Retatrutide (LY3437943)

Triple GLP-1/GIP/Glucagon Agonist | Weight Loss & Diabetes

Weight: 4,731.33 Da
Half-life: ~6 days
Chain: 39 amino acids
6 studies
2025 latest
3 recent
Extensively Studied
Dose 0.5mg starting, titrate up to 8-12mg weekly
Frequency Once weekly (same day each week)
Cycle Continuous therapy as prescribed
Storage Reconstituted: 2-8°C, use within 28 days
Accumulation Plotter

Community Research

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Novel triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors. Phase II trials demonstrated 24.2% weight loss at 48 weeks—the highest recorded for obesity medications.

Mechanism of Action

Activates GLP-1 for appetite suppression, GIP for insulin sensitivity, and glucagon for increased energy expenditure and hepatic fat oxidation.

01 Superior weight loss (24.2% at 48 weeks)
02 Improved glycemic control (HbA1c reduction up to 2.16%)
03 Enhanced cardiovascular benefits
04 Hepatic fat reduction (up to 82%)
05 Triple mechanism addresses obesity through multiple pathways

Molecular Data

Molecular Weight
4,731.33 Da
Chain Length
39 amino acids
Type
Triple GLP-1/GIP/glucagon agonist
Amino Acid Sequence
One-letter: HUEGTFTSDVSSYLEGQAAKEFIAWLVRGRGPSSGAPPPS
H₂N
H 1
O ‖ C
N
U 2
O ‖ C
N
E 3
O ‖ C
N
H
G 4
O ‖ C
N
T 5
O ‖ C
N
F 6
O ‖ C
N
T 7
O ‖ C
N
S 8
O ‖ C
N
D 9
O ‖ C
N
V 10
O ‖ C
N
S 11
O ‖ C
N
S 12
O ‖ C
N
Y 13
O ‖ C
N
L 14
O ‖ C
N
E 15
O ‖ C
N
H
G 16
O ‖ C
N
Q 17
O ‖ C
N
A 18
O ‖ C
N
A 19
O ‖ C
N
K 20
O ‖ C
N
E 21
O ‖ C
N
F 22
O ‖ C
N
I 23
O ‖ C
N
A 24
O ‖ C
N
W 25
O ‖ C
N
L 26
O ‖ C
N
V 27
O ‖ C
N
R 28
O ‖ C
N
H
G 29
O ‖ C
N
R 30
O ‖ C
N
H
G 31
O ‖ C
N
P 32
O ‖ C
N
S 33
O ‖ C
N
S 34
O ‖ C
N
H
G 35
O ‖ C
N
A 36
O ‖ C
N
P 37
O ‖ C
N
P 38
O ‖ C
N
P 39
O ‖ C
N
S 40
COOH
His
1

Histidine

Position 1

Aib
2

Aminoisobutyric Acid

Position 2

Glu
3

Glutamic Acid

Position 3

Gly
4

Glycine

Position 4

Thr
5

Threonine

Position 5

Phe
6

Phenylalanine

Position 6

Thr
7

Threonine

Position 7

Ser
8

Serine

Position 8

Asp
9

Aspartic Acid

Position 9

Val
10

Valine

Position 10

Ser
11

Serine

Position 11

Ser
12

Serine

Position 12

Tyr
13

Tyrosine

Position 13

Leu
14

Leucine

Position 14

Glu
15

Glutamic Acid

Position 15

Gly
16

Glycine

Position 16

Gln
17

Glutamine

Position 17

Ala
18

Alanine

Position 18

Ala
19

Alanine

Position 19

Lys
20

Lysine

Position 20

Glu
21

Glutamic Acid

Position 21

Phe
22

Phenylalanine

Position 22

Ile
23

Isoleucine

Position 23

Ala
24

Alanine

Position 24

Trp
25

Tryptophan

Position 25

Leu
26

Leucine

Position 26

Val
27

Valine

Position 27

Arg
28

Arginine

Position 28

Gly
29

Glycine

Position 29

Arg
30

Arginine

Position 30

Gly
31

Glycine

Position 31

Pro
32

Proline

Position 32

Ser
33

Serine

Position 33

Ser
34

Serine

Position 34

Gly
35

Glycine

Position 35

Ala
36

Alanine

Position 36

Pro
37

Proline

Position 37

Pro
38

Proline

Position 38

Pro
39

Proline

Position 39

Ser
40

Serine

Position 40

N-terminus C-terminus
Hydrophobic
Polar
Positive (+)
Negative (-)
Modified
Peak 0.0 mcg
Trough 0.0 mcg
SS Peak 0.0 mcg
SS Trough 0.0 mcg

Research Indications

Weight Loss
Superior Weight Reduction most effective

Clinical trials show 17.5% weight loss at 24 weeks and 24.2% at 48 weeks.

Sustained Weight Management most effective

Continuous weight loss with no plateau at 48 weeks suggests greater long-term potential.

Triple Mechanism most effective

Addresses obesity through appetite suppression, energy expenditure, and metabolic efficiency.

Type 2 Diabetes
Superior Glycemic Control most effective

HbA1c reductions up to 2.16% with 82% achieving target levels below 6.5%.

Glucose-Dependent Regulation effective

Balanced glycemic control with minimal hypoglycemia risk.

Insulin Sensitivity effective

Marked improvements in sensitivity with potential for reduced exogenous insulin requirements.

Cardiovascular/Metabolic
Lipid Improvement effective

Non-HDL cholesterol reductions up to 26.9%, triglyceride reductions up to 40.6%.

Blood Pressure Optimization effective

Consistent decreases in systolic and diastolic blood pressure across trials.

Hepatic Fat Reduction most effective

Up to 82% reduction in liver fat with normalization in 90% of participants.

Dosing Protocols

Weekly subcutaneous injection into abdomen, thigh, or upper arm with site rotation.

GoalDoseFrequencyRoute
Starting Dose (Week 1-4)0.5mgOnce weeklySubQ
Low Maintenance (Week 4-8)1mgOnce weeklySubQ
Escalation (Week 8-12)2mgOnce weeklySubQ
Moderate (Week 12-16)4mgOnce weeklySubQ
Advanced (Week 16-20)8mgOnce weeklySubQ
Maximum Efficacy (Week 20+)12mgOnce weeklySubQ

Reconstitution Instructions

Materials Needed:
  • Sterile bacteriostatic water for injection
  • Lyophilized Retatrutide vial
  • Insulin syringes (0.3-1mL capacity)
  • Alcohol swabs
  • Sharps disposal container
  1. 1 Allow vial to reach room temperature (15-20 minutes)
  2. 2 Clean vial top with alcohol swab and air dry completely
  3. 3 Add calculated bacteriostatic water slowly down vial side
  4. 4 Gently swirl in circular motions—avoid vigorous shaking
  5. 5 Allow full dissolution (2-3 minutes); solution should be clear and colorless
  6. 6 Store reconstituted solution refrigerated at 2-8°C for up to 28 days
  7. 7 Inject subcutaneously; rotate sites weekly

Interactions

!
Tirzepatide
Do not combine with other dual/triple agonists—risk of severe hypoglycemia and excessive GI effects.
avoid
!
Semaglutide
Do not combine—overlapping GLP-1 agonist mechanisms increase severe hypoglycemia risk.
avoid
~
Cagrilintide
Both cause significant GI effects. Not recommended without specialist supervision.
monitor
~
Insulin
May significantly reduce insulin requirements. Monitor blood glucose and adjust insulin doses accordingly.
monitor
+
Metformin
Safe combination tested in clinical trials. Different mechanisms work complementarily for glucose control.
compatible
+
SGLT2 Inhibitors
Clinical trials included SGLT2 inhibitors with no safety concerns.
compatible
+
BPC-157
Safe combination; BPC-157 may provide GI protective benefits during retatrutide use.
compatible
~
Oral Contraceptives
Space oral contraceptives by 1 hour before retatrutide due to delayed gastric emptying.
monitor

What to Expect

Week 1-2
Initial appetite suppression and mild GI effects as body adapts to triple hormone activation
Week 2-4
Noticeable food cravings reduction and portion size decrease; early weight loss (2-5%)
Week 4-8
Significant appetite control and steady weight loss (5-10%); improved glucose control
Week 8-16
Substantial weight reduction (10-18%) with enhanced energy expenditure
Week 16-24
Major weight loss milestone (15-22%) with cardiovascular benefits and liver fat reduction
Week 24-48
Maximum clinical efficacy (20-24.2%) with comprehensive metabolic improvements

Side Effects & Safety

Common Side Effects

  • Gastrointestinal effects (nausea, vomiting, diarrhea)—typically mild to moderate
  • Heart rate increases—common especially in first 24 weeks
  • Appetite suppression
  • Mild dehydration

Stop Signs - Discontinue if:

  • Severe persistent nausea or vomiting preventing adequate nutrition
  • Signs of pancreatitis: severe abdominal pain radiating to back
  • Severe hypoglycemia symptoms: confusion, dizziness, sweating
  • Excessive weight loss (>3 lbs per week consistently or >25% total body weight)
  • Gallbladder problems: severe right upper abdominal pain

Contraindications

  • Personal or family history of medullary thyroid carcinoma
  • MEN2 syndrome
  • Severe renal impairment

Quality Checklist

Good Signs

  • Pharmaceutical-grade white powder with uniform texture
  • Proper cold chain maintenance (2-8°C refrigeration)
  • Clear, colorless reconstituted solution without particles
  • Stable extended half-life effects (consistent appetite suppression between doses)

Warning Signs

  • Source verification critical—counterfeit versions circulate due to investigational status

Bad Signs

  • Rapid tolerance or effectiveness loss suggests degraded or counterfeit product
  • Unusual side effect profile may indicate contamination

References

  • Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
    Jastreboff, A.M., et al.
    New England Journal of Medicine (2023)

    Landmark phase 2 RCT showing dose-dependent weight loss: 24.2% at 48 weeks with 12mg dose — the highest recorded for any obesity medication at the time. Weight reduction of ≥15% achieved in 83% of 12mg recipients.

  • Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a phase 2 trial
    Rosenstock, J., et al.
    The Lancet (2023)

    Phase 2 trial in type 2 diabetes demonstrating clinically meaningful HbA1c reductions and robust weight loss of up to 16.9% at 36 weeks, with safety profile consistent with GLP-1 receptor agonists.

  • Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
    Sanyal, A.J., et al.
    Nature Medicine (2024)

    Dose-dependent liver fat reduction: 82.4% at 12mg dose. Normal liver fat (<5%) achieved in 86% of 12mg recipients vs 0% placebo at 24 weeks. Improvements linked to changes in body weight, abdominal fat, and insulin sensitivity.

  • Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide
    Li, W., et al.
    Cell Discovery (2024)

    Cryo-EM structures reveal how retatrutide simultaneously activates GLP-1R, GIPR, and GCGR through distinct receptor-binding modes, explaining the molecular basis for its triple agonist activity and superior clinical efficacy.

  • TRIUMPH registrational clinical trials: Rationale and design
    Aronne, L.J., et al.
    Obesity (2025)

    Phase 3 TRIUMPH program design: four multicenter, randomized, double-blind studies assessing weekly retatrutide for obesity, obstructive sleep apnea, knee osteoarthritis, and weight management in cardiovascular disease populations.

  • Effects of retatrutide on body composition in people with type 2 diabetes: a phase 2 substudy
    Rosenstock, J., et al.
    The Lancet Diabetes & Endocrinology (2025)

    Substudy demonstrating significant total body fat mass reduction with retatrutide vs placebo and dulaglutide. Proportion of lean mass loss to total weight loss was similar to other obesity treatments.

Related Peptides

BPC-157 compatible

Safe combination; BPC-157 may provide GI protective benefits during retatrutide use.

Disclaimer

This information is for educational and research purposes only. Consult a healthcare professional before use.