ja|2型糖尿病]]の高血糖を軽減する。それらは食物摂取を減少させ、それによって体重も減少させるため、肥満の有効な治療法となっている。別のクラスの抗糖尿病薬である[[dipeptidyl peptidase-4 inhibitor/ja|DPP-4阻害薬]]は、内因性GLP-1の分解を減少させることで作用し、一般的にGLP-1アゴニストよりも効力が弱いと考えられている。げっ歯類におけるGLP-1アゴニストの代謝作用の一部は、線維芽細胞増殖因子21（[[FGF21/ja|FGF21]]）の合成増加を介して媒介される。デュアルGLP-1/FGF21受容体作動薬は、製薬会社によって開発されている。

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==Indications==
===Type 2 diabetes===
GLP-1 agonists were developed initially for [[type 2 diabetes]]. The 2022 [[American Diabetes Association]] (ADA) standards of medical care in diabetes include GLP-1 agonist or [[SGLT2 inhibitor]] as a first line [[pharmacological therapy]] for type 2 diabetes in patients who have or are at high risk for [[atherosclerotic cardiovascular disease]] or [[heart failure]]. They are also a first line treatment for people with both type 2 diabetes and kidney disease. Both types of medication can be combined with [[metformin]]. One of the advantages of GLP-1 agonists over older [[anti-diabetic medication#Secretagogues|insulin secretagogues]], such as [[sulfonylurea]]s or [[meglitinide]]s, is that they have a lower risk of causing [[hypoglycemia]]. The ADA also recommends use of GLP-1 agonists instead of starting insulin in people with type 2 diabetes who need additional glucose control, except where there is catabolism, hyperglycemia above a certain threshold, or autoimmune diabetes is suspected.
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A 2021 meta-analysis found a 12 percent reduction in all-cause mortality when GLP-1 analogs are used in the treatment of type 2 diabetes, as well as significant improvements in cardiovascular and renal outcomes. A meta-analysis including 13 cardiovascular outcome trials found that [[SGLT2 inhibitor|SGLT-2 inhibitor]]s reduce the risk for three-point [[Major adverse cardiovascular events|MACE]], especially in subjects with an [[estimated glomerular filtration rate]] (eGFR) below 60&nbsp;mL/min, whereas GLP-1 receptor agonists were more beneficial in persons with higher eGFR. Likewise, the risk reduction due to SGLT-2 inhibitors was larger in populations with a higher proportion of [[albuminuria]], but this relationship was not observed for GLP-1 receptor agonists. This suggests differential use of the two substance classes in patients with preserved and reduced renal function or with and without [[diabetic nephropathy]], respectively. GLP-1 agonists and SGLT2 inhibitors work to reduce [[HbA1c]] by different mechanisms, and can be combined for enhanced effect. It is also possible that they provide additive cardioprotective effects.
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GLP-1 agonists are not FDA approved for [[type 1 diabetes]], but can be used off-label in addition to insulin to help type 1 diabetes patients improve their body weight and glucose control.
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===Cardiovascular disease===
GLP-1 agonists have demonstrated a cardioprotective effect when used to treat obesity.
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===Obesity===
GLP-1 agonists are recommended as an add-on therapy to lifestyle intervention (calorie restriction and exercise) in people with a [[Body mass index|BMI]] over 30 or a BMI over 27 with at least one weight-related comorbidity. Although some GLP-1 agonists such as semaglutide are more effective than other weight loss drugs, they are still less effective than [[bariatric surgery]] in causing weight loss. GLP-1 agonists' weight reduction effects come from a combination of peripheral effects as well as activity in the brain via the [[central nervous system]].
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===Non-alcoholic fatty liver disease===
GLP-1 agonists are being studied for the treatment of [[non-alcoholic fatty liver disease]] (NAFLD). They are at least as effective as the medications in current use, [[pioglitazone]] and [[Vitamin E]], and significantly reduce steatosis, ballooning necrosis, lobular inflammation, and fibrosis according to a 2023 systematic review. Semaglutide is in a Phase III study for [[non-alcoholic steatohepatitis]], the more severe form of NAFLD, as of 2023.
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===Polycystic ovary syndrome===
GLP-1 agonists are recommended as a treatment for [[polycystic ovary syndrome]], alone or in combination with [[metformin]]. The combination therapy has shown greater efficacy in improving body weight, insulin sensitivity, [[hyperandrogenism]], and [[menstrual cycle]] irregularities. This usage is off label.
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===Depression===
GLP-1 agonists have shown [[antidepressant]] and [[neuroprotective]] effects. They can also be used as treatment for the negative metabolic consequences of [[second-generation antipsychotics]].
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===Reward system disorders===
GLP-1 agonists are under development for [[substance use disorder]], a condition with few pharmacological treatment options. They reduce the self-administered intake of drugs and alcohol in non-human animals, although this effect has not been proven in humans. The mechanism of this addiction-reducing effect is unknown. GLP-1 agonists are also under investigation for the treatment of [[binge eating disorder]], which is the most common eating disorder.
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==Adverse effects==
The most common adverse effects of GLP-1 agonists are gastrointestinal. These adverse effects limit the maximum tolerated dose and require gradual [[dose escalation]]. Nausea is directly related to the serum concentration of the GLP-1 agonist and is more commonly reported, in up to three-quarters, of people using short-acting GLP-1 agonists but fewer of those using long-acting agonists. Reactions at the injection site are also common, especially with shorter acting drugs.
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Human trials and meta-analyses have found no association between the drugs and [[pancreatitis]] or [[pancreatic cancer]]. However, some case reports of pancreatitis have emerged in postmarketing reports, and the [[American Association of Clinical Endocrinologists]] recommends caution in people with a history of pancreatitis. Discontinuation is recommended if acute pancreatitis occurs. A FDA black box warning is required for the risk of [[thyroid C-cell tumors]], and the drugs are contraindicated if there is a family or personal history of [[medullary thyroid cancer]] or [[multiple endocrine neoplasia type 2a]] or [[multiple endocrine neoplasia type 2b|2b]]. In mice, long-term use of GLP-1 agonists stimulates [[calcitonin]] secretion, leading to [[Parafollicular cell|C-cell]] hypertrophy and an increased risk of thyroid cancer. However, no increased secretion of calcitonin has been observed in humans.
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Like insulin, GLP-1 agonists can cause or exacerbate [[retinopathy]], but this is believed to be caused indirectly by a rapid drop in glucose rather than a direct effect. Some patients develop [[anti-drug antibodies]], which are more common with [[exenatide]] (the antibodies were detectable in a third or more of patients) than other GLP-1 agonists and can decrease the efficacy of the drug. GLP-1 agonists increase the risk of [[gallstones]] when used to induce rapid weight loss.
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Patients who take glucagon-like peptide 1 (GLP-1) receptor agonists may be at increased risk of aspiration during anesthesia, due to delayed gastric emptying, according to case reports. In 2023, the American Society of Anesthesiologists suggested holding the GLP-1 agonists on the day of the procedure/surgery or a week prior.
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==Drug delivery==
Native GLP-1 is a peptide hormone with a [[half-life]] of 2 minutes because it is rapidly cleared by the enzyme [[dipeptidyl peptidase-4]]. As a result, different GLP-1 agonist drugs are modified in various ways to extend the half-life, resulting in drugs that can be dosed multiple times per day, daily, weekly, or even less often. Most synthetic GLP-1 agonists are delivered via [[subcutaneous injection]], which is a barrier to their use and reason for discontinuation. Self-injected drugs are especially difficult for people with vision or motor difficulties, which are common in people with type 2 diabetes. Attempts to develop an orally bioavailable GLP-1 agonist, either a modified peptide, as in the case of oral semaglutide, or a [[small molecule]] drug have produced additional drug candidates. Other companies have tested inhaled or [[transdermal]] administration.
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==Cost==
GLP-1 agonists are more expensive than other treatments for type 2 diabetes. A study compared the cost effectiveness of GLP-1 agonists to [[long-acting insulin]] in Taiwanese type 2 diabetes patients. In patients with CVD, GLP-1 agonists were estimated to save money due to fewer cardiovascular incidents. In patients without CVD, the cost per QALY was $9,093. In the United States, cost is the highest barrier to GLP-1 agonist usage and was reported as the reason for discontinuation in 48.6 percent of US patients who stopped using the drugs. According to another study, GLP-1 agonists are not cost effective for pediatric obesity in the United States.
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==Approved==
*[[exenatide]] (brand names Byetta and Bydureon, manufactured by [[AstraZeneca]]), approved in 2005/2012
*[[liraglutide]] (Victoza for diabetes, Saxenda for obesity, manufactured by [[Novo Nordisk]]), approved in 2010
*[[albiglutide]] (Tanzeum, manufactured by [[GlaxoSmithKline|GSK]]), approved in 2014
*[[dulaglutide]] (Trulicity, manufactured by [[Eli Lilly and Company|Eli Lilly]]), approved in 2014
*[[lixisenatide]] (Lyxumia in Europe, Adlyxin in the United States, manufactured by [[Sanofi]]), approved in 2016
*[[semaglutide]] (Ozempic and Rybelsus for diabetes, Wegovy for obesity, manufactured by Novo Nordisk), approved in 2017
*[[tirzepatide]] (dual GLP-1 and [[Gastric inhibitory polypeptide receptor|GIP]] agonist; Mounjaro for diabetes, Zepbound for obesity, manufactured by Eli Lilly), approved in 2022
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==Combination and multiple target drugs==
{{see also|GLP1 poly-agonist peptides}}
Some GLP-1 agonists, such as [[tirzepatide]], are also agonists of the [[GIP receptor]] and/or [[glucagon receptor]]. These additional targets are hoped to improve the amount of weight loss caused by the drugs. Combination with glucagon agonism is likely to make the drugs more efficacious for weight loss, at the expense of additional risk and a lower [[therapeutic index]].
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GLP-1 agonists are available as combination medications with insulin to treat type 2 diabetes, although it is unclear whether these combination formulas offer an advantage over dosing insulin and GLP-1 agonists separately. The experimental formula [[cagrilintide/semaglutide]] combines semaglutide with a [[dual amylin and calcitonin receptor agonist]] for additional weight loss.
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==Off-label and recreational use==
Besides their medical uses, GLP-1 agonists are also sought by many people for cosmetic weight loss, popularized by [[influencer]]s and [[celebrities]]. [[Gray market]] sellers offer unauthorized products claimed to be GLP-1 agonists online. This practice is illegal in the United States, but some buyers turn to unauthorized retailers due to being denied insurance coverage and not being able to afford the name brand drug. Buyers face risks due to counterfeit or substandard drugs sold by unauthorized sellers.
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{{Oral hypoglycemics and insulin analogs}}
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{{二次利用|date=1 January 2024}}
[[Category:GLP-1 receptor agonists| ]]
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