GLP-1 receptor agonist

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Glucagon-like peptide-1 (GLP-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 been approved to treat obesity. GLP-1 agonists 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. [1]

Contents

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

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 (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 by subcutaneous injection, which is a barrier to their use and reason for discontinuation. [6] Most GLP-1 medications are approved by the FDA and sold as drug-device combination 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 a small molecule drug, have produced additional drug candidates. [8] Other companies have tested inhaled or transdermal administration. [5]

Uses

Type 2 diabetes

GLP-1 agonists were initially developed to treat type 2 diabetes. [9] The 2025 American Diabetes Association (ADA) 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. [10] 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. [10] GLP-1 receptor agonists are not recommended for use in combination with DPP-4 enzyme inhibitors due to lack of evidence. [11]

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. [10] 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. [12]

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. [13] 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 (eGFR) below 60 mL/min, whereas GLP-1 receptor agonists were more beneficial in people with higher eGFRs. [14] 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. [14] 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. [15]

The US FDA has not approved GLP-1 agonists for type 1 diabetes, but they have been used off-label in addition to insulin. [12]

Obesity

GLP-1 agonists are recommended as an add-on therapy to lifestyle intervention (calorie restriction and exercise) 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. [16] 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. [17] GLP-1 agonists' weight-reducing effects come from a combination of peripheral effects and activity in the central nervous system. [18] 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. [19]

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 (semaglutide), [20] Zepbound (tirzepatide), [21] and Saxenda (liraglutide). [22] 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 (50–70%) of the lost weight within a year after discontinuing any of these medications. [23]

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 (MASLD) as the medications in current use, pioglitazone and Vitamin E. It noted a reduction in steatosis, ballooning necrosis, lobular inflammation, and fibrosis. [24] 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. [25] Clinical trials are ongoing.

Polycystic ovary syndrome

GLP-1 agonists are recommended[ who? ] 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. [26] This usage is off-label. [27]

Adverse effects

GLP-1 agonists' most common adverse effects are gastrointestinal. [16] These limit the maximum tolerated dose and require gradual dose escalation. [8] Nausea, vomiting, diarrhea, and constipation are commonly reported. [16] 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 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. [28]

Some people develop anti-drug antibodies, which are more common with exenatide (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. [16]

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. [29]

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. [30] 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. [31] Additionally, while adolescents taking GLP-1 drugs experienced more gastrointestinal symptoms, they had a lower risk of acute pancreatitis compared to the control group. [32] A similar study in adults reported similar results for semaglutide. [33]

A 2025 study suggested that GLP-1 agonists increased risks of hypotension (low blood pressure), syncope (fainting), joint diseases, nephrolithiasis (kidney stones), interstitial nephritis, and acute pancreatitis. [34]

Thyroid cancer

The FDA requires a boxed warning in the package inserts of GLP-1 agonists due to the risk of thyroid C-cell tumors, including medullary thyroid cancer (MTC). GLP-1 agonists are contraindicated in people with a family or personal history of MTC or multiple endocrine neoplasia type 2. [12] In mice, long-term use of GLP-1 agonists stimulates calcitonin secretion, leading to C-cell hypertrophy and increased risk of thyroid cancer, but no increased secretion of calcitonin has been observed in humans. [5] A retrospective 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, [35] but other large retrospective studies have not reported a similar association, [36] including with long-term use of GLP-1 agonists and over 10 years of followup. [37]

Society and culture

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 a Taiwanese population with type 2 diabetes. In people with CVD, GLP-1 agonists were estimated to save money due to fewer cardiovascular incidents. In people without CVD, the cost per QALY was $9,093. [38] 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. [39] According to a 2023 study, GLP-1 agonists were not cost-effective for pediatric obesity in the U.S. [40] As of late 2025, prices dropped substantially. [41]

Discontinued:

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. [49] [8]

Off-label and gray-market usage

Influencers and celebrities popularized GLP-1 agonists in the early 2020s, causing many people to seek them for cosmetic or health-based weight loss. [50] Gray market sellers offer unauthorized products they claim are GLP-1 agonists. This is illegal in the U.S., but some buyers turn to unauthorized retailers if they cannot afford the name-brand drug. [51] [52] [53] [54] [55] Buyers face risks due to counterfeit or substandard drugs. [56]

In the U.S., the FDA declared shortages of injectable versions of semaglutide, tirzepatide, dulaglutide, liraglutide, and exenatide in 2022. The tirzepatide shortage ended in 2024. [57] During a declared shortage, compounding pharmacies may sell custom-made versions of the drug if they obtain the active pharmaceutical ingredient from an FDA-approved facility. [58] An estimated 95% of online pharmacies were operating illegally in 2024. [59]

History

During the 1980s, Jean-Pierre Raufman worked as a postdoctoral researcher at the National Institutes of Health for John Pisano, a biochemist who specialized in collecting venom from various animals and looking for novel substances that could affect human physiology. [60] In the course of this work, Raufman focused on the Gila monster, because he was curious about its practice of eating once or twice per year. [61] He reported that Gila monster venom had biologically active molecules that provoked inflammation of the pancreas in test animals. [61] [62]

In 1992, after learning of Raufman's findings, John Eng of the Veterans Administration Medical Center in New York City used radioimmunoassay to isolate a novel substance from Gila monster venom. [61] [60] [62] 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. [60] [62]

Eng filed a patent application for exendin-4 in 1993. [60] He then spent three years searching for a pharmaceutical industry partner interested in commercializing exendin-4. [61] [60] [62] In 1996, Amylin Pharmaceuticals licensed Eng's patent and created a synthetic version of exendin-4 called exenatide. [61] [60] [62] In 2002, Eli Lilly partnered with Amylin to develop exenatide and secure approval to market the drug. [63] Exenatide's 2005 approval by the U.S. Food and Drug Administration [64] showed that targeting the GLP-1 receptor was a viable strategy and inspired other pharmaceutical companies to focus on that receptor. [60] [62]

In 2011, Lilly and Amylin dissolved their partnership, with Amylin keeping the rights to exenatide. [65] Lilly continued to develop drugs of the same class.

The 2024 American Diabetes Association conference included presentations on at least 27 GLP-1 receptor agonists then in development. [66] By July 2024, Novo Nordisk's semaglutide and Eli Lilly's tirzepatide were ranked among the world's most popular and lucrative drugs. [67] Novo Nordisk's rollout of semaglutide turned it into the most valuable company in Europe in 2024. [68] [69] 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. [68] [69] By October 2024, tirzepatide had turned Eli Lilly into the world's most valuable drug company. [70]

Research

A retrospective 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 and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer's disease and other dementias), coagulation disorders, cardiometabolic disorders, infectious diseases, and several respiratory conditions relative to nonusers. [34]

Under research are GLP1 poly-agonist peptides, dual and triple receptor agonists such as tirzepatide (GLP-1 + GIP) and retatrutide (GLP-1 + GIP + glucagon), and combinations such as cagrilintide/semaglutide, which combines semaglutide with a dual amylin and calcitonin receptor agonist. [5] [71] [72]

Alzheimer's disease

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. Hypothesizes included the ability of these drugs to reduce neuroinflammation, oxidative stress, amyloid β deposition and tau hyperphosphorylation in animal models. [34]

In November 2025, Novo Nordisk announced [73] top-line results from two large-scale studies, evoke and evoke+. The studies reported failure to slow the progression of Alzheimer's disease vs placebo. [74]

Cardiovascular effects

A 2022 study reported that GLP-1 agonists have cardioprotective effects when used to treat obesity, beyond their primary roles in glycemic control and weight reduction. [75]

A 2025 study reported that GLP-1 agonists may be beneficial in heart failure with preserved ejection fraction. [76]

Cancer

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. [77]

Depression

Studies have reported GLP-1 agonists to produce antidepressant and neuroprotective effects and to treat the metabolic consequences of second-generation antipsychotics, such as obesity. [78] [79]

Parkinson's disease

A 2022 UK study failed to find any advantage of using GLP-1 agonists to treat Parkinson's disease. [80]

Reward system disorders

GLP-1 agonists are under development for substance use disorder, a condition with few pharmacological treatment options. A 2022 study reported reductions in drug and alcohol use in non-human animals. [81]

GLP-1 agonists are under investigation for the treatment of binge eating disorder. [82] [83]

References

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