GLP-1 Receptor Agonist
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Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1RAs, or incretin mimetics, are a class of
anorectic An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...
drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous
incretin Incretins are a group of metabolic hormones that decrease Blood sugar level, blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from Pancreas, pancreatic beta cells of the islets of Langerhans ...
hormone
GLP-1 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 certai ...
, which is released by the gut after eating. GLP-1 agonists were initially developed for
type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
. The 2022
American Diabetes Association The American Diabetes Association (ADA) is a United States-based nonprofit that seeks to educate the public about diabetes and to help those affected by it through funding research to manage, cure and prevent diabetes, including type 1 diabetes ...
standards of medical care recommend GLP-1 agonists as a first-line therapy for type 2 diabetes, specifically in patients with
atherosclerotic cardiovascular disease Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
or
obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
. The drugs were also noted to reduce food intake and body weight significantly, and some have been approved to treat obesity and other components of the
metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...
in the absence of diabetes. They are also in development for other indications, such as
non-alcoholic fatty liver disease An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...
,
polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...
, and diseases of the
reward system The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and c ...
such as
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
s.


Mechanism of action

GLP-1 agonists work by activating the GLP-1 receptor. They slow gastric emptying, inhibit the release of
glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
, and stimulate
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
production, thereby improving glucose homeostasis and reducing the risk of
hyperglycemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluc ...
in people with
type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
. They also significantly reduce food intake, promote the development of a negative energy balance, and potently decrease body weight over time, making them an effective treatment for obesity. Another class of anti-diabetes drugs,
DPP-4 inhibitors Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that Enzyme inhibitors, block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2. The first agent of ...
, 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 Fibroblast growth factor 21 (FGF-21) is a protein that in mammals is encoded by the ''FGF21'' gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily whi ...
). Pharmaceutical companies have developed dual GLP-1/FGF21 receptor agonists.


Indications


Broad beneficial profile and risks

A retrospective cohort study of more than 2 million people evaluated GLP-1 agonists' benefits and risks compared to other anti-diabetic medications. The study suggested 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. GLP-1 agonists increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis, and drug-induced pancreatitis.


Type 2 diabetes

GLP-1 agonists were initially developed for
type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
. The 2022
American Diabetes Association The American Diabetes Association (ADA) is a United States-based nonprofit that seeks to educate the public about diabetes and to help those affected by it through funding research to manage, cure and prevent diabetes, including type 1 diabetes ...
(ADA) standards of medical care in diabetes include GLP-1 agonists or
SGLT2 inhibitor SGLT2 inhibitors (also called gliflozins or flozins) are a class of medications that inhibit sodium-glucose transport proteins in the nephron (the functional units of the kidney), unlike SGLT1, SGLT1 inhibitors that perform a similar function in ...
s as a first-line pharmacological therapy for type 2 diabetes in patients who have or are at high risk for
atherosclerotic cardiovascular disease Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
or
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
. 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 Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...
. One advantage of GLP-1 agonists over older insulin secretagogues, such as
sulfonylurea Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea ...
s or meglitinides, is that they have a lower risk of causing
hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...
. 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 Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...
, hyperglycemia above a certain threshold, or
autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
diabetes is suspected. 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. A meta-analysis including 13 cardiovascular outcome trials found that
SGLT-2 inhibitor SGLT2 inhibitors (also called gliflozins or flozins) are a class of medications that inhibit sodium-glucose transport proteins in the nephron (the functional units of the kidney), unlike SGLT1 inhibitors that perform a similar function in the i ...
s reduce the risk for three-point MACE, especially in subjects with an
estimated glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearance (medicine), clearing toxins; absorption of glucose, amino acids, and other small molecules; reg ...
(eGFR) below 60 mL/min, whereas GLP-1 receptor agonists were more beneficial in people with higher eGFR. Likewise, the risk reduction due to SGLT-2 inhibitors was larger in populations with a higher proportion of
albuminuria Albuminuria is a pathological condition of elevated albumin protein in the urine (often measured as urine albumin-to-creatinine ratio of >30 milligrams of albumin per 1 gram of creatinine per day). It is a type of proteinuria, and is the most com ...
, 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 Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) and end-stage renal disease ...
, respectively. GLP-1 agonists and SGLT2 inhibitors work to reduce
HbA1c Glycated hemoglobin, also called glycohemoglobin, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose, and fructose, spontaneously (that is, non-enzymatically) bond with hemoglob ...
by different mechanisms, and can be combined for enhanced effect. It is also possible that they provide additive cardioprotective effects. The FDA has not approved GLP-1 agonists for
type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone require ...
, but they can be used
off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...
in addition to insulin to help type 1 diabetes patients improve their body weight and glucose control.


Cardiovascular disease

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


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. Some GLP-1 agonists, such as semaglutide, are more effective than other weight loss drugs, but are still less effective than
bariatric surgery Bariatric surgery (also known as metabolic surgery or weight loss surgery) is a surgical procedure used to manage obesity and obesity-related conditions. Long term weight loss with bariatric surgery may be achieved through alteration of gut ho ...
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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
. 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).


Metabolic dysfunction–associated steatotic liver disease

GLP-1 agonists are being studied for the treatment of
metabolic dysfunction–associated steatotic liver disease Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a type of chronic liver disease. This condition is diagnosed when there is excessive fat build-up in the l ...
(MASLD). They are at least as effective as the medications in current use,
pioglitazone Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not ...
and
Vitamin E Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen speci ...
, and significantly reduce steatosis, ballooning necrosis, lobular inflammation, and fibrosis according to a 2023 systematic review. Semaglutide is in a Phase III study for MASH, a more severe form of MASLD, as of 2023.


Polycystic ovary syndrome

GLP-1 agonists are recommended as a treatment for
polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...
, alone or in combination with
metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...
. The combination therapy has shown greater efficacy in improving body weight, insulin sensitivity,
hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infre ...
, and
menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...
irregularities. This usage is off label.


Depression

GLP-1 agonists have shown
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
and neuroprotective effects. They can also be used to treat the metabolic consequences of
second-generation antipsychotics The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurole ...
, such as obesity.


Reward system disorders

GLP-1 agonists are under development for
substance use disorder Substance use disorder (SUD) is the persistent use of drugs despite substantial harm and adverse consequences to self and others. Related terms include ''substance use problems'' and ''problematic drug or alcohol use''. Along with substance-ind ...
, 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. GLP-1 agonists are also under investigation for the treatment of
binge eating disorder Binge eating disorder (BED) is an eating disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without the compensatory behaviors common to bulimia nervosa, OSFE ...
, the most common eating disorder.


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.


Adverse effects

GLP-1 agonists' most common adverse effects are gastrointestinal. These limit the maximum tolerated dose and require gradual dose escalation. Nausea, vomiting, diarrhea, and constipation are all commonly reported. 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. Human trials and meta-analyses have found no association between the drugs and
pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...
or
pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of ...
, 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. The FDA requires a
boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
in the package inserts of GLP-1 agonists due to the risk of thyroid C-cell tumors, including
medullary thyroid cancer Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...
(MTC), with a warning that GLP-1 agonists are contraindicated in patients with a family or personal history of MTC or
multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma (codons 630 and 634) and amyloid producing medullary thyroid carcinoma", "PTC syndrome," and "Sipple syndrome") is a group of medical disorders associated with tumors of the endo ...
. In mice, long-term use of GLP-1 agonists stimulates
calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the ...
secretion, leading to C-cell hypertrophy and an increased risk of thyroid cancer, but no increased secretion of calcitonin has been observed in humans. GLP-1 agonists appear to significantly increase the risk of non-diabetic retinopathy, although further research is needed to establish if the observed association is
causal Causality is an influence by which one Event (philosophy), event, process, state, or Object (philosophy), object (''a'' ''cause'') contributes to the production of another event, process, state, or object (an ''effect'') where the cause is at l ...
. Some patients develop anti-drug antibodies, which are more common with
exenatide 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 sulf ...
(the antibodies were detectable in a third or more of patients) than other GLP-1 agonists and can decrease the drug's efficacy. GLP-1 agonists increase the risk of
gallstones A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of ...
when used to induce rapid weight loss. Patients who take GLP-1 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. As of March 2024, there are 58 personal injury lawsuits for
gastroparesis Gastroparesis (gastro- from Ancient Greek  – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis") is a medical disorder of ineffective neuromuscular contractions (peristalsis) of the stomach, resulting in food and l ...
,
ileus Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction. The word 'ileus' derives . The term 'subileus' refers to a partial obstruction. Signs and symptoms S ...
and intestinal blockage or obstruction in MDL 3094 before Judge Gene E.K. Pratter in the Eastern District of Pennsylvania. A study published in '' JAMA Pediatrics'' suggests that GLP-1 weight-loss medications do not increase the risk of
suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...
or suicidal thoughts in children and adolescents, contrary to some previous concerns. 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. Additionally, while adolescents taking GLP-1 drugs experienced more gastrointestinal symptoms, they had a lower risk of
acute pancreatitis Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes include a gallstone impacted in the common bile duct or the pancreatic duct, heavy alcohol use, systemic disease, trauma, elevated calcium levels, hypertriglyceridemia (w ...
compared to the control group. A similar study in adults found similar results for semaglutide. 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.


Drug delivery

Native GLP-1 is a peptide hormone with a
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
of two 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 less often. Most synthetic GLP-1 agonists are delivered via
subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...
, which is a barrier to their use and reason for discontinuation. Most approved by the
US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
are sold as drug-device combination products. 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 In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; ...
drug, have produced additional drug candidates. Other companies have tested inhaled or
transdermal Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointm ...
administration.


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 The quality-adjusted life year (QALY) is a generic measure of disease burden, including both the quality and the quantity of life lived. It is used in economic evaluation to assess the value of medical interventions. One QALY equates to one year ...
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% of U.S. patients who stopped using the drugs. According to another study, GLP-1 agonists are not cost-effective for pediatric obesity in the U.S.


Approved

*
exenatide 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 sulf ...
(brand names Byetta and Bydureon, manufactured by
AstraZeneca AstraZeneca plc () (AZ) is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, UK. It has a portfolio of products for major diseases in areas includi ...
), approved in 2005/2012 *
liraglutide Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects ...
(Victoza for diabetes, Saxenda for obesity, manufactured by
Novo Nordisk Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, with production facilities in nine countries and affiliates or offices in five. Novo Nordisk is controlled by majority shareholder Novo Holdings A/S ...
), approved in 2010 * albiglutide (Tanzeum, manufactured by GSK), approved in 2014 *
dulaglutide 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 cardio ...
(Trulicity, manufactured by
Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was a Union Army officer, pharmacist, chemist, and businessman who founded Eli Lilly and Company. Lilly enlisted in the Union Army during the American Civil War and recruited a company of men to ...
), approved in 2014 * lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured by
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
), approved in 2016 *
semaglutide Semaglutide is an anti-diabetic medication used for the treatment of type2 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 ...
(Ozempic and Rybelsus for diabetes, Wegovy for obesity, manufactured by Novo Nordisk), approved in 2017 * tirzepatide (dual GLP-1 and GIP agonist; Mounjaro for diabetes, Zepbound for obesity, manufactured by Eli Lilly), approved in 2022


Combination and multiple target drugs

Some GLP-1 agonists, such as tirzepatide, are also agonists of the GIP receptor,
glucagon receptor The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors ( secretin receptor family), coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation o ...
, and/or
amylin receptor The amylin receptors (AMYRs) are heterodimers of the calcitonin receptor and receptor activity modifying proteins (RAMPs). They are bound to by amylin with high affinity and consist of AMY1, AMY2, and AMY3. Amylin mimetics that are agonists at t ...
. These additional targets are hoped to increase the amount of weight loss the drugs cause. 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 The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...
. 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. The experimental formula cagrilintide/semaglutide combines semaglutide with a dual amylin and calcitonin receptor agonist for additional weight loss.


Off-label and gray market usage

Influencer A social media influencer, or simply influencer (also known as an online influencer), is a person who builds a grassroots online presence through engaging content such as photos, videos, and updates. This is done by using direct audience intera ...
s and
celebrities Celebrity is a condition of fame and broad public recognition of a person or group due to the attention given to them by mass media. The word is also used to refer to famous individuals. A person may attain celebrity status by having great w ...
have popularized GLP-1 agonists, causing many people to seek them for cosmetic or health-based weight loss.
Gray market A grey market or dark market (sometimes confused with the similar term " parallel market") is the trade of a commodity through distribution channels that are not authorised by the original manufacturer or trademark proprietor. Grey market prod ...
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. Buyers face risks due to counterfeit or substandard drugs. In the United States, the FDA declared shortages of injectable versions of
semaglutide Semaglutide is an anti-diabetic medication used for the treatment of type2 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 ...
, tirzepatide,
dulaglutide 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 cardio ...
,
liraglutide Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects ...
, and
exenatide 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 sulf ...
in 2022. The tirzepatide shortage ended in 2024. During a declared shortage, compounding pharmacies are allowed to sell custom-made versions of the drug if they obtain the
active pharmaceutical ingredient An active ingredient is any ingredient that provides biological activity, biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of ...
from an FDA-approved facility. An estimated 95% of online pharmacies were still operating illegally.The U.S.
National Association of Boards of Pharmacy National Association of Boards of Pharmacy (NABP) is a 501(c)(3) nonprofit organization that assists member boards of pharmacy for the purpose of protecting public health. It has 54 active members and 12 associate members. Active member boards inc ...
operates
search tool
to identify properly licensed online pharmacies.


History

During the 1980s, Jean-Pierre Raufman of the
National Institutes of Health The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
investigated the
Gila monster The Gila monster (''Heloderma suspectum'', ) is a species of venomous lizard native to the Southwestern United States and the northwestern Mexico, Mexican state of Sonora. It is a heavy, slow-moving reptile, up to long, and it is the only ve ...
because he was curious about how it eats only once or twice per year. He found that Gila monster venom had biologically active molecules that provoked inflammation of the pancreas in test animals. In 1992, after learning of Raufman's findings, John Eng of the Veterans Administration Medical Center in New York City used the
radioimmunoassay A radioimmunoassay (RIA) is an immunoassay that uses radioactive tracer, radiolabeled molecules in a stepwise formation of immune complexes. A RIA is a very sensitive in vitro assay technique used to measure concentrations of substances, usually m ...
technique he had learned from Nobel laureate
Rosalyn Sussman Yalow Rosalyn Sussman Yalow (July 19, 1921 – May 30, 2011) was an American medical physicist, and a co-winner of the 1977 Nobel Prize in Physiology or Medicine (together with Roger Guillemin and Andrew Schally) for development of the radioimmunoass ...
to isolate a novel substance from Gila monster venom. 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. Eng's employer, the U.S. Department of Veterans Affairs, had no interest in obtaining a
drug patent A chemical patent, pharmaceutical patent or drug patent is a patent for an invention in the chemical or pharmaceuticals industry. Strictly speaking, in most jurisdictions, there are essentially no differences between the legal requirements to o ...
on exendin-4, so Eng filed the
patent application A patent application is a request pending at a patent office for the grant of a patent for an invention described in the patent specification and a set of one or more claim (patent), claims stated in a formal document, including necessary officia ...
himself in 1993. He then spent three years searching for a
pharmaceutical industry The pharmaceutical industry is a medical industry that discovers, develops, produces, and markets pharmaceutical goods such as medications and medical devices. Medications are then administered to (or self-administered by) patients for curing ...
partner interested in commercializing exendin-4. In 1996, Amylin Pharmaceuticals licensed Eng's patent and created a synthetic version of exendin-4 called exenatide. In 2002, Eli Lilly entered into an alliance with Amylin to further develop exenatide and secure official approval to market the drug. Exenatide's 2005 approval by the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
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. 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. The June 2024 conference of the
American Diabetes Association The American Diabetes Association (ADA) is a United States-based nonprofit that seeks to educate the public about diabetes and to help those affected by it through funding research to manage, cure and prevent diabetes, including type 1 diabetes ...
in
Orlando, Florida Orlando ( ) is a city in and the county seat of Orange County, Florida, United States. The city proper had a population of 307,573 at the 2020 census, making it the fourth-most populous city in Florida behind Jacksonville, Florida, Jacksonville ...
, included presentations on at least 27 GLP-1 receptor agonists then in development. By July 2024, Novo Nordisk's semaglutide and Eli Lilly's tirzepatide were ranked among the most popular and lucrative drugs in the world. Novo Nordisk's successful rollout of semaglutide turned it into the most valuable company in Europe in 2024. 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. 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. 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 GlobalData Plc is a data analytics and consulting company, headquartered in London, England. The company was established in 1999, and, under different names, has been listed on the London Stock Exchange's Alternative Investment Market (AIM) since ...
, $125 billion by 2033; Oppenheimer, $100 billion by 2034;
Goldman Sachs The Goldman Sachs Group, Inc. ( ) is an American multinational investment bank and financial services company. Founded in 1869, Goldman Sachs is headquartered in Lower Manhattan in New York City, with regional headquarters in many internationa ...
, $100 billion by 2030;
BMO Capital Markets BMO Capital Markets is the investment banking subsidiary of Canadian Bank of Montreal. The company offers corporate, institutional and government clients access to a range of financial services. These include equity and debt underwriting, corp ...
, $150 billion by 2033; and Leerink Partners, $158 billion by 2032. The prospect of such an enormous market led dozens of other pharmaceutical companies to initiate development of drugs of the same class.


References

{{Oral hypoglycemics and insulin analogs