What is the recommended approach for switching from tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist) to semaglutide (GLP-1 receptor agonist)?

Switching from Tirzepatide to Semaglutide

Direct Switching Protocol

When switching from tirzepatide to semaglutide, discontinue tirzepatide and initiate semaglutide at 0.25 mg weekly the following week, then follow the standard titration schedule to reach the maintenance dose of 2.4 mg weekly over 16 weeks. 1

Titration Schedule for Semaglutide After Switch

The standard semaglutide titration must be followed to minimize gastrointestinal adverse effects, regardless of prior tirzepatide dose 1:

• Week 1-4: Start semaglutide 0.25 mg weekly 1
• Week 5-8: Increase to 0.5 mg weekly 1
• Week 9-12: Increase to 1.0 mg weekly 1
• Week 13-16: Increase to 1.7 mg weekly 1
• Week 17+: Reach maintenance dose of 2.4 mg weekly 1

Critical Considerations

Why Standard Titration is Mandatory

You cannot start at a higher semaglutide dose even if the patient was on tirzepatide 15 mg. The gradual dose escalation is essential to minimize gastrointestinal adverse effects including nausea, vomiting, and diarrhea, which occur in 17-40% of patients 2, 3. Starting at higher doses significantly increases treatment discontinuation rates 1, 4.

Expected Outcomes After Switching

• Weight loss will likely decrease compared to tirzepatide. Semaglutide 2.4 mg achieves 14.9% weight loss versus tirzepatide's 20.9%, representing a 6% absolute difference 4, 5
• Glycemic control may be slightly reduced. Tirzepatide 15 mg reduces HbA1c by 2.30% versus semaglutide 1.0 mg at 1.86%, though semaglutide 2.4 mg provides comparable glycemic control 2, 3
• Gastrointestinal side effects may recur during titration despite prior tolerance to tirzepatide, as each medication has distinct receptor mechanisms 2, 3

Insulin Adjustment if Applicable

If the patient is on insulin therapy 4:

• Reduce basal insulin by 20% when initiating semaglutide to prevent hypoglycemia 4
• Consider discontinuing or reducing prandial insulin by 50% at initiation 4
• Monitor glucose closely: Check fasting glucose daily and pre-meal glucose for the first 2 weeks 4
• If glucose <70 mg/dL occurs, reduce insulin further by 10-20% immediately 4

Contraindications and Safety Monitoring

Absolute Contraindications

• Personal or family history of medullary thyroid cancer 1, 4
• Multiple endocrine neoplasia syndrome type 2 1, 4

Monitoring Requirements

• Assess for gastrointestinal symptoms at each dose escalation, particularly nausea and vomiting 1, 2
• Monitor for pancreatitis symptoms: persistent severe abdominal pain 1, 4
• Watch for gallbladder disease signs: right upper quadrant pain, jaundice 1, 4
• Blood pressure monitoring: Weight loss may necessitate antihypertensive medication adjustment 4

Medication Interactions

• Do not combine with other GLP-1 receptor agonists or dipeptidyl peptidase-4 inhibitors 1
• Use caution with insulin secretagogues (sulfonylureas) due to hypoglycemia risk 1
• May affect absorption of oral medications requiring rapid onset due to delayed gastric emptying 1

Managing Missed Doses

• If 2 consecutive doses missed: Resume at the same dose if previously well-tolerated, otherwise consider lowering the dose 1
• If 3 or more consecutive doses missed: Restart the entire titration schedule from 0.25 mg weekly 1

Clinical Rationale for Switching

Common reasons for switching from tirzepatide to semaglutide include 4:

• Cost or insurance coverage issues: Tirzepatide costs approximately $1,272-$1,600 per month versus semaglutide at similar pricing, but insurance authorization may differ 4
• Cardiovascular disease: Semaglutide 2.4 mg has proven cardiovascular benefit with 20% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80), while tirzepatide cardiovascular outcome data is pending 1, 4
• Supply chain issues or medication availability 4

Important Caveats

• Weight regain is expected during the transition period as you titrate up semaglutide from subtherapeutic doses 4
• Counsel patients about temporary reduction in efficacy during the 16-week titration period 1, 4
• Some patients may achieve adequate response at submaximal doses (e.g., 1.0 mg or 1.7 mg weekly) and can continue long-term at that dose 1
• Lifelong treatment is typically required as discontinuation results in regain of 50-67% of lost weight within one year 4