Retatrutide Dosing for Obesity and Type 2 Diabetes
Start retatrutide at 2 mg subcutaneously once weekly, then escalate every 4 weeks through 4 mg, 8 mg, to a maintenance dose of 12 mg weekly, based on the phase 2 trial demonstrating 24.2% weight loss at 48 weeks with this regimen. 1
Standard Dosing Protocol
The evidence-based titration schedule for retatrutide follows this specific sequence 1:
- Weeks 1-4: 2 mg subcutaneously once weekly
- Weeks 5-8: 4 mg subcutaneously once weekly
- Weeks 9-12: 8 mg subcutaneously once weekly
- Week 13 onward: 12 mg subcutaneously once weekly (maintenance dose)
This gradual escalation strategy was specifically designed to mitigate gastrointestinal adverse events, which were dose-related and mostly mild to moderate in severity. 1 The phase 2 trial demonstrated that starting at 2 mg versus 4 mg partially reduced the incidence of nausea, diarrhea, and vomiting. 1
Administration Technique
Inject retatrutide subcutaneously in the abdomen, thigh, or upper arm at any time of day, with or without meals, on the same day each week. 1 The injection site should be rotated within the same anatomical area to minimize absorption variability.
Expected Efficacy Outcomes
At 48 weeks, the 12 mg maintenance dose achieved 1:
- Mean weight loss: 24.2% from baseline
- ≥5% weight reduction: 100% of participants
- ≥10% weight reduction: 93% of participants
- ≥15% weight reduction: 83% of participants
For type 2 diabetes management, the 12 mg dose reduced HbA1c by 2.02% at 24 weeks, significantly superior to both placebo and dulaglutide 1.5 mg. 2
Dose Modification for Intolerance
If gastrointestinal symptoms are severe at any dose level, maintain the current dose for an additional 4 weeks before continuing escalation. 1 This approach was validated in the phase 2 trial where slower escalation improved tolerability without compromising efficacy. 1
Alternative dosing for patients unable to tolerate 12 mg 1:
- 8 mg weekly: Achieved 22.8% weight loss at 48 weeks
- 4 mg weekly: Achieved 17.1% weight loss at 48 weeks
Critical Safety Monitoring
Cardiovascular monitoring is mandatory because retatrutide increased heart rate by up to 6.7 beats per minute in phase 2 trials, with peak increases at 24 weeks that declined thereafter. 3, 1 This tachycardic effect may offset some cardiovascular benefits of weight loss and requires clinical vigilance. 3
Monitor for dose-dependent adverse events 1, 2:
- Gastrointestinal effects: Nausea, diarrhea, vomiting, constipation (most common, typically mild-to-moderate)
- Pancreatitis risk: Consistent with GLP-1 receptor agonist class effects 2
- Gallbladder disease: Monitor for symptoms during treatment 2
Special Populations
No dose adjustment is required for renal impairment of any severity, including end-stage renal disease, based on the phase 2 trial inclusion criteria and safety profile. 2 Similarly, no hepatic dose adjustment was necessary in the studied population. 2
Contraindications
Retatrutide is contraindicated in patients with 2:
- Personal or family history of medullary thyroid cancer
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
- Pregnancy or lactation
- History of severe hypersensitivity to retatrutide
Concomitant Therapy Requirements
Mandatory lifestyle interventions must accompany retatrutide therapy, though specific caloric deficit and exercise targets were not explicitly defined in the retatrutide trials. 1 The phase 2 study included diet and exercise counseling as standard background therapy. 2
For patients with type 2 diabetes on insulin or sulfonylureas, consider dose reduction of these agents when initiating retatrutide to prevent hypoglycemia, though no severe hypoglycemia was reported in the phase 2 trial. 2
Treatment Duration
Retatrutide should be considered long-term therapy, as the phase 2 trial demonstrated continued weight loss through 48 weeks with no plateau effect. 1 The 12 mg dose showed progressive weight reduction from 17.5% at 24 weeks to 24.2% at 48 weeks. 1
Common Pitfalls to Avoid
Do not escalate doses faster than every 4 weeks, as this increases gastrointestinal adverse events without improving efficacy. 1 The trial data clearly showed that starting at 4 mg versus 2 mg increased adverse event rates. 1
Do not combine retatrutide with other GLP-1 receptor agonists or GIP receptor agonists, as this would provide no additional benefit and increase adverse effects. 2 The triple-receptor agonism of retatrutide makes combination therapy with similar agents redundant and potentially harmful.