What is the proper way to microdose semaglutide (glucagon-like peptide-1 receptor agonist)?

Semaglutide Dosing: Gradual Titration Protocol

The proper way to "microdose" semaglutide is through the FDA-approved gradual dose titration protocol, starting at 0.25 mg subcutaneously once weekly for 4 weeks, then escalating by increments every 4 weeks to minimize gastrointestinal adverse effects while achieving therapeutic benefit. 1, 2

Standard Titration Schedule

The evidence-based approach requires slow, protocolized dose escalation rather than arbitrary "microdosing":

For Weight Management (2.4 mg target dose):

• Week 1-4: 0.25 mg subcutaneously once weekly 2
• Week 5-8: 0.5 mg once weekly 2
• Week 9-12: 1.0 mg once weekly 2
• Week 13-16: 1.7 mg once weekly 2
• Week 17+: 2.4 mg once weekly (maintenance dose) 1, 2

For Type 2 Diabetes (1 mg target dose):

• Initial: 0.25 mg once weekly for 4 weeks 2
• Maintenance: Increase to 0.5 mg, then 1 mg weekly as needed for glycemic control 2

Critical Implementation Points

Gradual titration is not optional—it is essential to minimize gastrointestinal adverse effects including nausea (the most common side effect), vomiting, and diarrhea. 1, 2 These effects are dose-dependent and more frequent with rapid escalation. 1

Flexibility in Titration:

• Clinical judgment should guide adjustments to the titration schedule based on individual response, tolerance, and adverse effects 2
• If gastrointestinal symptoms persist, maintain the current dose longer before advancing rather than discontinuing therapy, as symptoms typically diminish over time 3
• Some patients achieve strong therapeutic responses at submaximal doses (e.g., 1.0 mg or 1.7 mg) and could continue at that dose long-term 2

Administration Technique

• Inject subcutaneously once weekly at any time of day, independent of meals 3
• Rotate injection sites within the abdomen, thigh, or upper arm 3
• The same day each week is recommended for consistency 2

Common Pitfalls to Avoid

Do not skip the initial low-dose phase. The 0.25 mg starting dose is specifically designed for treatment initiation and gastrointestinal tolerability, not for therapeutic effect. 4 Patients who start at higher doses experience significantly more nausea and vomiting. 1

Do not combine with other GLP-1 receptor agonists or DPP-4 inhibitors. 2, 3 This provides no additional benefit and increases adverse effects.

Monitor for hypoglycemia if using concurrent insulin or insulin secretagogues. While semaglutide has very low hypoglycemia risk as monotherapy, risk increases substantially when combined with these agents. 2 Reduce doses of insulin or sulfonylureas when initiating semaglutide. 3

Monitoring During Titration

• Assess gastrointestinal symptoms at each dose escalation 3
• Monitor body weight every 4 weeks during dose escalation 3
• If patient has type 2 diabetes, monitor glucose levels more frequently during titration 3

Contraindications

Absolute contraindications include: 1

• Personal or family history of medullary thyroid cancer
• Multiple endocrine neoplasia syndrome type 2
• Pregnancy and breastfeeding 3

Use with caution in patients with history of pancreatitis. 1 Current guidelines recommend caution if GLP-1 receptor agonists are needed in patients with prior pancreatitis. 1

Long-Term Considerations

Semaglutide should be considered lifelong therapy. Weight regain occurs after discontinuation, and cardiovascular benefits require ongoing treatment. 2, 3 The STEP trials demonstrated mean weight loss of 14.9% at 72 weeks with the 2.4 mg dose, but this benefit is lost upon cessation. 1

The cardiovascular benefits are substantial: in patients with pre-existing cardiovascular disease, semaglutide 2.4 mg weekly reduced the primary cardiovascular endpoint (death from cardiovascular causes, non-fatal MI, or non-fatal stroke) from 8.2% to 6.5% (p=0.001). 1