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, which is released by the gut after eating.

Contents

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 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

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, 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). Pharmaceutical companies have developed dual GLP-1/FGF21 receptor agonists. [4]

Indications

Broad beneficial profile and risks

A large study of more than 2 million people evaluated GLP-1 agonists' benefits and risks. The study showed that GLP-1 agonists reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer’s disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses, and several respiratory conditions. [5] GLP-1 agonists increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis, and drug-induced pancreatitis. [6]

Type 2 diabetes

GLP-1 agonists were initially developed for type 2 diabetes. [7] The 2022 American Diabetes Association (ADA) standards of medical care in diabetes include GLP-1 agonists or SGLT2 inhibitor s 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. [8] [9] One advantage of GLP-1 agonists over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia. [10] 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. [8]

A 2021 meta-analysis found a 12% 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. [11] 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 people with higher eGFR. [12] 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. [12] 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. [13]

The FDA has not approved GLP-1 agonists for type 1 diabetes, but they can be used off-label in addition to insulin to help type 1 diabetes patients improve their body weight and glucose control. [8]

Cardiovascular disease

GLP-1 agonists have demonstrated a cardioprotective effect when used to treat obesity. [14]

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. [15] Some GLP-1 agonists, such as semaglutide, are more effective than other weight loss drugs, but are still less effective than bariatric surgery in causing weight loss. [16] 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. [17] In the brain, GLP-1 agonists reduce weight by crossing the blood-brain barrier in the brain and directly activating the satiety hormones in the ventromedial hypothalamus (Hariyanto, 2021).

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. [18] Semaglutide is in a Phase III study for non-alcoholic steatohepatitis, the more severe form of NAFLD, as of 2023. [19]

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. [20] This usage is off label. [21]

Depression

GLP-1 agonists have shown antidepressant and neuroprotective effects. They can also be used to treat the metabolic consequences of second-generation antipsychotics, such as obesity. [22] [23]

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, though this effect has not been proven in humans. The mechanism of this addiction-reducing effect is unknown. [24] GLP-1 agonists are also under investigation for the treatment of binge eating disorder, the most common eating disorder. [25] [26]

Cancer reduction

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. Compared to people using insulin, 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. Kidney cancers showed an increased risk with GLP-1 treatment relative to those treated with metformin. [27]

Adverse effects

GLP-1 agonists' most common adverse effects are gastrointestinal. [15] These limit the maximum tolerated dose and require gradual dose escalation. [28] Nausea, vomiting, diarrhea, and constipation are all commonly reported. [15] Nausea is directly related to the GLP-1 agonist's serum concentration and is 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. [29]

Human trials and meta-analyses have found no association between the drugs and pancreatitis or pancreatic cancer, but 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. [8] In mice, long-term use of GLP-1 agonists stimulates calcitonin secretion, leading to C-cell hypertrophy and an increased risk of thyroid cancer, but no increased secretion of calcitonin has been observed in humans. [29]

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. [8] 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 drug's efficacy. [29] GLP-1 agonists increase the risk of gallstones when used to induce rapid weight loss. [15]

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 earlier. [30]

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. [31]

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. [32] The study included over 54,000 U.S. adolescents and found a 33% reduction in the risk of suicidal thoughts and attempts among those using the drugs compared to those who did not. [33] Additionally, while adolescents taking GLP-1 drugs experienced more gastrointestinal symptoms, they had a lower risk of acute pancreatitis compared to the control group. [34] A similar study in adults found similar results for semaglutide. [35]

A large study published in Nature Medicine suggested that GLP-1 agonists may result in hypotension (low blood pressure), syncope (fainting), arthritic disorders, nephrolithiasis (kidney stones), interstitial nephritis, and drug-induced pancreatitis. [36]

Drug delivery

Native GLP-1 is a peptide hormone with a half-life of two minutes because it is rapidly cleared by the enzyme dipeptidyl peptidase-4. [29] 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 less often. [29] Most synthetic GLP-1 agonists are delivered via subcutaneous injection, which is a barrier to their use and reason for discontinuation. [37] Most approved by the US FDA are sold as drug-device combination products. [38] Self-injected drugs are especially difficult for people with vision or motor difficulties, which are common in people with type 2 diabetes. [29] Attempts to develop an orally bioavailable GLP-1 agonist, either a modified peptide, as in the case of oral semaglutide, [37] or a small molecule drug, have produced additional drug candidates. [28] Other companies have tested inhaled or transdermal administration. [29]

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. [39] 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% of U.S. patients who stopped using the drugs. [40] According to another study, GLP-1 agonists are not cost-effective for pediatric obesity in the U.S. [41]

Approved

Combination and multiple target drugs

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 increase the amount of weight loss the drugs cause. [48] [28] 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. [28]

GLP-1 agonists are available as combination medications with insulin to treat type 2 diabetes, but it is unclear whether these combination formulas offer an advantage over dosing insulin and GLP-1 agonists separately. [29] [49] The experimental formula cagrilintide/semaglutide combines semaglutide with a dual amylin and calcitonin receptor agonist for additional weight loss. [50]

Off-label and gray market usage

Influencers and celebrities have popularized GLP-1 agonists, causing many people to seek them for cosmetic or health-based weight loss. [51] Gray market sellers offer unauthorized products online claimed to be GLP-1 agonists. This is illegal in the U.S., but some buyers turn to unauthorized retailers after being denied insurance coverage and being unable to afford the name-brand drug. [52] [53] [54] [55] [56] Buyers face risks due to counterfeit or substandard drugs. [57]

In the United States, the FDA declared shortages of injectable versions of semaglutide, tirzepatide, dulaglutide, liraglutide, and exenatide in 2022. The tirzepatide shortage ended in 2024. [58] During a declared shortage, compounding pharmacies are allowed to sell custom-made versions of the drug if they obtain the active pharmaceutical ingredient from an FDA-approved facility. [59] An estimated 95% of online pharmacies were still operating illegally. [60] [61]

History

During the 1980s, Jean-Pierre Raufman of the National Institutes of Health investigated the Gila monster because he was curious about how it eats only once or twice per year. [62] [63] He found that Gila monster venom had biologically active molecules that provoked inflammation of the pancreas in test animals. [62] [64]

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. [62] [63] [64] 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. [63] [64]

Eng's employer, the U.S. Department of Veterans Affairs, had no interest in obtaining a drug patent on exendin-4, so Eng filed the patent application himself in 1993. [63] He then spent three years searching for a pharmaceutical industry partner interested in commercializing exendin-4. [62] [63] [64] In 1996, Amylin Pharmaceuticals licensed Eng's patent and created a synthetic version of exendin-4 called exenatide. [62] [63] [64] In 2002, Eli Lilly entered into an alliance with Amylin to further develop exenatide and secure official approval to market the drug. [65] Exenatide's 2005 approval by the U.S. Food and Drug Administration [66] was a landmark event that 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. [63] [64]

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 lack of interest. [64] The June 2024 conference of the American Diabetes Association in Orlando, Florida, included presentations on at least 27 GLP-1 receptor agonists then in development. [67] By July 2024, Novo Nordisk's semaglutide and Eli Lilly's tirzepatide were ranked among the most popular and lucrative drugs in the world. [68] Novo Nordisk's successful rollout of semaglutide turned it into the most valuable company in Europe in 2024. [69] [70] 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 country's largest taxpayer, and its rapid growth drove nearly all of the expansion of Denmark's economy. [69] [70] By October 2024, tirzepatide had turned Eli Lilly into the world's most valuable drug company, with a $842 billion market capitalization, the highest valuation ever achieved by a drug company, followed only by Novo Nordisk. [71]

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; [72] Oppenheimer, $100 billion by 2034; [73] Goldman Sachs, $100 billion by 2030; [69] BMO Capital Markets, $150 billion by 2033; [74] and Leerink Partners, $158 billion by 2032. [74] The prospect of such an enormous market led dozens of other pharmaceutical companies to initiate development of drugs of the same class. [64] [68]

Related Research Articles

Drugs used in diabetes treat types of diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin.

<span class="mw-page-title-main">Dipeptidyl peptidase-4 inhibitor</span> Enzyme blocker and diabetes treatment drug

Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal peptide hormone involved in glucose homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

Albiglutide is a glucagon-like peptide-1 agonist drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. In 2017 GSK announced Albiglutide's withdrawal from the worldwide market for economic reasons, and remaining stocks in the supply chain were effectively depleted by 2018.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors.

<span class="mw-page-title-main">Setmelanotide</span> Chemical compound

Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.

Semaglutide is an anti-diabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold by Novo Nordisk under the brand names Ozempic and Rybelsus for diabetes, and under the brand name Wegovy for weight management and weight loss.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic and weight loss medication

Tirzepatide is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections. In the United States, it is sold under the brand name Mounjaro for diabetes treatment, and Zepbound for weight loss and treatment of obstructive sleep apnea.

<span class="mw-page-title-main">Orforglipron</span> Chemical compound

Orforglipron (LY-3502970) is an oral, non-peptide, small molecule glucagon-like peptide-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company. It is easier to produce than current peptide GLP-1 agonists and is expected to be cheaper.

Cagrilintide/semaglutide, marketed as CagriSema, is a combination of cagrilintide, a dual amylin and calcitonin receptor agonist, and semaglutide, a GLP-1 agonist. It is injected once weekly and is being tested in type 2 diabetes and obesity. Preliminary trial results found a greater weight loss compared to either medication alone. HbA1c was significantly improved compared to cagrilintide alone and non-significantly better than semaglutide alone. In a Phase II trial, weight loss averaged -15.6 percent after 32 weeks, making CagriSema comparable in efficacy to tirzepatide. A future trial sponsored by Novo Nordisk is comparing tirzepatide and CagriSema head-to-head.

NNC9204-1706 or NN9423 is a GLP-1/GIP/glucagon receptor triple agonist developed by Novo Nordisk. It was evaluated in a clinical trial; adverse effects such as "dose-dependent increases in heart rate and reductions in reticulocyte count, increases in markers of inflammation and hepatic disturbances, and impaired glucose tolerance at the highest dosages" meant that the drug was declared to have an inadequate safety profile and discontinued.

Glucagon receptor agonists are a class of drugs under development for the treatment of obesity, non-alcoholic fatty liver disease, and congenital hyperinsulinism.

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

VK2735 is a dual agonist of the GLP-1 receptor and GIP receptor, with a similar mechanism of action as tirzepatide, which acts on the same receptors. It is injectable and is being developed by Viking Therapeutics.

Lotte Bjerre Knudsen is a Danish scientist and university professor. She led the development of liraglutide and oversaw the development of semaglutide, two notable drugs approved for indications in the treatment of diabetes and obesity.

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