Retatrutide: Proper Use and Dosage
Critical Information
The provided evidence contains no information about Retatrutide—all guideline documents 1, 2, 3, 4 pertain to tuberculosis medications (ethionamide, streptomycin, ethambutol, pyrazinamide), azithromycin, and curcumin, which are completely unrelated to your question.
What Retatrutide Actually Is
Retatrutide is a novel triple-hormone-receptor agonist (GLP-1, GIP, and glucagon receptors) currently in Phase 2 clinical trials for obesity and type 2 diabetes—it is NOT yet FDA-approved and has no established clinical dosing guidelines. 5, 6
Investigational Dosing from Clinical Trials
Obesity Treatment (Phase 2 Trial)
The most effective dose in the 48-week obesity trial was 12 mg subcutaneously once weekly, resulting in 24.2% mean weight reduction, with 83% of participants achieving ≥15% weight loss. 5
- Dosing regimen tested: 1 mg, 4 mg, 8 mg, or 12 mg subcutaneously once weekly 5
- Dose escalation strategy: Starting doses of 2 mg were better tolerated than 4 mg initial doses, with fewer gastrointestinal side effects 5
- Weight loss was dose-dependent: Higher doses (8-12 mg) produced significantly greater weight reduction than lower doses 5
Type 2 Diabetes (Phase 2 Trial)
- Doses evaluated: 0.5 mg to 12 mg subcutaneously once weekly 7
- Body composition effects: The 8 mg dose (pooled) produced 26.1% reduction in total fat mass at 36 weeks, significantly superior to placebo and dulaglutide 1.5 mg 7
- Pharmacokinetics support once-weekly dosing 8
Safety Profile from Clinical Trials
Common Adverse Events
- Gastrointestinal effects are the most frequent: Nausea, diarrhea, and vomiting occur in a dose-dependent manner and are mostly mild-to-moderate in severity 5, 6
- Mitigation strategy: Lower starting doses (2 mg vs 4 mg) partially reduce GI adverse events 5
Cardiovascular Considerations
- Heart rate increases are dose-dependent: Peak increases of up to 6.7 beats/min occurred at 24 weeks, then declined 5, 6
- This heart rate elevation may be detrimental and could offset some cardiovascular benefits of weight loss 6
Serious Adverse Events
- Low incidence: Serious adverse events occurred in 3-9% of participants across dose groups in the diabetes substudy, with no deaths reported 7
Current Clinical Status
Retatrutide is NOT approved for clinical use—it remains investigational with ongoing Phase 2b mechanistic studies (TRANSCEND-CKD) and a planned cardiovascular-kidney outcomes trial (TRIUMPH-Outcomes). 9
What This Means for Practice
- You cannot prescribe retatrutide outside of clinical trials
- No FDA-approved dosing, indications, or safety monitoring guidelines exist
- Comparator studies against semaglutide and tirzepatide are notably absent from the development program, representing a major gap 6, 8
Key Caveats
- The glucagon receptor agonism component is poorly defined: Its specific contribution to efficacy and safety in obesity/diabetes treatment remains unclear 8
- Long-term safety data are lacking: Trials to date are limited to 48 weeks maximum 5
- Lean mass preservation: The proportion of lean mass loss to total weight loss appears similar to other obesity treatments, which may provide reassurance 7