GLP-1 receptor agonist
Glucagon-like peptide-1 'receptor agonists, also known as GLP-1 agonists, GLP-1RAs, GLP-1 analogs, or incretin mimetics', are a class of medications that activate the GLP-1 receptor, causing reduced blood sugar, reduced appetite, and reduced energy intake. Originally developed to treat type 2 diabetes, some GLP-1 agonists have been approved to treat obesity. They mimic the actions of the endogenous incretin hormone GLP-1, which is released in the small intestine and can inhibit glucagon release and increase insulin secretion.
GLP-1 receptor agonists are used to treat type 2 diabetes and obesity, and are under study for treatment of non-alcoholic fatty liver disease, polycystic ovary syndrome, and diseases of the reward system, such as addictions.
Pharmacology
Mechanism of action
GLP-1 agonists work by activating the GLP-1 receptor, which is found all around the body. Some sites are on beta cells in the pancreas and on neurons in the brain. GLP-1 receptor activation slows gastric emptying, inhibits the release of glucagon, and stimulates insulin production, thereby improving glucose homeostasis in people with type 2 diabetes. GLP-1 receptor activation also stimulates satiety, 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. 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. Some of the metabolic effects of GLP-1 agonists in rodents are mediated via increased synthesis of fibroblast growth factor 21. Pharmaceutical companies have developed dual GLP-1/FGF21 receptor agonists.Pharmacokinetics
The naturally occurring native GLP-1 hormone is considered a peptide hormone. It has a half-life of only about two minutes, because the dipeptidyl peptidase-4 enzyme rapidly breaks it down. 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. Many commonly used synthetic GLP-1 agonists are delivered weekly by subcutaneous injection, which is a barrier to their use and reason for discontinuation. Most GLP-1 medications are approved by the FDA and sold as drug-device combination products, which include auto-injecting pens. Self-injected drugs are especially difficult for people with vision or motor difficulties, which commonly accompany 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 drug, have produced additional drug candidates. Other companies have tested inhaled or transdermal administration. An oral semaglutide pill was approved by the FDA in December 2025 and entered mass production in January 2026.Uses
Type 2 diabetes
GLP-1 agonists were initially developed to treat type 2 diabetes. The 2025 American Diabetes Association standard of care in diabetes include GLP-1 agonists or SGLT2 inhibitors as a first-line pharmacological therapy for type 2 diabetes in people who have or are at high risk for atherosclerotic cardiovascular disease or heart failure. ADA also recommends GLP-1 agonists for people with both type 2 diabetes and kidney disease. GLP-1 agonists and SGLT2 inhibitors can be combined with metformin, which has shown an enhanced lowering of A1C. GLP-1 receptor agonists are not recommended for use in combination with DPP-4 enzyme inhibitors due to lack of evidence.One advantage of GLP-1 agonists over older insulin secretagogues such as sulfonylureas or meglitinides is that they have a lower risk of hypoglycemia, while improving weight and cardiovascular and kidney health. ADA also recommends use of GLP-1 agonists instead of starting insulin therapy in people with type 2 diabetes who need additional glucose control, except when catabolism, hyperglycemia, or autoimmune diabetes is suspected.
A 2021 meta-analysis reported 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 relative to nonusers. A 2023 meta-analysis including 13 cardiovascular outcome trials reported that SGLT2 inhibitors reduce the risk for three-point major adverse cardiovascular events, especially in subjects with an estimated glomerular filtration rate below 60 mL/min, whereas GLP-1 receptor agonists were more beneficial in people with higher eGFRs. Likewise, the relative risk reduction of SGLT-2 inhibitor treatment 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 people with preserved and reduced renal function or with and without diabetic nephropathy, respectively. GLP-1 agonists and SGLT2 inhibitors work to reduce HbA1c by different mechanisms and can be combined for enhanced effects. They may provide additive cardioprotective effects.
The US FDA has not approved GLP-1 agonists for type 1 diabetes, but they have been used off-label in addition to insulin.
Obesity
GLP-1 agonists are recommended as an add-on therapy to lifestyle intervention in people with a BMI 30 kg/m² or with a BMI 27 kg/m² with at least one weight-related comorbidity, which can include high blood pressure or high cholesterol. Some GLP-1 agonists are more effective than other weight-loss drugs, but bariatric surgery is still considered the most effective and sustainable way to lose weight. GLP-1 agonists' weight-reducing effects come from a combination of peripheral effects and activity in the central nervous system. In the brain, GLP-1 agonists reduce weight by crossing the blood–brain barrier, via passive diffusion or receptor mediated transcytosis, and directly activating the satiety hormones in the hypothalamus.In recent years, GLP-1 agonists have become more popular for both on- and off-label uses. Three GLP-1 auto-injector medications are approved specifically for weight management: Wegovy, Zepbound, and Saxenda. Each of their clinical trials reported a significant reduction of BMI in participants, ranging from 16% to 20%.
Studies reported that on average people regain more than half of the lost weight within a year after discontinuing any of these medications.
Metabolic dysfunction–associated steatotic liver disease
In a 2023 systematic review, researchers reported that GLP-1 agonists are as effective a treatment for metabolic dysfunction–associated steatotic liver disease as the medications in current use, pioglitazone and Vitamin E. It noted a reduction in steatosis, ballooning necrosis, lobular inflammation, and fibrosis. The review also reported promising signs for the continuation of GLP-1 medication therapy to treat MASLD.Wegovy is approved by the FDA to treat MASH 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. Clinical trials are ongoing.
Polycystic ovary syndrome
GLP-1 agonists are recommended as a treatment for polycystic ovary syndrome, alone or in combination with metformin. The combination therapy achieved greater efficacy in improving body weight, insulin sensitivity, hyperandrogenism, and menstrual cycle irregularities. This usage is off-label.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 commonly reported. 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.Human trials and meta-analyses reported no reliable 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.
GLP-1 agonists appear to increase the risk of non-arteritic anterior ischemic optic neuropathy, but further research is needed to establish causality.
Some people develop anti-drug antibodies, which are more common with exenatide than other GLP-1 agonists and can decrease efficacy. Gallstones may form while attempting to induce rapid weight loss.
The risk of aspiration under anesthesia is higher due to delayed gastric emptying, according to case reports. In 2023, the American Society of Anesthesiologists suggested suspending GLP-1 agonist treatment on the day of the procedure/surgery or a week earlier.
A 2024 study suggested 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. 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. Additionally, while adolescents taking GLP-1 drugs experienced more gastrointestinal symptoms, they had a lower risk of acute pancreatitis compared to the control group. A similar study in adults reported similar results for semaglutide.
A 2025 study suggested that GLP-1 agonists increased risks of hypotension, syncope, joint diseases, nephrolithiasis, interstitial nephritis, and acute pancreatitis.