Retatrutide Dosing Guide: Starting Protocol and Titration Schedule

Retatrutide (LY3437943, developed by Eli Lilly) is the first triple incretin receptor agonist to reach Phase 3 clinical trials. It activates GLP-1, GIP, and glucagon receptors concurrently. The glucagon component distinguishes it from tirzepatide and is thought to drive additional energy expenditure on top of the appetite suppression seen with dual agonists.

What You Need for Reconstitution

• Retatrutide vial (research sizes typically 2 mg, 5 mg, or 10 mg)
• Bacteriostatic water (BAC water) for injection
• U-100 insulin syringes (0.3 mL, 0.5 mL, or 1 mL, 28-31 gauge)
• Alcohol swabs
• Refrigerator at 36-46°F (2-8°C)

Concentration Selection

Retatrutide research protocols begin at low doses (1-2 mg/week) and titrate slowly. At these early doses, a lower concentration such as 1 mg/mL gives larger, easier-to-measure draw volumes. As the dose increases toward 8-12 mg/week, a higher concentration (4-5 mg/mL) keeps injection volumes practical.

• 5 mg vial + 5 mL BAC water = 1 mg/mL (20 units per 2 mg starting dose)
• 5 mg vial + 2.5 mL BAC water = 2 mg/mL (20 units per 4 mg dose)
• 10 mg vial + 2.5 mL BAC water = 4 mg/mL (18 units per 7 mg dose)
• 10 mg vial + 2 mL BAC water = 5 mg/mL (24 units per 12 mg dose)

Step-by-Step Reconstitution

1. Wipe the top of both vials (retatrutide and BAC water) with an alcohol swab. Let dry.
2. Draw your chosen BAC water volume into the syringe.
3. Insert the needle into the retatrutide vial at a 45-degree angle.
4. Inject BAC water slowly down the inner glass wall, not directly onto the powder.
5. Remove the needle and gently swirl the vial until fully dissolved. Do not shake.
6. Verify the solution is clear and colorless. Discard if cloudy or discolored.
7. Label the vial with the reconstitution date and concentration.

Retatrutide Titration Schedule

The Phase 2 NEJM trial used the following weekly subcutaneous dosing schedule. Doses escalated every 4 weeks when tolerated, with the option to hold at any step if gastrointestinal side effects were significant.

1. Weeks 1-4: 1 mg per week
2. Weeks 5-8: 2 mg per week
3. Weeks 9-12: 4 mg per week
4. Weeks 13-16: 4 mg or 8 mg per week (two arms in the trial)
5. Weeks 17-20: 8 mg or 12 mg per week
6. Week 21+: maintenance at 8 mg or 12 mg per week

Phase 2 Clinical Trial Data

The Phase 2 NEJM study (Jastreboff et al., 2023) enrolled 338 adults with obesity across five dose groups plus placebo. At 48 weeks, participants in the 12 mg arm lost a mean of 24.2% of body weight, the highest figure reported in any incretin agonist trial at the time of publication. The 8 mg arm averaged 22.8% and the 4 mg arm 17.5%.

For comparison, tirzepatide 15 mg achieved 20.9% at 72 weeks in SURMOUNT-1, and semaglutide 2.4 mg achieved 14.9% at 68 weeks in STEP-1. Retatrutide's results are not directly comparable since the populations, trial lengths, and designs differed, but the data positioned it as the most potent agent in the class.

Using the PeptiTools Calculator for Retatrutide

Open the PeptiTools retatrutide calculator and enter your vial size (mg), BAC water volume (mL), and weekly dose (mg). The calculator outputs the exact number of units to draw on your U-100 syringe and shows a live diagram marking the fill line. As your dose increases during titration, simply update the dose field to get the new draw amount.

How Retatrutide Compares to Tirzepatide and Semaglutide

All three compounds are weekly subcutaneous injections that share GLP-1 receptor activity and a similar GI side effect profile. The key distinction is the glucagon receptor component in retatrutide, which is believed to increase basal metabolic rate and hepatic glucose output in a way the other two do not. See the semaglutide vs tirzepatide comparison for a detailed breakdown of those two compounds.