How do you initiate a Glucagon-Like Peptide-1 (GLP-1) receptor agonist?

How to Initiate a GLP-1 Receptor Agonist

Start with semaglutide 0.25 mg subcutaneously once weekly, then titrate to 0.5 mg after 4 weeks, and if needed, increase to 1 mg weekly after at least another 4 weeks. 1

Pre-Initiation Screening

Before starting any GLP-1 receptor agonist, screen for absolute contraindications:

• Personal or family history of medullary thyroid carcinoma (MTC) 2, 1
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 2, 1
• History of serious hypersensitivity reaction to the drug 2
• Severe renal impairment or ESRD (for exenatide and lixisenatide specifically) 2

Use caution but not contraindicated in:

• History of pancreatitis (use liraglutide with caution; consider alternative for others) 2
• Severe renal impairment (use liraglutide and semaglutide with caution) 2
• History of gastroparesis (shorter-acting agents delay gastric emptying) 2
• Proliferative diabetic retinopathy (caution with semaglutide and dulaglutide due to rapid A1C reduction) 2

Dosing Strategy by Agent

Once-weekly agents (preferred for adherence):

• Semaglutide: 0.25 mg weekly × 4 weeks → 0.5 mg weekly (maintenance or titrate further) → 1 mg weekly if needed after ≥4 weeks 1
• Dulaglutide: Start at standard dose per product labeling 2
• Exenatide extended-release: Once weekly dosing 2

Daily agents:

• Liraglutide: Once daily dosing 2
• Lixisenatide: Once daily dosing 2

Concomitant Medication Adjustments

If HbA1c is well-controlled at baseline or patient has history of frequent hypoglycemia: 2

• Discontinue or wean sulfonylureas when starting GLP-1 RA 2
• Reduce total daily insulin dose by approximately 20% 2
• GLP-1 RAs have minimal hypoglycemia risk as monotherapy but increase hypoglycemic potential when combined with insulin or sulfonylureas 2

Patient Education at Initiation

Gastrointestinal symptoms management: 2

• Nausea, vomiting, and diarrhea occur in 15-20% of patients 3
• These symptoms are typically transient and diminish over several weeks with dose titration 3
• Start at low doses and titrate slowly to minimize GI side effects 4

Monitoring instructions: 2

• Monitor glucose more closely at home for the first 4 weeks of therapy, especially if on insulin, sulfonylurea, or glinides 2
• Educate regarding symptoms of hypoglycemia if combined with insulin or secretagogues 2

Administration technique:

• Inject subcutaneously in abdomen, thigh, or upper arm 1
• Administer once weekly at any time of day, with or without meals 1
• If a dose is missed, administer within 5 days of the missed dose 1

Clinical Context for Selection

Prioritize GLP-1 RAs with proven cardiovascular benefit in patients with: 2

• Established atherosclerotic cardiovascular disease (ASCVD)
• Type 2 diabetes at high cardiovascular risk
• At time of ASCVD diagnosis, at time of T2D diagnosis in patient with ASCVD, or at hospital discharge after ASCVD event 2

Agents with demonstrated cardiovascular benefit include: 4

• Liraglutide (LEADER trial: 13% relative risk reduction in CV death, non-fatal MI, or stroke) 4
• Semaglutide (SUSTAIN-6 trial: RR 0.74 for CV outcomes) 4
• Dulaglutide (REWIND trial) 2

Consider GLP-1 RAs as first injectable therapy before insulin in most patients, given similar or superior HbA1c reduction with additional weight loss and no intrinsic hypoglycemia risk 5

Common Pitfalls to Avoid

• Never share a GLP-1 RA pen between patients, even if the needle is changed 1
• Do not combine GLP-1 RAs with DPP-4 inhibitors - no added glucose-lowering benefit beyond GLP-1 RA alone 2
• Avoid in recent heart failure decompensation 4
• Monitor renal function in patients with renal impairment who report severe gastrointestinal reactions, as acute kidney injury can occur through hemodynamic derangement from nausea, vomiting, and diarrhea 1, 6
• Discontinue in women at least 2 months before planned pregnancy due to long washout period for semaglutide 1