Currently Available GLP-1 Receptor Agonists in the United States
In the United States, the currently available GLP-1 receptor agonists include short-acting agents (exenatide and lixisenatide) and long-acting formulations available as once-daily (liraglutide) or once-weekly injections (semaglutide, dulaglutide, albiglutide, and exenatide extended-release), plus the dual GIP/GLP-1 receptor agonist tirzepatide. 1
Short-Acting GLP-1 Receptor Agonists
The short-acting agents available in the U.S. are:
- Exenatide (administered twice daily)
- Lixisenatide (administered once daily)
These agents primarily target postprandial glucose excursions by reducing postprandial hyperglycemia spikes 1. They require more frequent dosing but offer superior control of post-meal glucose levels compared to long-acting formulations 2.
Long-Acting GLP-1 Receptor Agonists
Once-Daily Formulation:
- Liraglutide - FDA approved in 2014 at 3 mg daily for weight management in people with BMI >30 or >27 with comorbidities 3
Once-Weekly Formulations:
- Semaglutide (subcutaneous) - FDA approved in 2021 at 2.4 mg weekly for obesity management 3
- Dulaglutide
- Albiglutide
- Exenatide extended-release (encapsulated in microspheres for gradual depot release) 3
There is also an oral formulation of semaglutide available, representing the first oral GLP-1 receptor agonist 4.
Long-acting formulations provide better control of both fasting and postprandial glucose levels and may improve patient adherence due to less frequent dosing 1, 5.
Dual GIP/GLP-1 Receptor Agonist
- Tirzepatide - This represents a newer class combining GIP and GLP-1 receptor agonism, demonstrating superior efficacy with mean weight loss of 15-20.9% at higher doses (15 mg), exceeding traditional GLP-1 receptor agonists 3
Key Clinical Distinctions
Efficacy differences matter for patient selection:
- GLP-1 RAs reduce HbA1c by 1-2% in adults with type 2 diabetes 1
- GIP/GLP-1 RAs (tirzepatide) reduce HbA1c by 1-2.4%, with demonstrated superiority over basal insulins 1
- Weight loss ranges from 6.1-17.4% with GLP-1 RAs, with greater effects in non-diabetic patients 3
- Tirzepatide has shown the most substantial weight reduction (up to 20.9%) 3
Cardiovascular outcomes vary by agent: With the exception of lixisenatide, all GLP-1 RAs show decreased MACE events 1. Liraglutide (LEADER trial) specifically reduced cardiovascular and all-cause mortality, not just MACE 1. Semaglutide demonstrated cardiovascular safety in SUSTAIN-6 and PIONEER-6 trials, while dulaglutide showed lower MACE-3 incidence in the REWIND trial 1, 3.
Important Clinical Caveats
Common adverse effects include nausea, vomiting, and diarrhea, which are dose-dependent and more frequent with short-acting agents 3. Slow titration significantly improves gastrointestinal tolerability 3, 5.
Delayed gastric emptying occurs with all agents and has been demonstrated via scintigraphy for exenatide, liraglutide, and semaglutide 3. This has critical peri-operative implications and requires careful timing considerations.
Hypoglycemia risk is low when used as monotherapy but increases when combined with insulin secretagogues or insulin 5.