How do Glucagon-like peptide-1 (GLP-1) receptor agonists work?

From the Guidelines

GLP-1 receptor agonists work by mimicking the action of the naturally occurring hormone glucagon-like peptide-1 (GLP-1) in the body, binding to GLP-1 receptors primarily in the pancreas, stimulating insulin release when blood sugar levels are high while simultaneously suppressing glucagon secretion. These medications have been shown to have a significant impact on morbidity, mortality, and quality of life, particularly in patients with type 2 diabetes mellitus at high cardiovascular risk, as demonstrated by the LEADER trial 1 and the SUSTAIN 6 trial 1. The primary mechanism of action of GLP-1 receptor agonists includes:

• Stimulating insulin release when blood sugar levels are high
• Suppressing glucagon secretion, which helps prevent the liver from releasing stored glucose
• Slowing gastric emptying, which helps create a feeling of fullness and reduces appetite by acting on the brain's hunger centers Common GLP-1 receptor agonists include semaglutide (Ozempic, Wegovy), dulaglutide (Trulicity), liraglutide (Victoza, Saxenda), and tirzepatide (Mounjaro). The use of GLP-1 receptor agonists has been associated with several benefits, including:
• Improved blood pressure and lipid profiles
• Reduced risk of cardiovascular events, as demonstrated by the SELECT study 1
• Significant weight loss, as demonstrated by the STEP trials 1 However, GLP-1 receptor agonists can also cause side effects, including:
• Nausea and vomiting, which can be managed by avoiding gastroparesis and starting the medication at a low dose and titrating upward slowly 1
• Diarrhea, which can be managed by reducing meal size 1
• Gastrointestinal reflux, which can be managed by limiting alcohol and carbonated drinks 1 These medications are typically administered as subcutaneous injections with frequencies ranging from daily to weekly depending on the specific drug. Overall, the use of GLP-1 receptor agonists has been shown to have a significant impact on morbidity, mortality, and quality of life, and should be considered as a treatment option for patients with type 2 diabetes mellitus at high cardiovascular risk, as well as for patients with obesity.

From the FDA Drug Label

Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner.

GLP-1 receptor agonists, such as semaglutide, work by:

• Stimulating insulin secretion in a glucose-dependent manner
• Lowering glucagon secretion in a glucose-dependent manner
• Causing a minor delay in gastric emptying in the early postprandial phase 2

From the Research

Mechanism of Action

• GLP-1 receptor agonists work by activating GLP-1 receptors in the pancreas, leading to enhanced insulin release and reduced glucagon release, which are both glucose-dependent, resulting in a low risk for hypoglycemia 3, 4
• They also affect GLP-1 receptors in the CNS and the gastrointestinal tract, causing reduced appetite and delayed glucose absorption due to slower gastric emptying 4, 5
• The primary pharmacodynamic difference between short-acting and long-acting GLP-1 RAs is that short-acting agents primarily delay gastric emptying, while long-acting agents affect both fasting glucose and postprandial glucose 6

Effects on Glucose Control and Weight

• GLP-1 RAs have been shown to significantly improve glycemic parameters and reduce body weight 3, 4
• Long-acting GLP-1 RAs have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin 3
• Short-acting agents have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment 3

Administration and Tolerability

• GLP-1 RAs are administered as subcutaneous injections, at different dosing intervals, with some agents available for once-daily or once-weekly administration 3, 7
• The most common adverse effects are gastrointestinal, which are transient and less common with the long-acting drugs 4
• Long-acting GLP-1 RAs have smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler administration schedules, which may improve treatment adherence and persistence 6