What are the first-line treatment options for type 2 diabetes, considering GLP-1 (Glucagon-Like Peptide-1) receptor agonists?

First-Line Treatment Options for Type 2 Diabetes with GLP-1 Receptor Agonists

Metformin remains the preferred initial pharmacologic agent for type 2 diabetes, but GLP-1 receptor agonists should be added immediately (independent of A1C level) in patients with established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. 1, 2

Initial Treatment Algorithm

Step 1: Start with Metformin

• Metformin should be initiated at diagnosis of type 2 diabetes unless contraindicated. 1
• Metformin is effective, safe, inexpensive, and may reduce cardiovascular events and death. 1
• Continue metformin as long as tolerated throughout the treatment course, even when adding other agents. 1
• Metformin can be safely used in patients with eGFR ≥30 mL/min/1.73 m². 1

Step 2: Add GLP-1 Receptor Agonist Based on Comorbidities

For patients WITH established cardiovascular disease or high-risk indicators:

• Add a GLP-1 receptor agonist with proven cardiovascular benefit immediately, regardless of baseline A1C level. 1, 2
• High-risk indicators include: age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73m², or albuminuria. 2
• This decision should be made independently of glycemic control. 2

For patients WITH chronic kidney disease:

• Add a GLP-1 receptor agonist if eGFR <60 mL/min/1.73m² or albuminuria ≥30 mg/g, particularly if SGLT2 inhibitors are not tolerated. 2
• GLP-1 receptor agonists can be used safely with eGFR as low as 2 mL/min/1.73m² with no dosage adjustments required. 2

For patients WITHOUT cardiovascular disease or kidney disease:

• Add a GLP-1 receptor agonist when metformin alone fails to achieve glycemic targets. 1, 2
• GLP-1 receptor agonists are preferred over insulin when additional glucose-lowering is needed beyond oral agents. 1, 2
• Consider GLP-1 receptor agonists particularly in patients with obesity due to weight reduction benefits. 2

Specific GLP-1 Receptor Agonist Selection

When selecting among GLP-1 receptor agonists, consider:

• Individual preference and frequency of injection (twice daily, once daily, or once weekly options available). 1
• For patients with established cardiovascular disease, choose agents with proven cardiovascular benefit (liraglutide, semaglutide, dulaglutide). 1, 3, 4, 3
• Both oral and injectable GLP-1 receptor agonists are appropriate. 1

Exception: When to Use Insulin First

Insulin should be the first injectable therapy (instead of GLP-1 receptor agonist) when:

• Symptoms of hyperglycemia are present. 1
• A1C >10% (>86 mmol/mol) or blood glucose ≥300 mg/dL (≥16.7 mmol/L). 1
• Type 1 diabetes is a diagnostic possibility. 1

Combination Therapy Considerations

• If A1C remains above goal on metformin plus GLP-1 receptor agonist, consider adding basal insulin. 1
• Fixed-ratio combination products (IDegLira or iGlarLixi) can be used for patients requiring both GLP-1 receptor agonist and basal insulin. 1
• Early combination therapy with metformin plus GLP-1 receptor agonist can be considered at diagnosis in some patients with A1C levels 1.5–2.0% above goal. 1

Critical Contraindications and Precautions

GLP-1 receptor agonists are contraindicated in:

• Personal or family history of medullary thyroid carcinoma. 3, 4, 3
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). 3, 4, 3

Use with caution in:

• Patients with history of pancreatitis (consider alternative therapy). 3
• Patients with diabetic retinopathy should be monitored. 3

Common side effects (≥5% of patients):

• Nausea, vomiting, diarrhea, abdominal pain, and constipation. 3

Special Population: Youth with Type 2 Diabetes

• For children and adolescents aged 10 years and older with type 2 diabetes, GLP-1 receptor agonists are safe and effective for decreasing A1C. 1, 4
• Initial treatment should include metformin when insulin is not required. 1
• GLP-1 receptor agonists should not be used in youth with family history of medullary thyroid cancer. 1

Timing of Treatment Intensification

Do not delay treatment intensification (avoid therapeutic inertia). 1

• Reevaluate medication regimen every 3–6 months. 1
• Each new class added to metformin generally lowers A1C by approximately 0.7–1.0%. 1