GLP-1 agonists: Uses, common brands, and safety info

Diabetes and obesity are two of the most impactful disorders on the health of our society. The American Diabetes Association estimates that approximately 12% of our population has diabetes. The Centers for Disease Control and Prevention (CDC) estimates the prevalence of obesity at approximately 42% in the United States. There is a significant correlation between obesity and diabetes. Obesity is a risk factor for the development of diabetes, and the CDC estimates that 23% of obese American adults have diabetes.

Diabetes and obesity can have a significant effect on both healthcare costs and the cost of living. The total annual cost of diagnosed diabetes in Americans is estimated to be $413 billion People who are overweight have a higher incidence of other disorders including high blood pressure, heart failure, cancer, and diabetes. Fortunately, there have been significant medical advancements in the treatment of both diabetes and obesity in recent years thanks to numerous clinical trials. Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) are a unique class of medications with approved indications to treat both diabetes and obesity. 

Most recently, the active ingredient tirzepatide provides dual agonist action as a GLP-1 agonist as well as glucose-dependent insulinotropic polypeptide (GIP) agonist. These drugs have made a substantial impact on patient lives by enabling effective weight loss and diabetes control. Here we will discuss the different types of GLP-1 agonists, the way they work, and their side effects and safety profiles. Your healthcare professional can help you determine if a GLP-1 analogue drug could be right for you.

Other GLP-1 agonists

• Tanzeum (albiglutide)

• Byetta (exenatide)

• Bydureon BCise (exenatide extended-release)

• Adlyxin (lixisenatide)

What are GLP-1 agonists?

Glucagon-like peptide-1 receptor agonists are glucose-lowering class of medications medications used in the treatment of Type 2 diabetes, obesity, and cardiovascular risk reduction. Type 2 diabetes is a condition that causes elevated blood glucose, or hyperglycemia. The body of a patient who has Type 2 diabetes typically doesn't make enough insulin naturally to control their blood glucose levels, or the insulin they do make doesn’t function as it should. GLP-1 agonists activate the glucagon-like peptide receptor in the pancreas, which enhances insulin output. GLP-1 agonists also have an effect on GLP-1 receptors in the central nervous system, which have been shown to decrease appetite and delay the emptying of your stomach after you ingest food. Dual agonists, which also target the GIP receptor, are thought to further regulate food intake and feelings of hunger. The American Diabetes Association prefers the antidiabetic drug metformin as a first-line treatment for Type 2 diabetes mellitus. GLP-1 agonists and dual agonists are considered a second-line therapy and are used in combination with other antidiabetic therapies such as metformin, sulfonylureas, thiazolidinediones, or basal insulin. 

How do GLP-1 agonists work?

Glucagon-like peptide-1 receptor agonists are sometimes referred to as incretin mimetics because they mimic natural incretin hormones in your body. The GLP-1 incretin hormone in your body is normally released after the consumption of dietary carbohydrates and fats. Patients with Type 2 diabetes have decreased or insufficient GLP-1. These incretin mimetic medications enhance insulin secretion, suppress glucagon secretion, slow gastric emptying, reduce appetite, and promote an increase in beta cells, the specific cells of the pancreas where insulin is secreted. The effects of GLP-1 agonists lead to improved glycemic control. The additional action of GIP agonists in the dual agonist products helps to control hunger.

What are GLP-1 agonists used for?

• Type 2 diabetes mellitus (All GLP-1 agonists)

• Obesity [Saxenda (liraglutide), Wegovy (semaglutide), Mounjaro (tirzepatide)]

• Cardiovascular risk reduction [Trulicity (dulaglutide), Saxenda (liraglutide), Wegovy (semaglutide)]

• Weight management [Saxenda (liraglutide), Wegovy (semaglutide), Zepbound (tirzepatide)]

Types of GLP-1 agonists

Oral GLP-1 receptor agonists

There is only one oral form of a GLP-1 agonist on the market, Rybelsus (semaglutide). Rybelsus, an oral semaglutide formulation, is only approved for the treatment of Type 2 diabetes in combination with diet and exercise. Oral semaglutide is not FDA approved for the reduction of cardiovascular disease, the treatment of obesity, or weight management. 

Example of oral GLP-1 agonist: 

• Semaglutide

Short-acting injectable GLP-1 receptor agonists

Short-acting injectable GLP-1 agonists are subcutaneous injections dosed either once or twice daily. How often a GLP-1 agonist must be dosed is mostly determined by the drug's half-life, which refers to how quickly or slowly the body metabolizes and excretes a drug. Short-acting GLP-1 agonists have a shorter half-life and are eliminated more quickly than their long-acting counterparts. Short-acting GLP-1 agonists are best suited for patients whose blood sugars are high after meals, also known as postprandial hyperglycemia.

Example of short-acting GLP-1 agonists: 

• Exenatide

• Lixisenatide

Long-acting injectable GLP-1 receptor agonists

Long-acting injectable GLP-1 agonists offer the advantage of once-weekly dosing because they have a longer half-life. This is important because many times, patients on GLP-1 agonists are on other injectable drugs like insulin, and this decreases the number of daily injections. The mechanism of action of long-acting and short-acting GLP-1 agonists is the same, and the biggest difference is how frequently they have to be dosed. Long-acting GLP-1 agonists are better suited for patients who have a high fasting blood glucose level.

Example of long-acting GLP-1 agonists: 

• Albiglutide 

• Dulaglutide

• Semaglutide

Dual-action injectable GLP-1 / GIP receptor agonists

Combining long-acting GLP-1 action with GIP activity enhances the ability to control hunger and the need for food intake. The SURPASS-5 randomized clinical trial, a recent study, showed that dual-action agonists provided superior results in producing lower blood sugar levels and greater weight loss as compared to single-action GLP-1 agonists. This was especially true at higher doses of the dual-action agonist. However, higher doses of GLP-1 agonists are associated with a higher risk of side effects.

Example of dual GLP-1 / GIP agonists:

• Tirzepatide

Who can take GLP-1 agonists?

Can adults take GLP-1 agonists?

Women and men can safely take GLP-1 agonists, assuming their kidney function is normal. However, some GLP-1 agonists do need dose adjustments in patients with kidney disease or decreased renal function. 

Can women take GLP-1 agonists while pregnant or breastfeeding?

Using any GLP-1 agonist medication for weight loss or obesity treatment during pregnancy is contraindicated as the potential for harm to the fetus from weight loss during pregnancy. Prescribing Saxenda (liraglutide) requires adequate contraception methods to ensure it is not used in pregnancy. There may be rare instances where the use of a GLP-1 agonist will be recommended in a pregnant patient to control blood sugar, but overall, the use of human insulin is the preferred treatment for diabetes in pregnant patients. Endocrinology and obstetric doctors and specialists may work together to determine what is best for the patient.

Can children take GLP-1 agonists?

Victoza (liraglutide) and Bydureon BCise (exenatide extended-release) are the only approved GLP-1 agonists for use in children who have a diagnosis of Type 2 diabetes and are at least 10 years of age. GLP-1 agonists should not be used in children for any other indications such as weight loss or improved cardiovascular outcomes.

Can seniors take GLP-1 agonists?

Because older patients are at an increased risk of experiencing decreasing renal function or chronic kidney disease, they must be monitored closely when on GLP-1 agonists. Dose adjustments need to be made for most GLP-1 agonists when kidney function is decreased. Generally, long-acting GLP-1 agonists would be safer in the older population.

Are GLP-1 agonists safe?

Recalls

No active recalls at this time.

Restrictions

Do not take GLP-1 agonists if you have ever had a hypersensitivity reaction to any other GLP-1 agonists. 

GLP-1 agonists have been shown to cause gastrointestinal side effects early in treatment. Typically these are transient and resolve without intervention. Slow titration of dosing helps to ease these effects. Patients with pre-existing gastrointestinal diseases, however, may experience more frequent and severe side effects due to the use of GLP-1 agonists. The most common gastrointestinal side effects are nausea, diarrhea, constipation, and vomiting. These side effects may come and go intermittently. Long-acting GLP-1 agonists may be the best option for patients with pre-existing stomach disorders if GLP-1 therapy is necessary, as they are linked to a lesser incidence of side effects.

There is a risk of a patient’s blood sugar levels going too low with the use of GLP-1 agonists. This is known as hypoglycemia. This risk is very low, but it is increased by the concurrent use of insulins and sulfonylureas.

The slowed rate of gastric emptying could affect the absorption of other drugs or agents, leading to unintended clinical effects. Your prescriber should consider this when prescribing oral medications.

After initiating GLP-1 agonists, patients should monitor for signs and symptoms of pancreatitis. These include upper abdominal pain (especially if it radiates to the back or is worse after eating), abdominal tenderness, fever, rapid heart rate, nausea, and vomiting. Seek help immediately if these symptoms occur.

GLP-1 agonists carry a black box warning from the Food and Drug Administration (FDA). This warning concerns the use of GLP-1 agonists in patients with a personal or family history of certain types of thyroid cancer, such as thyroid C-cell tumors or medullary thyroid carcinoma. Clinical studies have found that the risk of these cancers is increased when using GLP-1 RAs.

Other patient populations who should not use GLP-1 agonists or use them cautiously include those with a history of angioedema, multiple endocrine neoplasia syndrome Type 2 (MEN 2), or thrombocytopenia.

GLP-1 agonists are not approved for the treatment of Type 1 diabetes. Type 1 diabetes is different from Type 2 in that the patient’s body is not capable of producing insulin. Type 1 diabetics should not use GLP-1 agonists for weight loss.

Diabetes treatment with biguanides or other diabetes drugs does not negate the need for regular diabetes care and check-ups regarding feet, eyes, and kidneys. Diabetes can have dangerous effects on other organs, and these should be monitored closely.

A healthy diet and exercise regimen should accompany the use of the GLP-1 drug class to produce the best results in blood sugar control and effective weight loss.

Are GLP-1 agonists controlled substances?

No, GLP-1 agonists are not controlled substances.

Common GLP-1 agonists side effects

• Constipation

• Diarrhea

• Dyspepsia

• Hypoglycemia

• Injection site reaction

• Nausea

• Vomiting

• Abdominal pain

• Gastroesophageal reflux (GERD)

• Dizziness

• Eructation

• Fatigue

• Headache

• Anorexia

How much do GLP-1 agonists cost?

Unfortunately, GLP-1 agonists are not available generically at this time. They are all single-source, brand-name products. Insurance coverage may vary greatly by the plan. Most plans will cover at least one type of GLP-1 agonist for the treatment of Type 2 diabetes. It is not uncommon for a plan to have a formulary restriction where only certain GLP-1 agonists are covered. Your insurance can provide more information on your formulary coverage. Saxenda and Wegovy, approved for the treatment of obesity and weight loss, may have even more limited coverage than GLP-1 agonists used for Type 2 diabetes.

If your plan offers no coverage or you are uninsured, SingleCare could provide significant cost savings through prescription savings coupons. Be sure to ask your pharmacist to check your SingleCare coupon before finalizing your purchase of these medications.

Sources

• Statistics about diabetes, American Diabetes Association (2024)

• Adult obesity facts, Centers for Disease Control and Prevention (2024)

• Glucagon-Like Peptide-1 Receptor Agonists, StatePearlsNational Library of Medicine (2024)

• Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with Type 2 Diabetes: The SURPASS-5 randomized clinical trial, JAMA (2022)

• MOUNJARO- tirzepatide injection, solution, DailyMed, (2024)