GLP1 poly-agonist peptides are a class of drugs that activate multiple

peptide hormone Peptide hormones are hormones composed of peptide molecules. These hormones influence the endocrine system of animals, including humans. Most hormones are classified as either amino-acid-based hormones (amines, peptides, or proteins) or steroid h ...

receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as

GLP-1 receptor agonist Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1RAs, or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of ...

s—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 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 ...

. The first such drug to receive approval is

tirzepatide Tirzepatide is an antidiabetic medication used to treat type2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections (under the skin). In the United States, it is sold under the brand name Mounjaro for diabetes ...

, a dual agonist of GLP-1 and

GIP receptor The gastric inhibitory polypeptide receptor (GIP-R), also known as the glucose-dependent insulinotropic polypeptide receptor, is a protein that in humans is encoded by the ''GIPR'' gene. GIP-R is a member of the class B family of G protein c ...

GLP-1 and GIP receptor dual agonists

Tirzepatide Tirzepatide is an antidiabetic medication used to treat type2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections (under the skin). In the United States, it is sold under the brand name Mounjaro for diabetes ...

, a dual agonist of GLP-1 and

s, is approved for type 2 diabetes and obesity. With an average 20 percent weight loss at a high dosage, it appears to be more effective than GLP-1 mono agonists although there have been no head to head trials as of 2023.

GLP-1 and glucagon receptor dual agonists

Glucagon is a hormone that generally opposes the action of

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 ...

. It increases blood glucose by stimulating the production of glucose in the liver via

glycogenolysis Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase. Mechanis ...

(breakdown of

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body. Glycogen functions as one of three regularly used forms ...

) and

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...

(production of glucose from non-carbohydrate sources). Glucagon also increases the breakdown of lipids and

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s and the production of

ketones In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

. Unlike currently approved

weight loss drug 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 con ...

s, glucagon receptor agonists increase

energy expenditure Energy expenditure, often estimated as the total daily energy expenditure (TDEE), is the amount of energy burned by the human body. Causes of energy expenditure Resting metabolic rate Resting metabolic rate generally composes 60 to 75 percent of ...

. Combination GLP-1/glucagon receptor agonists provide the thermogenic benefits of glucagon activation while almost eliminating hyperglycemia induced by glucagon receptor activation. Several such drugs have reached human trials for obesity, diabetes, and non-alcoholic fatty liver disease but adverse effects have hampered development. The most advanced of these drugs is

mazdutide Mazdutide (also known as IBI362 or LY3305677) is a dual agonist of the GLP-1 receptor and glucagon receptor. It is an analog of oxyntomodulin (OXM). The drug is developed by Eli Lilly and is currently in multiple Phase III studies. In May 2025, a ...

which is in a phase III trial as of 2023.

GLP-1, GIP, and glucagon receptor triple agonists

Following the discovery of GLP-1/GIP and GLP-1/glucagon dual agonists, it was hoped that a triple agonist would provide additive or synergistic metabolic benefits. A clinical trial of the triple agonist

retatrutide Retatrutide (LY-3437943) is an experimental drug for obesity developed by American pharmaceutical company Eli Lilly and Company. It is a triple glucagon hormone receptor agonist (GLP-1, GIP, and GCGR receptors). It has been shown to achieve a m ...

found an average −24.2 percent weight reduction in the highest dosage group after 24 weeks.

Conjugates

Attaching other hormones such as

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones triiodothyronine, T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus r ...

(T3), and

dexamethasone Dexamethasone is a fluorinated glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive pulmonary disease (COPD), croup, brain swelling, eye pain following eye su ...

to GLP-1 or glucagon restrict the activity of the attached hormone to cells that express GLP-1 or glucagon. GLP-1 and

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 ...

agonist conjugates have also been tested in preclinical trials.

GLP-1 and neuropeptide Y multi-agonists

In 2023, researchers disclosed the discovery of multiple peptides that activated the GLP-1 receptor, neuropeptide Y receptor Y1, and neuropeptide Y receptor Y2. Since neuropeptide Y receptors were a previous anti-obesity target, it is hoped that the combination might be more efficacious than GLP-1 receptor agonists.

References