What are examples of Glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes management?

GLP-1 Receptor Agonists for Type 2 Diabetes

Available GLP-1 Receptor Agonists

The commercially available GLP-1 receptor agonists include both short-acting and long-acting formulations, with the long-acting agents demonstrating superior efficacy for HbA1c reduction and fasting glucose control. 1

Short-Acting Agents (Twice Daily or Once Daily)

• Exenatide (twice daily): Administered within 60 minutes prior to morning and evening meals, approximately 6 hours apart 2, 3
• Lixisenatide (once daily): Available in China and Europe, provides greater postprandial glucose control 1, 3
• Liraglutide (once daily): Demonstrated cardiovascular benefit in the LEADER trial with 13% reduction in major adverse cardiovascular events 1, 4

Long-Acting Agents (Once Weekly)

• Exenatide extended-release (once weekly): Provides more profound effects on fasting plasma glucose compared to twice-daily formulation 1, 3
• Dulaglutide (once weekly): Showed cardiovascular benefit in the REWIND trial and slowed GFR decline compared to insulin glargine 1
• Semaglutide (once weekly subcutaneous): Demonstrates the greatest glucose-lowering efficacy within the class, reducing HbA1c more effectively than other agents 1, 5, 3
• Albiglutide (once weekly): Reduced major adverse cardiovascular events but is not currently available 1, 4

Oral Formulation

• Semaglutide (oral): Recently approved oral preparation with clinical effectiveness close to the once-weekly subcutaneous preparation 3, 4

Agents Available in China

• Beinaglutide: Listed as commercially available in China alongside exenatide, liraglutide, and lixisenatide 1

Mechanism of Action

All GLP-1 receptor agonists share common mechanisms: they enhance insulin secretion and inhibit glucagon secretion in a glucose-dependent manner, delay gastric emptying to reduce postprandial glucose excursions, and reduce food intake through central appetite suppression 1, 3

Efficacy Differences Within the Class

Semaglutide demonstrates the greatest glucose-lowering efficacy, followed by dulaglutide and liraglutide, then exenatide once weekly, with exenatide twice daily and lixisenatide showing the least potent effects. 1, 3

• Long-acting agents have more profound effects on overnight and fasting plasma glucose and HbA1c reduction 3, 6
• Short-acting agents maintain greater effects on postprandial glucose control, particularly after meals with which they are administered 1, 6
• Effects on gastric emptying decrease over time (tachyphylaxis) with long-acting agents 3

Cardiovascular Benefits

For patients with type 2 diabetes and established atherosclerotic cardiovascular disease, GLP-1 receptor agonists with proven cardiovascular benefit (liraglutide, semaglutide, dulaglutide) are the preferred agents. 1

• Liraglutide, semaglutide, albiglutide, and dulaglutide reduced time to first major adverse cardiovascular events in cardiovascular outcomes trials 1, 4
• Liraglutide additionally reduced cardiovascular and all-cause mortality 4
• Injectable semaglutide reduced cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 26% (HR 0.74,95% CI 0.58-0.95) in the SUSTAIN 6 trial 1

Renal Benefits

GLP-1 receptor agonists with proven cardiovascular benefit are recommended for patients with type 2 diabetes and chronic kidney disease who do not meet glycemic targets with metformin and/or SGLT2 inhibitors 1

• These agents reduce albuminuria and slow eGFR decline 1
• Dulaglutide produced significantly slower GFR decline compared to insulin glargine in patients with moderate-to-severe CKD 1
• GLP-1 receptor agonists have been studied in patients with eGFR as low as 15 mL/min/1.73 m² 1

Common Adverse Effects

The most common adverse effects are gastrointestinal symptoms (nausea, vomiting, diarrhea) that occur mainly in the initial stage of treatment and gradually diminish over time 1, 5

• Gastrointestinal adverse events occur in 15-20% of patients with moderate-to-severe CKD but are usually tolerable with dose titration 1
• These symptoms are less frequent with longer-acting GLP-1 receptor agonists 6
• Heart rate typically increases by approximately 5 bpm but has not been associated with higher blood pressure or other adverse events 1

Hypoglycemia Risk

GLP-1 receptor agonists have minimal risk for hypoglycemia when used as monotherapy due to their glucose-dependent mechanism of action. 1, 7

• When combined with insulin or insulin secretagogues (particularly sulfonylureas), the risk of hypoglycemia increases significantly, requiring dose reduction of these agents 1, 7, 2
• In moderate-to-severe CKD, rates of hypoglycemia are reduced by one-half even with concurrent insulin therapy 1

Important Contraindications and Warnings

GLP-1 receptor agonists are contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 5

• Treatment is not recommended in patients at risk for thyroid C-cell tumors, pancreatic cancer, or pancreatitis based on theoretical risks 1
• Has not been studied in patients with a history of pancreatitis; consider alternative antidiabetic therapy 5
• Not indicated for use in type 1 diabetes mellitus or treatment of diabetic ketoacidosis 5
• Pulmonary aspiration during general anesthesia or deep sedation has been reported; patients should inform healthcare providers of planned surgeries 2