GLP-1 receptor agonist

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Glucagon-like peptide-1 analog
)

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics,

GLP-1
that is released by the gut after eating.

GLP-1 agonists were initially developed for

non-alcoholic fatty liver disease, polycystic ovary syndrome, and diseases of the reward system such as addictions
.

Mechanism of action

GLP-1 agonists work by activating the

FGF21). Dual GLP-1/FGF21 receptor agonists have been developed by pharmaceutical companies.[4]

Indications

Type 2 diabetes

GLP-1 agonists were developed initially for

insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia.[8] 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.[6]

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.

HbA1c by different mechanisms, and can be combined for enhanced effect. It is also possible that they provide additive cardioprotective effects.[11]

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.[6]

Cardiovascular disease

GLP-1 agonists have demonstrated a cardioprotective effect when used to treat obesity.[12]

Obesity

GLP-1 agonists are recommended as an add-on therapy to lifestyle intervention (calorie restriction and exercise) in people with a BMI over 30 or a BMI over 27 with at least one weight-related comorbidity.[13] 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.[14] The weight reduction effects of GLP-1 agonists come from a combination of peripheral effects as well as activity in the brain via the central nervous system.[15]

Non-alcoholic fatty liver disease

GLP-1 agonists are being studied for the treatment of

non-alcoholic steatohepatitis, the more severe form of NAFLD, as of 2023.[17]

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.[18] This usage is off label.[19]

Depression

GLP-1 agonists have shown

second-generation antipsychotics such as obesity.[20][21]

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.[22] GLP-1 agonists are also under investigation for the treatment of binge eating disorder, which is the most common eating disorder.[23][24]

Adverse effects

The most common adverse effects of GLP-1 agonists are gastrointestinal.[13] These adverse effects limit the maximum tolerated dose and require gradual dose escalation.[25] Nausea, vomiting, diarrhea, and constipation are all commonly reported.[13] Nausea is directly related to the serum concentration of the GLP-1 agonist and is reported in up to three-quarters of people using short-acting GLP-1 agonists but in fewer of those using long-acting agonists. Reactions at the injection site are also common, especially with shorter acting drugs.[26]

Human trials and meta-analyses have found no association between the drugs and

2b.[6] In mice, long-term use of GLP-1 agonists stimulates calcitonin secretion, leading to C-cell hypertrophy and an increased risk of thyroid cancer. However, no increased secretion of calcitonin has been observed in humans.[26]

Like insulin, GLP-1 agonists can cause or exacerbate

gallstones when used to induce rapid weight loss.[13]

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.[27]

As of March 2024, there are 58 personal injury lawsuits for gastroparesis, ileus and intestinal blockage or obstruction in MDL 3094 before Judge Gene E.K. Pratter in the Eastern District of Pennsylvania.[28]

Drug delivery

Native GLP-1 is a peptide hormone with a

combination products.[30] Self-injected drugs are especially difficult for people with vision or motor difficulties, which are common in people with type 2 diabetes.[26] Attempts to develop an orally bioavailable GLP-1 agonist, either a modified peptide, as in the case of oral semaglutide,[29] or a small molecule drug have produced additional drug candidates.[25] Other companies have tested inhaled or transdermal administration.[26]

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.[31] 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.[32] According to another study, GLP-1 agonists are not cost effective for pediatric obesity in the United States.[33]

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[34]
  • GSK), approved in 2014[35]
  • dulaglutide (Trulicity, manufactured by Eli Lilly), approved in 2014[36]
  • lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured by Sanofi), approved in 2016[37]
  • semaglutide (Ozempic and Rybelsus for diabetes, Wegovy for obesity, manufactured by Novo Nordisk), approved in 2017[38]
  • tirzepatide (dual GLP-1 and GIP agonist; Mounjaro for diabetes, Zepbound for obesity, manufactured by Eli Lilly), approved in 2022[39]

Combination and multiple target drugs

See also: GLP1 poly-agonist peptides

Some GLP-1 agonists, such as

GIP receptor and/or glucagon receptor. These additional targets are hoped to improve the amount of weight loss caused by the drugs.[25] 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.[25]

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.

dual amylin and calcitonin receptor agonist for additional weight loss.[41]

Off-label and recreational use

Besides their medical uses, GLP-1 agonists are also sought by many people for cosmetic weight loss, popularized by

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.[43][44][45][46][47] Buyers face risks due to counterfeit or substandard drugs sold by unauthorized sellers.[48]

References

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