Glucagon-like peptide-1 (GLP-1)receptoragonists, also known asGLP-1 agonists,GLP-1RAs,GLP-1 analogs, orincretin mimetics, are a class of medications that activate theGLP-1 receptor, causing reduced blood sugar, reducedappetite, and reduced energy intake. Originally developed to treattype 2 diabetes, some GLP-1 agonists have been approved to treatobesity. They mimic the actions of the endogenousincretin hormoneGLP-1, which is released in the small intestine and can inhibitglucagon release and increaseinsulin secretion.[1]
GLP-1 agonists work by activating theGLP-1 receptor, which is found all around the body. Some sites are onbeta cells in thepancreas and onneurons in the brain. GLP-1 receptor activation slowsgastric emptying, inhibits the release ofglucagon, and stimulatesinsulin production, thereby improving glucose homeostasis in people withtype 2 diabetes. GLP-1 receptor activation also stimulatessatiety, thus reducing food intake, promoting the development of a negative energy balance, and decreasing body weight over time, making GLP-1 agonists a treatment option 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 offibroblast growth factor 21. Pharmaceutical companies have developed dual GLP-1/FGF21 receptor agonists.[4]
The naturally occurring native GLP-1 hormone is considered apeptide hormone. It has ahalf-life of only about two minutes, because thedipeptidyl peptidase-4 (DPP-4) enzyme rapidly breaks it down.[5] 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 daily, weekly, or less often.[5] Many commonly used synthetic GLP-1 agonists are delivered weekly bysubcutaneous injection, which is a barrier to their use and reason for discontinuation.[6] Most GLP-1 medications are approved by theFDA and sold as drug-devicecombination products, which include auto-injecting pens.[7] Self-injected drugs are especially difficult for people with vision or motor difficulties, which commonly accompany type 2 diabetes.[5] Attempts to develop an orally bioavailable GLP-1 agonist, either a modified peptide, as in the case of oral semaglutide,[6] or asmall molecule drug, have produced additional drug candidates.[8] Other companies have tested inhaled ortransdermal administration.[5] An oral semaglutide pill was approved by the FDA in December 2025 and entered mass production in January 2026.[9]
One advantage of GLP-1 agonists over olderinsulin secretagogues such assulfonylureas ormeglitinides is that they have a lower risk ofhypoglycemia, while improving weight and cardiovascular and kidney health.[11] ADA also recommends use of GLP-1 agonists instead of startinginsulin therapy in people with type2 diabetes who need additional glucose control, except whencatabolism, hyperglycemia, orautoimmune diabetes is suspected.[13]
A 2021meta-analysis reported a 12% reduction in all-cause mortality when GLP-1 analogs are used in the treatment of type2 diabetes, as well as significant improvements in cardiovascular and renal outcomes relative to nonusers.[14] A 2023 meta-analysis including 13 cardiovascular outcome trials reported that SGLT2 inhibitors reduce the risk for three-pointmajor adverse cardiovascular events, especially in subjects with anestimated glomerular filtration rate (eGFR) below 60 mL/min, whereas GLP-1 receptor agonists were more beneficial in people with higher eGFRs.[15] Likewise, therelative risk reduction of SGLT-2 inhibitor treatment was larger in populations with a higher proportion ofalbuminuria, but this relationship was not observed for GLP-1 receptor agonists. This suggests differential use of the two substance classes in people with preserved and reduced renal function or with and withoutdiabetic nephropathy, respectively.[15] GLP-1 agonists and SGLT2 inhibitors work to reduceHbA1c by different mechanisms and can be combined for enhanced effects. They may provide additive cardioprotective effects.[16]
GLP-1 agonists are recommended as an add-on therapy to lifestyle intervention (calorie restriction andexercise) in people with aBMI30 kg/m² or with a BMI27 kg/m² with at least one weight-related comorbidity, which can include high blood pressure or high cholesterol.[17] Some GLP-1 agonists are more effective than otherweight-loss drugs, butbariatric surgery is still considered the most effective and sustainable way to lose weight.[18] GLP-1 agonists' weight-reducing effects come from a combination of peripheral effects and activity in thecentral nervous system.[19] In the brain, GLP-1 agonists reduce weight by crossing theblood–brain barrier, via passive diffusion or receptor mediatedtranscytosis, and directly activating the satiety hormones in the hypothalamus.[20]
Studies reported that on average people regain more than half (50–70%) of the lost weight within a year after discontinuing any of these medications.[24]
In a 2023 systematic review, researchers reported that GLP-1 agonists are as effective a treatment formetabolic dysfunction–associated steatotic liver disease (MASLD) as the medications in current use,pioglitazone andVitamin E. It noted a reduction insteatosis, ballooningnecrosis, lobular inflammation, andfibrosis.[25] The review also reported promising signs for the continuation of GLP-1 medication therapy to treat MASLD.
Wegovy (semaglutide) is approved by the FDA to treat MASH (metabolic dysfunction-associated steatohepatitis) with stage 2 or stage 3 liver fibrosis. The mechanism of action for this treatment is under investigation, but part 1 of its stage 3 clinical trials saw a 60% reduction in liver inflammation.[26] Clinical trials are ongoing.
GLP-1 agonists are recommended[who?] as a treatment forpolycystic ovary syndrome, alone or in combination with metformin. The combination therapy achieved greater efficacy in improving body weight, insulin sensitivity,hyperandrogenism, andmenstrual cycle irregularities.[27] This usage is off-label.[28]
GLP-1 agonists' most common adverse effects are gastrointestinal.[17] These limit the maximum tolerated dose and require gradual dose escalation.[8] Nausea, vomiting, diarrhea, and constipation are commonly reported.[17] Nausea is directly related to 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. Injection site reactions are common, especially with shorter-acting drugs.[5]
Human trials and meta-analyses reported no reliable association between the drugs andpancreatitis orpancreatic cancer, but some case reports of pancreatitis have emerged in postmarketing reports, and theAmerican Association of Clinical Endocrinologists recommends caution in people with a history of pancreatitis. Discontinuation is recommended if acute pancreatitis occurs.
Some people developanti-drug antibodies, which are more common withexenatide (the antibodies were detectable in a third or more of people) than other GLP-1 agonists and can decrease efficacy.[5]Gallstones may form while attempting to induce rapid weight loss.[17]
The risk of aspiration under anesthesia is higher due to delayed gastric emptying, according to case reports. In 2023, theAmerican Society of Anesthesiologists suggested suspending GLP-1 agonist treatment on the day of the procedure/surgery or a week earlier.[30]
A 2024 study suggested that GLP-1 weight-loss medications do not increase the risk ofsuicide or suicidal thoughts in children and adolescents, contrary to some previous concerns.[31] The study included over 54,000 U.S. adolescents and reported a 33% reduction in the risk of suicidal thoughts and attempts among those using the drugs compared to those who did not.[32] In January 2026, the USFood and Drug Administration requested removal of suicidal behavior and ideation warning from glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications.[33]
While adolescents taking GLP-1 drugs experienced more gastrointestinal symptoms, they had a lower risk ofacute pancreatitis compared to the control group.[34] A similar study in adults reported similar results for semaglutide.[35]
The USFood and Drug Administration requires aboxed warning in thepackage inserts of GLP-1 agonists due to the risk ofthyroid C-cell tumors, includingmedullary thyroid cancer (MTC). GLP-1 agonists are contraindicated in people with a family or personal history of MTC ormultiple endocrine neoplasia type 2.[13] In mice, long-term use of GLP-1 agonists stimulatescalcitonin secretion, leading toC-cell hypertrophy and increased risk of thyroid cancer, but no increased secretion of calcitonin has been observed in humans.[5] Aretrospective national cohort study in France reported an increased risk of thyroid cancer (all and medullary) after 1-3 years of treatment with GLP-1 agonists for diabetes,[37] but other large retrospective studies have not reported a similar association,[38] including with long-term use of GLP-1 agonists and over 10 years of followup.[39]
Influencers andcelebrities popularized GLP-1 agonists in the early 2020s, causing many people to seek them for cosmetic or health-based weight loss.[40]
GLP-1 agonists are more expensive than other treatments for type 2 diabetes. A study compared the cost-effectiveness of GLP-1 agonists tolong-acting insulin in a Taiwanese population with type 2 diabetes. In people with CVD (Cardiovascular disease), GLP-1 agonists were estimated to save money due to fewer cardiovascular incidents. In people without CVD, the cost perQALY was $9,093.[41] 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 people who stopped using the drugs.[42] According to a 2023 study, GLP-1 agonists were not cost-effective for pediatric obesity in the U.S.[43] As of late 2025, prices had dropped substantially.[44]
semaglutide (Ozempic and Rybelsus for diabetes, Wegovy for weight management, manufactured byNovo Nordisk), approved in 2021/2019/2021[47]
tirzepatide (aGIP analog with dual GLP-1 receptor andGIP receptor agonism; Mounjaro for diabetes, Zepbound for weight management, manufactured by Eli Lilly), approved in 2022/2024[48]
Discontinued:
exenatide (brand names Byetta and Bydureon, manufactured byAstraZeneca), approved 2005/2012,[49] discontinued in 2024
albiglutide (Tanzeum, manufactured byGSK), approved in 2014,[50] discontinued in 2017
lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured bySanofi), approved in 2016,[51] discontinued in 2023
Gray market sellers offer unauthorized products they claim are GLP-1 agonists. Some buyers turn to unauthorized retailers if they cannot afford the name-brand drug.[53][54][55][56][57] Buyers face risks due to counterfeit or substandard drugs.[58]
In the United States,compounding pharmacies may sell custom-made versions of a drug if there is a declared shortage and they obtain theactive pharmaceutical ingredient from an FDA-approved facility.[59] The FDA declared shortages of injectable versions ofsemaglutide,tirzepatide,dulaglutide,liraglutide, andexenatide in 2022. The tirzepatide shortage ended in 2024.[60] Al Carter, executive director of theNational Association of Boards of Pharmacy, a trade organization for pharmacy regulators, estimated that 95% of online compounding pharmacies were operating illegally in 2024.[61] As of January 2026[update], there were up to1.5 million users of compounded GLP-1 receptor agonist drugs in the U.S., according to Novo Nordisk CEO Mike Doustdar.[62] He decried the practice of selling what he called "unsafe, knock-off products" while conceding that compounding pharmacies capture price-sensitive consumers in a way that his company, with its more expensive branded offerings, cannot.[62]
During the 1980s, Jean-Pierre Raufman worked as apostdoctoral researcher at theNational Institutes of Health for John Pisano, a biochemist who specialized in collectingvenom from various animals and looking for novel substances that could affect human physiology.[63] In the course of this work, Raufman focused on theGila monster, because he was curious about its practice of eating once or twice per year.[64] He reported that Gila monster venom had biologically active molecules that provoked inflammation of the pancreas in test animals.[64][65]
In 1992, after learning of Raufman's findings, John Eng of theVeterans Administration Medical Center in New York City usedradioimmunoassay to isolate a novel substance from Gila monster venom.[64][63][65] The new substance, which Eng called exendin-4, was similar toGLP-1 in that it reducedblood 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][65]
In 2011, Lilly and Amylin dissolved their partnership, with Amylin keeping the rights to exenatide.[68] Lilly continued to develop drugs of the same class.
The 2024American Diabetes Association conference included presentations on at least 27 GLP-1 receptor agonists then in development.[69] By July 2024, Novo Nordisk's semaglutide and Eli Lilly's tirzepatide were ranked among the world's most popular and lucrative drugs.[70] Novo Nordisk's rollout of semaglutide turned it into the most valuable company in Europe in 2024.[71][72] 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 represented nearly all of Denmark's economic growth.[71][72] By October 2024, tirzepatide had turned Eli Lilly into the world's most valuable drug company.[73]
Aretrospective cohort study published in 2025 evaluated GLP-1 agonists' benefits and risks compared to other anti-diabetic medications. The study suggested that GLP-1 agonists reduced risks of substance use andpsychotic disorders, seizures, neurocognitive disorders (includingAlzheimer's disease and other dementias),coagulation disorders, cardiometabolic disorders,infectious diseases, and several respiratory conditions relative to nonusers.[36]
A 2025 study suggested that GLP-1 agonists may reduce risks of neurocognitive disorders, including Alzheimer’s disease, pointing to a then-emerging body of research. Hypotheses include that the drugs reduceneuroinflammation,oxidative stress,amyloid β deposition, and tau hyperphosphorylation in animal models.[36]
In November 2025, Novo Nordisk announced[76] top-line results from two large-scale studies, evoke and evoke+. The studies reported failure to slow the progression of Alzheimer's disease versus placebo.[77]
A 2022 study reported that GLP-1 agonists have cardioprotective effects when used to treatobesity, beyond their primary roles inglycemic control and weight reduction.[78]
In a 2024 retrospective study, GLP-1 exposure was associated with lower risks of specific types of obesity-associated cancers compared with insulin or metformin in people with type 2 diabetes. Compared to insulin, 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.[80]
GLP-1 agonists are under development forsubstance use disorder, a condition with few pharmacological treatment options. A 2022 study reported reductions in drug and alcohol use in non-human animals.[84]
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