What is the recommended micro‑dosing titration protocol for retatrutide in an adult with obesity (BMI ≥ 30 kg/m² or ≥ 27 kg/m² with comorbidities) who has no contraindications such as medullary thyroid carcinoma, MEN 2, pregnancy, pancreatitis, or severe gastroparesis?

Retatrutide Micro-Dosing Titration Protocol for Obesity

For adults with obesity (BMI ≥30 kg/m² or ≥27 kg/m² with comorbidities) and no contraindications, retatrutide should be initiated at 2 mg subcutaneously once weekly, then escalated every 4 weeks using a gradual micro-dosing approach: 2 mg → 4 mg → 8 mg → 12 mg, reaching the maximum dose by week 12.

Eligibility Confirmation

• BMI threshold met: Patient qualifies with BMI ≥30 kg/m² (obesity alone) or BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, type 2 diabetes, obstructive sleep apnea, cardiovascular disease). 1
• Absolute contraindications excluded: Screen for personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2)—these are absolute contraindications to all GLP-1-based therapies including retatrutide. 1, 2, 3
• Pregnancy/breastfeeding excluded: Retatrutide is contraindicated in pregnancy or lactation. 3
• Severe gastroparesis or pancreatitis history: Use with extreme caution; consider alternative therapy if severe gastrointestinal motility disorders are present. 1

Micro-Dosing Titration Schedule

The phase 2 trial demonstrated that starting at 2 mg (rather than 4 mg) significantly reduces gastrointestinal adverse events while maintaining efficacy. 4, 5

Week	Dose	Rationale
0–4	2 mg weekly	Lower starting dose mitigates nausea, vomiting, and diarrhea (most common adverse events). [4,5]
5–8	4 mg weekly	Gradual escalation maintains GI tolerability while initiating therapeutic weight loss. [4,6]
9–12	8 mg weekly	Dose-dependent weight loss accelerates; 8 mg achieved 22.8% mean weight loss at 48 weeks in phase 2 trials. [4,6]
13+	12 mg weekly	Maximum approved dose; 12 mg produced 24.2% mean weight loss at 48 weeks with 83% of patients achieving ≥15% weight reduction. [4,6]

• Administration: Subcutaneous injection in abdomen, thigh, or upper arm once weekly on the same day each week, with or without meals. 2
• Missed dose protocol: If ≤5 days late, administer immediately and resume schedule; if >5 days late, skip and resume at next scheduled dose. 2

Expected Outcomes by Dose

• 4 mg dose: Mean weight loss of 17.1% at 48 weeks; 92% achieve ≥5% weight loss, 75% achieve ≥10%, 60% achieve ≥15%. 4, 6
• 8 mg dose: Mean weight loss of 22.8% at 48 weeks; 100% achieve ≥5%, 91% achieve ≥10%, 75% achieve ≥15%. 4, 6
• 12 mg dose: Mean weight loss of 24.2% at 48 weeks; 100% achieve ≥5%, 93% achieve ≥10%, 83% achieve ≥15%. 4, 6

Monitoring Schedule

During Titration (Weeks 0–12)

• Every 4 weeks: Assess gastrointestinal tolerance (nausea, vomiting, diarrhea), body weight, blood pressure, and heart rate. 1, 3, 4
• Heart rate monitoring: Retatrutide increases heart rate by up to 6.7 beats/min, peaking at 24 weeks then declining; monitor closely in patients with cardiovascular disease. 7, 4
• Blood pressure: Expect systolic BP reduction of ~9.88 mm Hg and diastolic BP reduction of ~3.88 mm Hg; adjust antihypertensive medications accordingly. 8, 6

After Reaching Maintenance Dose (Week 13+)

• Every 3 months: Monitor weight, blood pressure, fasting glucose, HbA1c (if diabetic), lipid panel, and cardiovascular risk factors. 1, 3
• Efficacy assessment at 12–16 weeks: If weight loss is <5% after 12 weeks on therapeutic dose, consider discontinuation or alternative therapy. 1, 3

Concomitant Medication Adjustments

• Insulin: Reduce basal insulin by 20% when initiating retatrutide to prevent hypoglycemia. 1, 2
• Sulfonylureas: Discontinue or reduce dose by 50% before starting retatrutide due to additive hypoglycemia risk. 1, 2
• DPP-4 inhibitors: Stop all DPP-4 inhibitors (sitagliptin, linagliptin) before initiating retatrutide; no additional glycemic benefit from combination. 1, 2
• Antihypertensives: Anticipate need for dose reduction as weight loss lowers blood pressure. 1, 8

Adverse Event Management

Gastrointestinal Effects (Most Common)

• Nausea, vomiting, diarrhea: Occur in dose-dependent manner; typically mild-to-moderate and transient, resolving within 4–8 weeks. 4, 5, 6
• Mitigation strategies: Slow titration (2 mg starting dose), smaller meal portions, avoid high-fat foods, limit alcohol and carbonated beverages. 1, 4
• Persistent severe abdominal pain: Discontinue immediately and evaluate for pancreatitis or gallbladder disease. 1, 3

Cardiovascular Monitoring

• Heart rate elevation: Increases peak at 24 weeks (up to 6.7 bpm) then decline; may offset some cardiovascular benefits of weight loss. 7, 4
• Clinical significance: Monitor closely in patients with pre-existing cardiovascular disease or arrhythmias. 7

Lifestyle Integration (Mandatory)

• Caloric deficit: Combine retatrutide with 500-kcal daily reduction below maintenance requirements. 1, 3
• Physical activity: Minimum 150 minutes per week of moderate-intensity exercise. 1, 3
• Resistance training: Essential to preserve lean body mass during rapid weight loss. 1
• Behavioral counseling: Structured lifestyle modification support enhances long-term adherence. 1, 3

Discontinuation Criteria

• Inadequate response: <5% weight loss after 12–16 weeks on maximum tolerated dose. 1, 3
• Safety concerns: Persistent severe gastrointestinal symptoms, suspected pancreatitis, gallbladder disease, or intolerable adverse events. 1, 3
• Patient preference: Inability to tolerate weekly injections or adverse effects. 1

Comparative Context

Retatrutide demonstrates superior weight loss compared to currently approved agents:

• Tirzepatide 15 mg: 20.9% weight loss at 72 weeks. 1, 6
• Semaglutide 2.4 mg: 14.9% weight loss at 68 weeks. 1, 3
• Retatrutide 12 mg: 24.2% weight loss at 48 weeks. 4, 6

However, retatrutide lacks cardiovascular outcome data; for patients with established cardiovascular disease, semaglutide 2.4 mg remains preferred due to proven 20% reduction in MACE. 1, 3

Critical Pitfalls to Avoid

• Do not start at 4 mg or higher: Phase 2 data clearly show that 2 mg starting dose reduces gastrointestinal adverse events without compromising efficacy. 4, 5
• Do not escalate faster than every 4 weeks: Rapid titration increases discontinuation rates due to intolerable GI symptoms. 4, 5
• Do not overlook heart rate monitoring: Dose-dependent tachycardia may be clinically significant in vulnerable populations. 7, 4
• Do not prescribe without lifestyle intervention: Pharmacotherapy alone without caloric restriction and exercise yields suboptimal outcomes. 1, 3
• Do not assume superiority over semaglutide in all patients: Retatrutide's greater weight loss does not outweigh semaglutide's proven cardiovascular protection in high-risk patients. 1, 7