Pup's Guides

GLP-3 - Retatrutide

CAS ID: 2381089-83-2

About Retatrutide

Retatrutide (LY3437943) is an investigational, once-weekly injectable “triple hormone receptor agonist” being developed by Eli Lilly and Company. It’s a single molecule designed to activate three metabolic hormone receptors—GIP, GLP-1, and glucagon—and it’s not FDA-approved or commercially available at this time.

GLP-1 mainly helps you feel full and eat less, and it also improves blood sugar by boosting insulin release when glucose is high, lowering glucagon, and slowing stomach emptying. GIP also increases glucose-dependent insulin secretion and may support healthier energy balance and fat tissue signaling; in the brain, GIP receptors appear to influence “reward eating” mostly indirectly, in part by dampening nausea/aversion signals through brainstem circuits (AP/NTS), which can change how reinforcing food feels and improve tolerability of incretin therapy. Glucagon signaling tends to increase energy use and mobilize fuel (even though it can raise liver glucose output), so combining it with GLP-1/GIP aims to pair “more burn” with strong appetite control and glucose regulation.

Clinically, retatrutide has moved into Phase 3 testing across multiple indications, with Lilly describing an active Phase 3 program that includes obesity, type 2 diabetes, knee osteoarthritis, obstructive sleep apnea, chronic low back pain, cardiovascular/renal outcomes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Lilly also reported topline Phase 3 results (TRIUMPH-4) in December 2025 in people with obesity and knee osteoarthritis, and noted additional Phase 3 readouts are anticipated in 2026.

Reconstitution

Common Vial Sizes	BAC Water Amount for 10 mg/mL	BAC Water Amount for 20 mg/mL
10	1 mL	0.5 mL
20	2 mL	1 mL
30	3 mL	1.5 mL
40	4 mL (will need bigger vial)	2 mL
50	5 mL (will need bigger vial)	2.5 mL
60	6 mL (will need bigger vial)	3 mL

BEFORE DOING ANYTHING MAKE SURE TO WIPE EVERYTHING DOWN WITH AN ALCOHOL WIPE. Use a fresh, sterile needle and syringe (do not reuse needles). Many people use one needle to draw and a fresh one to inject later (if applicable). When reconstituting peptides, remove the vacuum by taking a needle, pulling the plunger out, and piercing the stopper to equalize pressure. Pull the desired amount of water and make sure to angle it to the side of the vial—do not spray the peptide directly. Once all the water is added, swirl or roll the vial (do not shake) until the solution is clear. You can also let it sit for about 20 minutes to fully dissolve. After it’s dissolved, inspect the solution for any cloudiness, particles, discoloration, or anything “stringy.” Once reconstituted, store the peptide in the fridge and don’t freeze it.

Dosage

Common Dosage	10mg/mL	20mg/mL
2 mg	20 units (0.2 mL)	10 units (0.1 mL)
4 mg	40 units (0.4 mL)	20 units (0.2 mL)
8 mg	80 units (0.8 mL)	40 units (0.4 mL)
10 mg	100 units (1.0 mL)	50 units (0.5 mL)
12 mg	120 units (1.2 mL))	60 units (0.3 mL)

Common dosing schedule

The phase II clinical trial had participants start with 2 mg dosed once a week for four weeks. After the four weeks they they administered 4 mg for four weeks, then 8 mg, then 12 mg for four weeks. Depending on how the titration is going that protocol could be followed or if a slower approach is wanted a 2 mg increase each week could prolong the titration schedule.

Common Dosing Schedule

Month	Dose/Week
1	2 mg
2	4 mg
3	8 mg
4	12 mg
5	12 mg

Reduced Dosing Schedule

Month	Dose/Week
1	2 mg
2	4 mg
3	6 mg
4	8 mg
5	10 mg
6	12 mg

While it is common to find a dose that works for someone and hold it there with Semiglutide and Tirzepatide, Retatrutide requires a minimum dose of 4 mg for full activation of the glucagon pathway, with clinical trails showing a 12 mg dose having no plateau in weight loss seen after the 48 weeks trial.

Swapping from Tirzepatide

There are two schools of thought when switching from Tirzepatide to Retatrutide. The first one is to stop the Tirzepatide completely and start with the common dosing schedule of Retatrutide. The downsides to this method is there is a period of time where the Retatrutide will not be high enough in the system and the Tirzepatide will be too low to remove any food noise.

The other school of thought revolves around the binding affinity of each molecule. The binding affinity of Tirzepatide and Retatrutide to the GLP-1 receptor is relatively similar, while the binding affinity of Retatrutide to GIP receptor is much less than Tirzepatide which explains why a higher dose is required to create equal food noise reductions. With that being said the major difference between the two molecules is the addition of the Glucagon receptor agonist. This is designed to increase metabolic expenditure. This in turn can create a heart rate increase, that is why a direct 1:1 swap between the two is not recommended. Instead a step up approach can be utilized in which on your shot day you reduce the dosage of Tirzepatide by 1 - 2 mg, then on the same shot day you would administer the same amount that you reduced by of Retatrutide (1 - 2mg). You would then continue to do this reduction in Tirzepatide and increase in Retatrutide each week until fully on Retatrutide. This gives your body and heart time to get used to the increased metabolic activity while reducing the lead time to be a serum dose.

Step Down Method

Week	Tirzep Dose	Reta Dose
0	10 mg	0 mg
1	8 mg	2 mg
2	6 mg	4 mg
3	4 mg	6 mg
4	2 mg	8 mg
5	0 mg	10 mg

Swapping from Semiglutide

As these molecules are very different from one another, stopping Semiglutide and following the common dosing schedule for Retatrutide is the recommended route.

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