What is the difference between Glucagon-like peptide-1 (GLP-1) and Glucagon-like peptide-2 (GLP-2) in terms of therapeutic use?

GLP-1 vs GLP-2: Distinct Peptides with Completely Different Therapeutic Applications

GLP-1 receptor agonists are used for type 2 diabetes and cardiovascular disease management, while GLP-2 analogs are used exclusively for short bowel syndrome—these are fundamentally different medications targeting different organ systems and disease states. 1

GLP-1 Receptor Agonists: Metabolic and Cardiovascular Therapy

Primary Indications

• Type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control 2
• Cardiovascular risk reduction in adults with type 2 diabetes and established cardiovascular disease 2
• Obesity management (liraglutide 3.0 mg specifically) 3

Mechanism of Action

• GLP-1 enhances glucose-dependent insulin secretion from pancreatic beta cells 4
• Inhibits glucagon secretion, gastric emptying, and reduces food intake 4, 5
• Stimulates beta-cell proliferation and has antiapoptotic effects on pancreatic tissue 5
• Exerts anti-inflammatory and cardioprotective effects through multiple pathways including reduced systemic inflammation and improved endothelial function 6

Clinical Guideline Recommendations

• First-line therapy for type 2 diabetes with CKD (eGFR ≥30 mL/min/1.73 m²) when metformin and SGLT2 inhibitors are insufficient or not tolerated 7
• Preferred agent for patients with type 2 diabetes and established atherosclerotic cardiovascular disease to reduce major adverse cardiovascular events 7, 8
• Liraglutide reduced cardiovascular death, non-fatal MI, or stroke by 13% in the LEADER trial 7, 8
• Semaglutide reduced cardiovascular outcomes by 26% in SUSTAIN-6 7, 8

Common Adverse Effects

• Gastrointestinal effects (nausea, vomiting, diarrhea) are most common, typically transient and resolve within 4-8 weeks 9, 10
• Rare risk of acute pancreatitis; use with caution in patients with pancreatitis history 6, 8
• Avoid in recent heart failure decompensation 6

GLP-2 Analogs: Intestinal Rehabilitation Therapy

Primary Indication

• Short bowel syndrome (SBS) in adults and pediatric patients ≥1 year old who are dependent on parenteral support 1
• This is the only FDA-approved indication for GLP-2 analogs 1

Mechanism of Action

• GLP-2 (teduglutide) binds to GLP-2 receptors on enteric nerves and enteroendocrine cells in the gastrointestinal tract 1
• Promotes nutrient absorption by expanding mucosal epithelium through stimulation of crypt cell proliferation and inhibition of apoptosis 4, 5
• Increases intestinal and portal blood flow while inhibiting gastric acid secretion 1
• Reduces epithelial permeability and improves intestinal barrier function 5

Clinical Effects

• Enhances gastrointestinal fluid absorption by approximately 750-1000 mL/day 1
• Increases villus height and crypt depth of intestinal mucosa 1
• Improves intestinal adaptation and nutrient absorption after major small bowel resection 4

Dosing Considerations

• Standard dose: 0.05 mg/kg/day subcutaneously 1
• Reduce dose by half in patients with eGFR <60 mL/min/1.73 m² (both pediatric and adult) 1
• No dose adjustment needed for mild-moderate hepatic impairment 1

Critical Distinctions

Receptor Specificity

• GLP-1 and GLP-2 act on completely different receptors despite being derived from the same proglucagon precursor 4, 5
• GLP-1 receptors are expressed in pancreas, brain, heart, lungs, kidneys, and gastrointestinal tract 3
• GLP-2 receptors are expressed on enteric nerves and enteroendocrine cells specifically in the gastrointestinal tract 1, 4

Non-Overlapping Clinical Applications

• GLP-1 agonists have no role in short bowel syndrome 1
• GLP-2 analogs have no role in diabetes or cardiovascular disease 1
• Attempting to use one for the other's indication would be inappropriate and ineffective 4, 5

Degradation Pathway

• Both peptides are inactivated by dipeptidyl peptidase IV (DP IV) cleavage at the N-terminal penultimate alanine 4
• This shared vulnerability led to development of DP IV-resistant analogs for both peptides 4

Common Pitfall to Avoid

Do not confuse these medications based on similar naming conventions. The "GLP" designation refers to their shared origin from proglucagon, but their therapeutic applications are entirely distinct. GLP-1 agonists (semaglutide, liraglutide, dulaglutide, exenatide) are metabolic/cardiovascular agents, while GLP-2 analogs (teduglutide) are gastrointestinal rehabilitation agents 2, 1.