When do we start insulin versus a Glucagon-like peptide-1 (GLP-1) receptor agonist for diabetes mellitus?

When to Start Insulin vs. GLP-1 Receptor Agonists for Diabetes Mellitus

For most patients with type 2 diabetes requiring injectable therapy, GLP-1 receptor agonists are preferred over insulin due to their superior efficacy, weight benefits, and lower hypoglycemia risk. 1

Decision Algorithm for Injectable Therapy Selection

Start with GLP-1 Receptor Agonists When:

• Patient has confirmed type 2 diabetes requiring injectable therapy
• Patient does not have symptoms of severe hyperglycemia
• Weight management is a priority (GLP-1 RAs promote weight loss)
• Hypoglycemia risk is a concern
• Cardiovascular disease is present (choose GLP-1 RAs with proven CV benefit)

Start with Insulin When:

• Evidence of ongoing catabolism (unexpected weight loss)
• Symptoms of hyperglycemia are present
• A1C >10% (>86 mmol/mol) or blood glucose ≥300 mg/dL (≥16.7 mmol/L)
• Type 1 diabetes is suspected 1
• Extreme and symptomatic hyperglycemia requiring rapid correction 1

Benefits of GLP-1 Receptor Agonists vs. Insulin

GLP-1 receptor agonists offer several advantages over insulin:

• Similar or better A1C reduction compared to basal insulin 1
• Weight loss instead of weight gain seen with insulin 1, 2
• Lower risk of hypoglycemia 1, 3
• Some formulations allow for once-weekly injections 3
• Cardiovascular and renal protective effects 2, 3

Important Clinical Considerations

When Starting GLP-1 RAs:

• Begin with lower doses and titrate gradually to minimize gastrointestinal side effects 4
• For semaglutide: Start with 0.25 mg once weekly for 4 weeks (initiation dose), then increase to 0.5 mg once weekly 4
• If additional glycemic control is needed after at least 4 weeks, may increase to 1 mg once weekly 4
• Monitor for common side effects: nausea, vomiting, diarrhea 4

When Starting Insulin:

• Start basal insulin at 0.1-0.2 units/kg/day or 10 units daily 5
• Titrate by 2-4 units or 10-15% every 3-4 days until fasting target is reached 5
• Consider continuing metformin and other glucose-lowering agents with complementary mechanisms 1
• When adding insulin to existing therapy, reassess the need for sulfonylureas or meglitinides to reduce hypoglycemia risk 1

Combination Therapy

If glycemic targets are not achieved with a GLP-1 RA alone:

• Consider adding basal insulin while continuing the GLP-1 RA 1, 6
• When adding a GLP-1 RA to existing insulin therapy, reduce insulin dose by approximately 20% if A1C ≤8% to prevent hypoglycemia 6
• Fixed-ratio combination products (IDegLira or iGlarLixi) may be considered for patients on both GLP-1 RA and basal insulin 1

Common Pitfalls to Avoid

1. Delaying insulin when indicated: In cases of severe hyperglycemia, catabolism, or suspected type 1 diabetes, insulin should not be delayed in favor of GLP-1 RAs 5

2. Overbasalization: Monitor for signs such as basal dose >0.5 units/kg/day, significant bedtime-to-morning glucose differential, hypoglycemia, or high glycemic variability 1

3. Ignoring cost considerations: GLP-1 RAs are generally more expensive than insulin, which may affect adherence and treatment effectiveness 1

4. Overlooking contraindications: GLP-1 RAs are contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 4

5. Not accounting for renal function: In advanced CKD (eGFR <30 mL/min/1.73 m²), GLP-1 RAs are preferred for glycemic management due to lower hypoglycemia risk 1

By following this evidence-based approach to selecting between insulin and GLP-1 receptor agonists, clinicians can optimize glycemic control while minimizing risks and maximizing benefits for patients with diabetes mellitus.