Glucagon-like Peptide-1 Analog

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 the endogenous incretin hormone GLP-1, which is released by the gut after eating.

GLP-1 agonists were initially developed for type 2 diabetes. The 2022 American Diabetes Association standards of medical care recommend GLP-1 agonists as a first-line therapy for type 2 diabetes, specifically in patients with atherosclerotic cardiovascular disease or obesity. 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 in the absence of diabetes. They are also in development for other indications, such as non-alcoholic fatty liver disease, polycystic ovary syndrome, and diseases of the reward system such as addictions.

Mechanism of action

GLP-1 agonists work by activating the GLP-1 receptor. They slow gastric emptying, inhibit the release of glucagon, and stimulate insulin production, thereby improving glucose homeostasis and reducing the risk of hyperglycemia in people with type 2 diabetes. 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, 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). 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. The 2022 American Diabetes Association (ADA) standards of medical care in diabetes include GLP-1 agonists or SGLT2 inhibitors as a first-line pharmacological therapy for type 2 diabetes in patients who have or are at high risk for atherosclerotic cardiovascular disease or heart failure. 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. One advantage of GLP-1 agonists over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia. 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, hyperglycemia above a certain threshold, or autoimmune 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 inhibitors reduce the risk for three-point MACE, 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 eGFR. Likewise, the risk reduction due to SGLT-2 inhibitors 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 patients 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 effect. It is also possible that they provide additive cardioprotective effects.

The FDA has not approved GLP-1 agonists for type 1 diabetes, but they can be used off-label 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 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. 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 (MASLD). They are at least as effective as the medications in current use, pioglitazone and Vitamin E, 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, alone or in combination with metformin. The combination therapy has shown greater efficacy in improving body weight, insulin sensitivity, hyperandrogenism, and menstrual cycle irregularities. This usage is off label.

Depression

GLP-1 agonists have shown antidepressant and neuroprotective effects. They can also be used to treat the metabolic consequences of second-generation antipsychotics, such as obesity.

Reward system disorders

GLP-1 agonists are under development for substance use disorder, 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, 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 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.

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), 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. In mice, long-term use of GLP-1 agonists stimulates calcitonin 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.

Some patients develop anti-drug antibodies, which are more common with exenatide (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 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, ileus 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 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 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 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, which is a barrier to their use and reason for discontinuation. Most approved by the US FDA 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 drug, have produced additional drug candidates. Other companies have tested inhaled or transdermal 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 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 (brand names Byetta and Bydureon, manufactured by AstraZeneca), approved in 2005/2012
* liraglutide (Victoza for diabetes, Saxenda for obesity, manufactured by Novo Nordisk), approved in 2010
* albiglutide (Tanzeum, manufactured by GSK), approved in 2014
* dulaglutide (Trulicity, manufactured by Eli Lilly), approved in 2014
* lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured by Sanofi), approved in 2016
*semaglutide (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, and/or amylin receptor. 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.

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

Influencers and celebrities have popularized GLP-1 agonists, causing many people to seek them for cosmetic or health-based weight loss. Gray market 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, tirzepatide, dulaglutide, liraglutide, and exenatide 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 from an FDA-approved facility. An estimated 95% of online pharmacies were still operating illegally.The U.S. National Association of Boards of Pharmacy operates
search tool
to identify properly licensed online pharmacies.

History

During the 1980s, Jean-Pierre Raufman of the National Institutes of Health investigated the Gila monster 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 technique he had learned from Nobel laureate Rosalyn Sussman Yalow 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 on exendin-4, so Eng filed the patent application himself in 1993. He then spent three years searching for a pharmaceutical industry 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 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 in Orlando, Florida, 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, $125 billion by 2033; Oppenheimer, $100 billion by 2034; Goldman Sachs, $100 billion by 2030; BMO Capital Markets, $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