Comparison of GLP-1 Receptor Agonists
Tirzepatide offers superior reductions in HbA1c and body weight compared to semaglutide and dulaglutide, making it the most effective GLP-1 receptor agonist currently available for glycemic control and weight management. 1
Pharmacological Differences
- GLP-1 receptor agonists share varying homology with endogenous GLP-1 but have been modified to extend their duration of action 1
- Exenatide was the first FDA-approved GLP-1 receptor agonist (2005) and shares 50% homology with GLP-1, making it resistant to dipeptidyl peptidase-4 cleavage 1
- Tirzepatide is unique as a dual GIP/GLP-1 receptor agonist, which explains its superior efficacy profile 1
- Semaglutide is a liraglutide analogue with greater albumin affinity, contributing to its prolonged half-life 1
- Albiglutide achieves prolonged action through non-covalent conjugation with albumin 1
- Dulaglutide's extended duration results from conjugation with the fragment crystallisable region of immunoglobulin G 1
- Long-acting exenatide utilizes microsphere encapsulation to gradually release the drug from a subcutaneous depot 1
Efficacy Comparison
- Short-acting GLP-1RAs (exenatide and liraglutide) provide better coverage of postprandial hyperglycemia 2
- Long-acting formulations (exenatide extended-release, dulaglutide, albiglutide) offer improved fasting plasma glucose control, potentially resulting in greater A1C reductions 2
- Tirzepatide produces greater reductions in HbA1c and body weight compared to both semaglutide and dulaglutide 1
- All GLP-1 receptor agonists reduce body weight and blood pressure to similar degrees, though the magnitude may vary 2, 3
- Some GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) have demonstrated cardiovascular benefits in patients with type 2 diabetes at high cardiovascular risk 1
Mechanism of Action Differences
- All GLP-1 receptor agonists stimulate insulin secretion in a glucose-dependent manner, explaining their low risk of hypoglycemia 1
- GLP-1 receptor agonists delay gastric emptying, but this effect varies between agents and may develop tachyphylaxis with continuous exposure 1
- Tirzepatide binds to both GIP and GLP-1 receptors, while its affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1 1
- GLP-1 receptor activation inhibits glucagon secretion, while GIP receptor activation has variable effects on glucagon based on blood glucose levels 1
Adverse Effect Profile
- Gastrointestinal adverse effects (nausea, vomiting, diarrhea) are the most common side effects across all GLP-1 receptor agonists 1, 4
- Gastrointestinal symptoms tend to abate over time with continued treatment and are less frequent with longer-acting GLP-1 receptor agonists 2
- Hypoglycemia risk is low but increases when GLP-1 receptor agonists are combined with insulin secretagogues or insulin 2, 4
- Small increases in heart rate have been observed across the class, though the clinical relevance remains unknown 2
- Concerns about pancreatitis, pancreatic cancer, and thyroid cancer have been raised, but meta-analyses have failed to establish a causal relationship 4
- Acute kidney injury has been reported with GLP-1 receptor agonists, primarily through hemodynamic derangement due to gastrointestinal symptoms 4
Administration Differences
- Exenatide is a short-acting GLP-1 receptor agonist requiring at least once-daily administration 1
- Long-acting formulations (semaglutide, dulaglutide, albiglutide, exenatide extended-release) allow for weekly dosing 1
- Semaglutide is available in both injectable and oral formulations, with the oral option potentially improving adherence for injection-averse patients 5
- Injection site reactions are common but rarely lead to treatment discontinuation 4
Clinical Considerations for Switching Between GLP-1 Receptor Agonists
- Medical triggers for switching include: unmet HbA1c targets, desire for additional weight loss, poor adherence, increased cardiovascular risk status, and adverse effects with current therapy 6
- Non-medical triggers include patient preference, cost considerations, formulary changes, and insurance mandates 6
- When switching between GLP-1 receptor agonists, slow up-titration and dietary modifications (reduced portion sizes and fat intake) can minimize gastrointestinal adverse effects 6
- Switching from one GLP-1 receptor agonist to another may provide clinical benefits and delay the need for treatment intensification 6
Perioperative Considerations
- GLP-1 receptor agonists are associated with increased risk of retained gastric contents, which is an important consideration for perioperative management 1
- Studies have shown higher incidence of gastric residue in patients using GLP-1 receptor agonists despite prolonged fasting periods 1
- This risk appears to be present with both short-acting and long-acting formulations 1