How do GLP-1 (Glucagon-Like Peptide-1) agonists work?

From the Guidelines

GLP-1 agonists work by mimicking the action of the naturally occurring hormone glucagon-like peptide-1 in the body, binding to GLP-1 receptors primarily in the pancreas and brain to stimulate insulin secretion, suppress glucagon secretion, slow gastric emptying, and reduce hunger and food intake. These medications, which include semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), dulaglutide (Trulicity), and tirzepatide (Mounjaro), are effective for both blood sugar control in type 2 diabetes and weight management because they address multiple physiological pathways involved in metabolism and appetite regulation 1.

The mechanism of action of GLP-1 agonists involves:

• Stimulating insulin secretion from pancreatic beta cells in a glucose-dependent manner, meaning insulin is only released when blood sugar levels are elevated
• Suppressing glucagon secretion from pancreatic alpha cells, which helps prevent the liver from releasing stored glucose
• Slowing gastric emptying, making you feel fuller longer after eating
• Acting on the brain's appetite center to reduce hunger and food intake

These medications are typically administered as subcutaneous injections, with dosing frequencies ranging from daily to weekly depending on the specific medication 1. Side effects commonly include nausea, vomiting, and diarrhea, which often improve over time.

The most recent and highest quality study, published in 2024, found that GLP-1 receptor agonists, such as semaglutide and liraglutide, are effective in reducing weight and improving weight-related comorbidities, and are associated with lower rates of gastrointestinal adverse events compared to other treatments 1. Additionally, the study found that GLP-1 receptor agonists decrease the risk of cardiovascular events in adults with overweight or obesity without diabetes.

Overall, GLP-1 agonists are a valuable treatment option for patients with type 2 diabetes and obesity, offering benefits for both blood sugar control and weight management, and reducing the risk of cardiovascular events.

From the FDA Drug Label

Liraglutide is an acylated human GLP-1 receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). Like endogenous GLP-1, liraglutide binds to and activates the GLP-1 receptor, a cell-surface receptor coupled to adenylyl cyclase activation through the stimulatory G-protein, Gs. GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Liraglutide lowers body weight through decreased calorie intake. Liraglutide does not increase 24-hour energy expenditure. As with other GLP-1 receptor agonists, liraglutide stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner.

GLP-1 Agonists Mechanism of Action:

• Bind to GLP-1 receptors: activating the receptor and stimulating a response
• Regulate appetite and calorie intake: reducing hunger and increasing feelings of fullness
• Stimulate insulin secretion: increasing insulin release in response to high blood glucose levels
• Reduce glucagon secretion: decreasing glucagon release and reducing blood glucose levels
• Delay gastric emptying: slowing the movement of food from the stomach to the small intestine

GLP-1 agonists, such as liraglutide and semaglutide, work by mimicking the action of the naturally occurring hormone GLP-1, which is involved in regulating appetite, calorie intake, and blood glucose levels. By activating GLP-1 receptors, these medications can help reduce body weight, improve glycemic control, and reduce the risk of major adverse cardiovascular events. 2 3

From the Research

Mechanism of Action of GLP-1 Agonists

• GLP-1 agonists work by stimulating insulin secretion and suppressing glucagon secretion in a glucose-dependent manner 4, 5
• They also delay gastric emptying, reduce appetite, and promote satiety, leading to weight loss 4, 6, 7
• The activation of GLP-1 receptors in the pancreas leads to enhanced insulin release and reduced glucagon release, with a consequent low risk for hypoglycemia 7
• GLP-1 agonists have been shown to improve glycemic parameters, reduce body weight, and have a low risk of hypoglycemia 4, 6, 7

Types of GLP-1 Agonists

• Short-acting GLP-1 agonists, such as exenatide and lixisenatide, are administered once or twice daily 6, 7
• Long-acting GLP-1 agonists, such as liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide, are administered once weekly 6, 7
• A daily oral preparation of semaglutide has also been approved, demonstrating clinical effectiveness close to the once-weekly subcutaneous preparation 6

Clinical Benefits of GLP-1 Agonists

• GLP-1 agonists have been shown to reduce HbA1c levels, fasting and postprandial glucose concentrations, and body weight 4, 6, 7
• They have also been shown to prevent cardiovascular events, such as acute myocardial infarction or stroke, and associated mortality 6, 8
• GLP-1 agonists may also help prevent renal complications of type 2 diabetes 6