What are GLP-1 (Glucagon-Like Peptide-1) agonists?

What are GLP-1 Agonists

GLP-1 (glucagon-like peptide-1) receptor agonists are a class of injectable medications that mimic the effects of the naturally occurring incretin hormone GLP-1, used primarily to treat type 2 diabetes mellitus and obesity by improving blood sugar control, promoting weight loss, and providing cardiovascular and renal protection. 1, 2

Mechanism of Action

GLP-1 receptor agonists work through multiple complementary pathways:

Pancreatic Effects

• Stimulate glucose-dependent insulin secretion from pancreatic beta cells, meaning insulin is only released when blood glucose is elevated 1
• Suppress glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, reducing hepatic glucose production 1
• This glucose-dependent mechanism explains the low risk of hypoglycemia compared to other diabetes medications 1, 3
• May promote beta-cell proliferation and protect against beta-cell death 1

Gastrointestinal Effects

• Delay gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, which is mediated through the vagus nerve 1
• Much of the glucose-lowering effect comes from delayed gastric emptying rather than pancreatic effects 1
• Increase satiety and reduce appetite through effects on GLP-1 receptors in the central nervous system 3, 4
• Slow the rate at which postprandial glucose appears in circulation 5

Cardiovascular and Renal Benefits

• Reduce rates of non-fatal myocardial infarction, stroke, and death in patients with type 2 diabetes and established cardiovascular disease 1
• Provide renoprotective effects 6

Available Medications

Short-Acting Agents

• Exenatide (twice daily) and lixisenatide 7, 3
• Primarily lower postprandial glucose by delaying gastric emptying 7
• Administered at least once daily 1

Long-Acting Agents

• Liraglutide (once daily), semaglutide (once weekly), dulaglutide (once weekly), albiglutide (once weekly), and exenatide extended-release (once weekly) 1, 7
• Affect both fasting and postprandial glucose through enhanced insulin secretion and reduced glucagon secretion 7
• Modified molecularly to prevent rapid degradation, with elimination half-lives ranging from 13 hours (liraglutide) to much longer for weekly formulations 1, 5
• Better gastrointestinal tolerability and more convenient dosing schedules compared to short-acting agents 7

Dual Agonists

• Tirzepatide is a dual GIP/GLP-1 receptor agonist that produces greater reductions in HbA1c and body weight compared to semaglutide and dulaglutide 1

Clinical Indications

FDA-Approved Uses

• Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus 2
• Reduce risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 2
• Weight management in patients with obesity (semaglutide at higher doses) 8

Limitations

• Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis 2
• Has not been studied in patients with a history of pancreatitis; consider alternative therapy 2

Pharmacology

How They Work Differently from Natural GLP-1

• Natural GLP-1 has a half-life of only 1.5-2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-IV) 1
• GLP-1 receptor agonists are molecularly modified to resist degradation, resulting in extended duration of action 1
• Exenatide shares 50% homology with natural GLP-1 and was the first FDA-approved agent in 2005 1
• Modifications include albumin binding (semaglutide), conjugation with immunoglobulin G (dulaglutide), or encapsulation in microspheres (long-acting exenatide) 1

Common Adverse Effects

• Gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain, constipation) are the most common, occurring in ≥5% of patients 2
• These effects are transient and less common with long-acting formulations 7, 3
• Injection-site reactions 4

Important Safety Considerations

Serious Warnings

• Risk of thyroid C-cell tumors observed in rodents; contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 2
• Pancreatitis has been reported; discontinue if suspected 2
• Diabetic retinopathy complications reported in clinical trials; monitor patients with history of diabetic retinopathy 2
• Acute kidney injury possible, especially in patients with severe gastrointestinal reactions causing dehydration 2, 5

Perioperative Concerns

• Increased risk of pulmonary aspiration due to delayed gastric emptying and retained gastric contents 1
• For weight management patients: withhold for at least three half-lives before elective surgery 1
• For diabetes patients, cessation requires individualized approach with endocrinology consultation due to glycemic control concerns 1

Drug Interactions

• Delays gastric emptying, which may impact absorption of concomitantly administered oral medications 2
• When used with insulin secretagogues or insulin, consider lowering their doses to reduce hypoglycemia risk 2

Clinical Positioning

• Recommended as second-line therapy in combination with metformin when metformin alone fails to achieve HbA1c goals 3, 6
• Can be combined with sulfonylureas, thiazolidinediones, or basal insulin 3
• Preferred over many other agents because they do not cause weight gain or significant hypoglycemia, and actually promote weight loss 1, 6
• Once-weekly formulations may improve treatment adherence 4