In an adult with type 2 diabetes who is appropriate for oral therapy, is a GLP‑2 (glucagon‑like peptide‑2) inhibitor an appropriate second‑line treatment after metformin?

GLP-2 Inhibitors Are Not Appropriate for Type 2 Diabetes Treatment

GLP-2 (glucagon-like peptide-2) inhibitors do not exist as a therapeutic class for type 2 diabetes. You are likely asking about GLP-1 receptor agonists (such as liraglutide, semaglutide, or tirzepatide), which are well-established second-line agents after metformin.

Clarification: GLP-1 vs GLP-2

• GLP-1 receptor agonists lower blood glucose by enhancing insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting weight loss 1
• GLP-2 is a distinct incretin hormone that primarily affects intestinal growth and nutrient absorption—it has no role in diabetes management 1
• The evidence base for diabetes treatment exclusively involves GLP-1 receptor agonists, not GLP-2 inhibitors 1, 2

Appropriate Second-Line Treatment After Metformin

If you meant GLP-1 receptor agonists, they are indeed appropriate second-line therapy after metformin, particularly in specific clinical contexts:

When to Prioritize GLP-1 Receptor Agonists

• Established atherosclerotic cardiovascular disease (ASCVD): GLP-1 RAs with proven cardiovascular benefit reduce major adverse cardiovascular events and all-cause mortality 1, 3
• Stroke risk or history: GLP-1 RAs specifically reduce stroke risk compared to other glucose-lowering agents 3
• Weight loss as treatment goal: GLP-1 RAs produce substantial weight loss (mean 8.47 kg with tirzepatide) and are preferred when obesity management is critical 2, 3
• Metabolic dysfunction-associated steatotic liver disease (MASLD): GLP-1 RAs improve steatohepatitis and slow fibrosis progression 1, 2

When to Prioritize SGLT-2 Inhibitors Instead

• Heart failure (reduced or preserved ejection fraction): SGLT-2 inhibitors reduce heart failure hospitalizations more effectively than GLP-1 RAs 1, 3
• Chronic kidney disease (eGFR 25-60 mL/min/1.73m² or UACR >200 mg/g): SGLT-2 inhibitors slow CKD progression and reduce cardiovascular mortality 1, 3
• Primary goal of cardiovascular mortality reduction: SGLT-2 inhibitors demonstrate high-certainty evidence for all-cause mortality reduction 3

Cost-Effectiveness Considerations

• GLP-1 RAs as second-line therapy (added to metformin) are probably of intermediate value ($50,000-$150,000 per QALY gained) compared to continuing metformin alone 1
• GLP-1 RAs may be of low value compared to adding a sulfonylurea, though this analysis does not account for cardiovascular benefits independent of glucose lowering 1
• Both SGLT-2 inhibitors and GLP-1 RAs should be added to metformin independent of HbA1c levels when cardiovascular or renal disease is present 1, 2

Critical Safety Points

• Reduce or discontinue sulfonylureas and insulin when adding GLP-1 RAs to minimize severe hypoglycemia risk 2, 3
• Do not combine GLP-1 RAs with DPP-4 inhibitors—this provides no additional glucose lowering and increases adverse events 2, 4
• GLP-1 RAs carry low hypoglycemia risk as monotherapy or with metformin but require dose adjustments when combined with insulin secretagogues 2, 3

Bottom Line

If you are asking about GLP-1 receptor agonists (not GLP-2 inhibitors, which don't exist for diabetes), they are appropriate and guideline-recommended second-line agents after metformin, particularly when cardiovascular disease, stroke risk, weight loss, or liver disease are present 1, 2, 3. Choose SGLT-2 inhibitors instead when heart failure or advanced CKD predominate 1, 3.