GLP-1 receptor agonist: Difference between revisions

{{Short description|Agonist of the GLP-1 receptor used in the treatment of type 2 diabetes}}

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!一般名

GLP-1 agonists were initially developed for [[type 2 diabetes]]. The 2022 [[American Diabetes Association]] standards of medical care recommend GLP-1 agonists as a first line therapy for type 2 diabetes, specifically in patients with [[atherosclerotic cardiovascular disease]] or [[obesity]]. The drugs were also noted to reduce food intake and body weight significantly, and some have also been approved to treat obesity in the absence of diabetes. They are also in development for other indications, such as [[non-alcoholic fatty liver disease]], [[polycystic ovary syndrome]], and diseases of the [[reward system]] such as addictions.

GLP-1 agonists work by activating the [[GLP-1 receptor]]. They slow [[gastric emptying]], inhibit the release of [[glucagon]], and stimulate [[insulin]] production, therefore reducing hyperglycemia in people with [[type 2 diabetes]]. They also reduce food intake and therefore body weight, making them an effective treatment for obesity. Another class of anti-diabetes drugs, the [[dipeptidyl peptidase-4 inhibitor|DPP-4 inhibitors]], work by reducing the breakdown of endogenous GLP-1, and are generally considered less potent than GLP-1 agonists. Some of the metabolic effects of GLP-1 agonists in rodents are mediated via increased synthesis of fibroblast growth factor 21 ([[FGF21]]). Dual GLP-1/FGF21 receptor agonists have been developed by pharmaceutical companies.

===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.

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.

GLP-1 agonists have demonstrated a cardioprotective effect when used to treat 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]].

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.

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.

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]].

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.

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.

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.

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.

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.

*[[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

*[[tirzepatide]] (dual GLP-1 and [[Gastric inhibitory polypeptide receptor|GIP]] agonist; Mounjaro for diabetes, Zepbound for obesity, manufactured by Eli Lilly), approved in 2022

{{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]].

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.

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.