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GLP-1 receptor agonist

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Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics,[1] are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

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.

Mechanism of action

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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.[2] Another class of anti-diabetes drugs, the DPP-4 inhibitors, work by reducing the breakdown of endogenous GLP-1, and are generally considered less potent than GLP-1 agonists.[3] 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.[4]

Indications

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Type 2 diabetes

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GLP-1 agonists were developed initially for type 2 diabetes.[5] 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.[6][7] One of the advantages of GLP-1 agonists over older 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.[9] A meta-analysis including 13 cardiovascular outcome trials found that SGLT-2 inhibitors reduce the risk for three-point MACE, especially in subjects with an estimated glomerular filtration rate (eGFR) below 60 mL/min, whereas GLP-1 receptor agonists were more beneficial in persons with higher eGFR.[10] 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.[10] 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.[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

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

Obesity

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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] In the brain, GLP-1 agonists reduce weight by crossing the blood-brain barrier in the brain and directly activate the satiety hormones in the ventromedial hypothalamus (Hariyanto, 2021).

Non-alcoholic fatty liver disease

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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.[16] Semaglutide is in a Phase III study for non-alcoholic steatohepatitis, the more severe form of NAFLD, as of 2023.[17]

Polycystic ovary syndrome

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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

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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 such as obesity.[20][21]

Reward system disorders

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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]

Cancer reduction

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In a retrospective study, GLP-1 exposure was associated with lower risks of specific types of obesity associated cancers compared with insulin or metformin in patients with Type 2 Diabetes. The patients taking GLP-1 agonists showed significant risk reduction in esophageal, colorectal, endometrial, gallbladder, kidney, liver, ovarian, and pancreatic cancer as well as meningioma and multiple myeloma compared to people using insulin. Kidney cancers showed an increased risk with GLP-1 treatment relative to those treated with metformin. [25]

Adverse effects

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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.[26] 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.[27]

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 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.[27]

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.[6] 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.[27] GLP-1 agonists increase the risk of 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.[28]

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.[29]

A study published in JAMA Pediatrics suggests that GLP-1 weight-loss medications do not increase the risk of suicide or suicidal thoughts in children and adolescents, contrary to some previous concerns.[30] The study which included over 54,000 U.S. adolescents found a 33% reduction in the risk of suicidal thoughts and attempts among those using the drugs compared to those who did not.[31] Additionally while adolescents taking GLP-1 drugs experienced more gastrointestinal symptoms, they had a lower risk of acute pancreatitis compared to the control group.[32] A similar study in adults found similar results for semaglutide.[33]

Drug delivery

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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.[27] 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.[27] Most synthetic GLP-1 agonists are delivered via subcutaneous injection, which is a barrier to their use and reason for discontinuation.[34] Most approved by the US FDA are sold as drug-device combination products.[35] Self-injected drugs are especially difficult for people with vision or motor difficulties, which are common in people with type 2 diabetes.[27] Attempts to develop an orally bioavailable GLP-1 agonist, either a modified peptide, as in the case of oral semaglutide,[34] or a small molecule drug have produced additional drug candidates.[26] Other companies have tested inhaled or transdermal administration.[27]

Cost

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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.[36] 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.[37] According to another study, GLP-1 agonists are not cost effective for pediatric obesity in the United States.[38]

Approved

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Combination and multiple target drugs

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See also: GLP1 poly-agonist peptides

Some GLP-1 agonists, such as tirzepatide, are also agonists of the GIP receptor, glucagon receptor, and/or amylin receptor. These additional targets are hoped to improve the amount of weight loss caused by the drugs.[45][26] 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.[26]

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.[27][46] The experimental formula cagrilintide/semaglutide combines semaglutide with a dual amylin and calcitonin receptor agonist for additional weight loss.[47]

Off-label and gray market usage

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Besides their medical uses, GLP-1 agonists are also sought by many people for cosmetic or health-based weight loss, popularized by influencers and celebrities.[48] Gray market sellers offer unauthorized products claimed to be GLP-1 agonists online. This practice is illegal in the US, but some buyers turn to unauthorized retailers due to being denied insurance coverage and not being able to afford the name brand drug.[49][50][51][52][53] Buyers face risks due to counterfeit or substandard drugs sold by unauthorized sellers.[54]

History

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During the 1980s, Jean-Pierre Raufman of the National Institutes of Health investigated the Gila monster because he was curious about how it only eats once or twice per year.[55][56] He found that Gila monster venom had biologically active molecules which provoked inflammation of the pancreas in test animals.[55][57]

In 1992, after learning of Raufman's findings, John Eng of the Veterans Administration Medical Center in New York City used the radioimmunoassay technique he had learned from Nobel laureate Rosalyn Sussman Yalow to isolate a novel substance from Gila monster venom.[55][56][57] The new substance, which Eng called exendin-4, was similar to GLP-1 in that it reduced blood glucose in diabetic mice, but exendin-4 had a much longer half-life than GLP-1, whose extremely short half-life had defeated earlier attempts to turn it into a drug.[56][57]

Eng's employer, the U.S. Department of Veterans Affairs, turned out to have no interest in obtaining a drug patent on exendin-4, so Eng filed the patent application himself in 1993.[56] He then spent three years searching for a pharmaceutical industry partner interested in commercializing exendin-4.[55][56][57] In 1996, Amylin Pharmaceuticals licensed Eng's patent and created a synthetic version of exendin-4 called exenatide.[55][56][57] In 2002, Eli Lilly entered into an alliance with Amylin to further develop exenatide and secure official approval to market the drug.[58] Exenatide's 2005 approval by the U.S. Food and Drug Administration[59] was a landmark event which proved that targeting the GLP-1 receptor was a viable strategy and inspired other pharmaceutical companies to focus their research and development on that receptor.[56][57]

Thirty years later, the pharmaceutical industry had come full circle from the mid-1990s, when Eng was attending one conference after another to present his poster about exendin-4 and was repeatedly met with a depressing lack of interest.[57] The June 2024 conference of the American Diabetes Association in Orlando, Florida included presentations on at least 27 GLP-1 receptor agonists currently in development.[60] By July 2024, Novo Nordisk's semaglutide and Eli Lilly's tirzepatide were ranked among the most popular and lucrative drugs in the world.[61] Novo Nordisk's successful rollout of semaglutide turned it into the most valuable company in Europe in 2024.[62][63] Its market capitalization of $570 billion was larger than the entire economy of its home country of Denmark, its $2.3 billion income tax bill for 2023 made it the largest taxpayer in the country, and its rapid growth was driving nearly all of the expansion of Denmark's economy.[62][63] By October 2024, tirzepatide had turned Eli Lilly into the most valuable drug company in the world with a $842 billion market capitalization, the highest valuation ever achieved by a drug company to date, followed only by Novo Nordisk.[64]

During 2024, several financial analysts estimated that GLP-1 receptor agonist drugs could bring in over $100 billion in annual revenue by the 2030s, differing only on the exact number and the year by which it would be achieved: GlobalData, $125 billion by 2033;[65] Oppenheimer, $100 billion by 2034;[66] Goldman Sachs, $100 billion by 2030;[62] BMO Capital Markets, $150 billion by 2033;[67] and Leerink Partners, $158 billion by 2032.[67] The prospect of such an enormous potential market led dozens of other pharmaceutical companies to initiate development of newer drugs of the same class.[57][61]

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