Retatrutide
Metabolic & Weight LossPhase 3Also known as: Triple Agonist, GLP-3, 4x Blend, RC-3R, PEP-3R, GLP-3 RT, GLP-R, Ion Peptide Retatrutide, GIP/GLP/Glucagon, ION-3R, GLP-3R, Retatrutide, Reta
Retatrutide (also coded LY3437943) is an investigational once-weekly triple-agonist at the GLP-1, GIP, and glucagon receptors — the third-generation incretin-based therapy developed by Eli Lilly. Where Semaglutide activates GLP-1 alone and Tirzepatide activates both GLP-1 and GIP, retatrutide adds glucagon receptor agonism for synergistic effects on energy expenditure, hepatic lipid metabolism, and weight reduction. As of April 2026, retatrutide is not FDA-approved — it remains in Phase 3 clinical development.
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Overview
At A Glance
Retatrutide is a 39-amino-acid synthetic peptide with balanced agonist activity at three receptors: GLP-1R, GIPR, and GCGR (glucagon receptor). It is chemically modified with a C20 fatty diacid side chain (similar to semaglutide) to bind albumin and extend its plasma half-life to…
Mechanism of Action
Retatrutide is a 39-amino-acid synthetic peptide with balanced agonist activity at three receptors: GLP-1R, GIPR, and GCGR (glucagon receptor). It is chemically modified with a C20 fatty diacid side chain (similar to semaglutide) to bind albumin and extend its plasma half-life to ~6 days, enabling once-weekly subcutaneous dosing.
1. GLP-1 receptor agonism (Gs / cAMP pathway on pancreatic beta cells and CNS)
- Activates GLP-1R on pancreatic β-cells → glucose-dependent insulin secretion
- Activates GLP-1R on hypothalamic POMC/NPY/AgRP neurons → appetite suppression
- Slows gastric emptying → reduced postprandial glucose excursion and prolonged satiety
- Same mechanism as semaglutide, tirzepatide, liraglutide
EC₅₀ at human GLP-1R is roughly comparable to semaglutide.
2. GIP receptor agonism (Gs / cAMP pathway on pancreatic beta cells and adipose tissue)
- Activates GIPR on pancreatic β-cells → enhanced glucose-dependent insulin secretion
- Activates GIPR on adipose tissue → complex effects on lipid storage and energy expenditure
- Adds to GLP-1 effect on insulin secretion and satiety
- Same "twincretin" mechanism as tirzepatide
EC₅₀ at GIPR is comparable to tirzepatide.
3. Glucagon receptor agonism — the retatrutide signature (Gs / cAMP pathway on hepatocytes and adipose tissue)
This is what distinguishes retatrutide from semaglutide and tirzepatide:
- Activates GCGR on hepatocytes → hepatic glucose output (transient, requires β-cell compensation)
- Activates GCGR on hepatocytes → stimulation of hepatic fatty acid oxidation and reduction of hepatic lipid accumulation (the likely mechanism for retatrutide's strong NAFLD effects)
- Activates GCGR on adipose tissue → enhanced lipolysis and energy expenditure (measurable ~3-5% increase in resting metabolic rate in Phase 2)
- Activates GCGR in hypothalamus → additional appetite-suppressive effects
The glucagon component is the reason retatrutide produces greater weight loss than GLP-1 + GIP alone. Glucagon drives both direct lipolysis and increased energy expenditure, adding to the appetite-suppressive effect of GLP-1/GIP. The net calculus:
| Effect | GLP-1 (semaglutide) | GLP-1 + GIP (tirzepatide) | GLP-1 + GIP + GCG (retatrutide) |
|---|---|---|---|
| Appetite suppression | Strong | Strong+ | Strong++ |
| Insulin secretion | Enhanced | Enhanced+ | Enhanced+ |
| Gastric emptying delay | Strong | Strong | Strong |
| Lipolysis | Indirect (via caloric deficit) | Modest direct effect | Strong direct effect |
| Energy expenditure | Neutral | Slight increase | +3-5% REE |
| Hepatic fat reduction | Modest | Moderate | Strong |
4. Balanced agonist design
Retatrutide is designed as a balanced triple agonist — relative potencies at GLP-1R, GIPR, and GCGR are within one order of magnitude of each other. This is in contrast to earlier experimental triple agonists that were biased toward one receptor. The balance enables the clinical profile observed in Phase 2.
5. Pharmacokinetics
- Plasma half-life: ~6 days (albumin-binding via C20 fatty diacid)
- Steady state: achieved at ~4 weeks of weekly dosing
- Dosing: once-weekly subcutaneous injection
- Distribution: extensive albumin binding; moderate CNS penetration (enough for appetite-suppressive central effects)
- Clearance: predominantly hepatic; minimal renal excretion
Characterized in Phase 1 by Urva et al., 2022.
6. Secondary mechanisms under investigation
- Brown adipose tissue activation — glucagon agonism likely activates BAT; may contribute to the energy expenditure increase
- CNS energy-sensing neurons — GLP-1/GIP/GCG all signal at hypothalamic energy-sensing neurons; triple activation may produce qualitatively different satiety signaling than GLP-1 alone
Overview
Retatrutide (also coded LY3437943) is an investigational once-weekly triple-agonist at the GLP-1, GIP, and glucagon receptors — the third-generation incretin-based therapy developed by Eli Lilly. Where Semaglutide activates GLP-1 alone and Tirzepatide activates both GLP-1 and GIP, retatrutide adds glucagon receptor agonism for synergistic effects on energy expenditure, hepatic lipid metabolism, and weight reduction.
As of April 2026, retatrutide is not FDA-approved — it remains in Phase 3 clinical development. Eli Lilly's TRIUMPH program is evaluating retatrutide for obesity, type 2 diabetes, NAFLD/MASH, and chronic kidney disease. The lead obesity indication (TRIUMPH-1) is expected to complete in 2026-2027 with potential FDA submission shortly thereafter.
The clinical excitement around retatrutide is driven by the Phase 2 obesity trial data published in NEJM in 2023: participants on retatrutide 12 mg weekly achieved 24.2% body weight reduction at 48 weeks — the largest weight loss demonstrated by any non-surgical intervention to date, exceeding both semaglutide (~15% at 68 weeks in STEP-1) and tirzepatide (~21% at 72 weeks in SURMOUNT-1) (Jastreboff et al., 2023).
Despite the strong efficacy signal, retatrutide's triple-receptor profile carries distinct safety considerations beyond the GLP-1 class:
- Heart rate elevation — mean ~6-8 bpm increase (larger than semaglutide or tirzepatide), likely driven by the glucagon-receptor component
- Transient elevation of fasting glucose during uptitration (glucagon receptor effect on hepatic glucose output) — usually self-limited
- Higher rate of GI adverse events at the 12 mg maximal dose compared to lower doses and compared to GLP-1-only agents
- Unknown long-term cardiovascular outcomes — large Phase 3 cardiovascular outcome trials are ongoing
Regulatory status: Not FDA-approved. Available only through clinical trials, research-chemical channels, and (controversially) compounding pharmacies in some jurisdictions using non-commercial retatrutide sourcing. The FDA has not announced an approval pathway timeline.
Typical dosing (extrapolated from Phase 2 uptitration schedule): starting 2 mg weekly SC, titrating to 8-12 mg weekly over 12-20 weeks. The maximal dose of 12 mg weekly is associated with the largest weight loss and the largest side-effect burden. See our Retatrutide Dosage Guide for uptitration specifics and our Semaglutide vs Tirzepatide vs Retatrutide comparison for class-selection context.
Potential Research Fields
Phase 2 Trial Data — Record-Breaking Weight Loss
Eli Lilly's Phase 2 trial (n=338, published in NEJM 2023) tested retatrutide at doses from 1mg to 12mg weekly over 48 weeks in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related condition.
24.2%
Mean weight loss at 12mg (48 wk)
26%
Participants losing ≥30% BW
86%
Reduction in liver fat
Dose-Response Weight Loss at 48 Weeks
Phase 3: TRIUMPH program currently enrolling for obesity and MASLD/NASH. Results expected 2025–2026.
Triple Agonism — Why 3 Receptors Matter
GLP-1 Receptor
Suppresses appetite, enhances insulin secretion, slows gastric emptying. Same pathway as semaglutide.
GIP Receptor
Modulates lipid metabolism and adipose tissue function. Combined with GLP-1 in tirzepatide.
Glucagon Receptor
Key differentiator. Increases hepatic energy expenditure, fat oxidation, and thermogenesis. Unique to retatrutide.
Retatrutide vs Tirzepatide vs Semaglutide
| Compound | Targets | Max Weight Loss | Trial | Status |
|---|---|---|---|---|
| Semaglutide | GLP-1 | ~15% | STEP trials | FDA Approved |
| Tirzepatide | GLP-1 + GIP | ~21% | SURMOUNT | FDA Approved |
| Retatrutidebest | GLP-1 + GIP + Glucagon | ~24.2% | Phase 2 / TRIUMPH | Phase 3 |
Cross-trial comparisons — interpret with caution due to study population differences.
Phase 2 Titration Schedule
Do not skip titration. Jumping to high doses significantly increases GI side effects. If intolerable, stay at current dose for 2 extra weeks before escalating.
Detailed Side Effects
Common (≥10%)
- •Nausea (dose-dependent, usually improves)
- •Diarrhea
- •Constipation
- •Decreased appetite
- •Vomiting (mostly during titration)
Less Common
- •Increased heart rate
- •Injection site reactions
- •Fatigue
- •Dizziness
- •Preclinical thyroid C-cell concerns
Contraindications: Do NOT combine with semaglutide, tirzepatide, or other GLP-1 agonists. Avoid if personal/family history of medullary thyroid carcinoma or MEN2.
Retatrutide FAQ
What is retatrutide (LY3437943)?
How does retatrutide differ from tirzepatide and semaglutide?
What were the retatrutide Phase 2 trial results?
What are retatrutide's side effects?
What is the retatrutide dosing protocol?
Is retatrutide FDA approved?
Can I stack retatrutide with semaglutide or tirzepatide?
Chemical Information
IUPAC Name
Not fully disclosed (Eli Lilly proprietary)
CAS Number
2381294-46-4
Molecular Formula
C221H342N46O68
Molecular Mass
4731 g/mol
Dosing & Protocols
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Interactions
Interaction Matrix
Contraindications
Absolute contraindications
- Personal or family history of medullary thyroid carcinoma (MTC) — GLP-1 class rodent carcinogenicity signal; absolute contraindication
- Multiple Endocrine Neoplasia syndrome type 2 (MEN-2) — same signal
- History of acute pancreatitis — GLP-1 class signal; recurrence risk
- Active gallbladder disease / acute cholecystitis — GLP-1 class worsens
- Active malignancy — relative to absolute depending on type; GLP-1 class has some residual oncology concerns
- Pregnancy or planning pregnancy — no safety data; avoid
- Breastfeeding — no safety data
- Age <18 — no pediatric data for retatrutide (some GLP-1 class drugs have pediatric obesity approvals; retatrutide does not)
- Severe gastroparesis or gastric outlet obstruction — GLP-1 mechanism would dramatically worsen
Relative contraindications (consult physician before use)
- History of chronic pancreatitis — increased recurrence risk
- Active proliferative diabetic retinopathy — rapid glycemic correction can worsen retinopathy
- Resting tachycardia (HR >90 at baseline) — retatrutide consistently raises HR; investigate baseline cause first
- Severe heart failure (NYHA III-IV) — limited data; the heart rate elevation may be problematic
- Active eating disorder (anorexia nervosa / bulimia) — appetite suppression is dangerous
- Severe hepatic impairment (Child-Pugh C) — hepatic clearance is primary
- Severe chronic kidney disease (eGFR <30) — limited data
Drug interactions
- Sulfonylureas (glipizide, glyburide) — hypoglycemia risk; reduce dose 50% when starting retatrutide
- Insulin — hypoglycemia risk; reduce insulin dose at retatrutide initiation
- Other GLP-1 receptor agonists — redundant; discontinue before starting retatrutide
- Warfarin — GLP-1 class may alter INR; monitor more frequently at dose changes
- Oral contraceptives — GLP-1-induced gastric delay may reduce efficacy; consider non-oral contraception during active uptitration
- Acetaminophen / paracetamol — gastric delay may reduce Cmax; usually not clinically significant
- Any drug with narrow therapeutic index requiring predictable absorption — monitor at dose changes
Specific populations requiring extra caution
- History of depression / suicidal ideation — some GLP-1 class drugs have FDA adverse event signals for suicidality; monitor
- History of retinopathy — annual ophthalmology during rapid weight loss
- Post-bariatric surgery — limited data on GLP-1 class post-surgery; absorption may be altered
Monitoring requirements
- Baseline: HbA1c, fasting glucose, lipid panel, CMP, liver function, thyroid (TSH + free T4), blood pressure, resting heart rate (seated, post-rest), pregnancy test (women of childbearing age), eye exam (for diabetics or high-risk)
- Every 4 weeks during uptitration: fasting glucose, blood pressure, heart rate, weight, subjective tolerance
- Every 12 weeks on maintenance: HbA1c, liver function, lipids, weight, body composition
- Annually: Full panel + cardiovascular assessment + ophthalmology (if diabetic)
Discontinuation criteria
Stop retatrutide and consult a clinician if you develop:
- Severe persistent GI symptoms limiting food intake
- Any suspected pancreatitis symptoms (severe abdominal pain radiating to back)
- Severe hypoglycemia (glucose <54 mg/dL)
- Resting HR >100 bpm or new arrhythmia
- Severe depression or suicidal ideation
- Acute gallbladder symptoms
- Unexplained dehydration or electrolyte derangement
- Planning pregnancy
Research Disclaimer
This interaction data is compiled from published research and community reports. It may not be exhaustive. Always consult a healthcare professional before combining compounds.
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RC-3R 10mg | vial | 10mg vial● In Stock | $119.99BEST | $11.999 | ||
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Pep-3R 10mg (Retatrutide) | vial | 1 vial● In Stock | $119.99 | $11.999 | ||
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Retatrutide (ION-3R) 5mg | vial | 1 vial● Out of Stock | $39.00 | $7.800 | — | Sign in for stock alert |
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Retatrutide (ION-3R) 6mg | vial | 1 vial● In Stock | $45.00 | $7.500 | — | |
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Retatrutide (ION-3R) 10mg | vial | 1 vial● In Stock | $58.50 | $5.850 | — | |
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Retatrutide (ION-3R) 12mg | vial | 1 vial● In Stock | $69.00 | $5.750 | — | |
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Retatrutide (ION-3R) 20mg | vial | 1 vial● In Stock | $99.95 | $4.998 | — | |
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Retatrutide (ION-3R) 25mg | vial | 1 vial● Out of Stock | $123.00 | $4.920 | — | Sign in for stock alert |
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Retatrutide (ION-3R) 30mg | vial | 1 vial● Out of Stock | $139.00 | $4.633 | — | Sign in for stock alert |
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Retatrutide (ION-3R) 50mg | vial | 1 vial● In Stock | $189.00 | $3.780 | — | |
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Retatrutide (ION-3R) 60mg | vial | 1 vial● In Stock | $219.00 | $3.650 | — | |
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Retatrutide 10mg | vial | 1 vial● In Stock | $99.99 | $9.999 | — | |
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Retatrutide 10mg | vial | 1 vial● In Stock | $119.99 | $11.999 | — | |
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Retatrutide 20mg | vial | 1 vial● In Stock | $159.99 | $8.000 | — | |
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Retatrutide 20mg | vial | 1 vial● In Stock | $199.99 | $10.000 | — | |
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Retatrutide (GLP-3 RT) 5mg Vial | vial | 1 vial● In Stock | $65.00 | $13.000 | ||
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Retatrutide (GLP-3 RT) 10mg Vial | vial | 1 vial● In Stock | $125.00 | $12.500 | ||
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Retatrutide (GLP-3 RT) 20mg Vial | vial | 1 vial● In Stock | $215.00 | $10.750 | ||
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Retatrutide (GLP-3 RT) 40mg Vial | vial | 1 vial● In Stock | $320.00 | $8.000 | ||
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Retatrutide (GLP-3 RT) 50mg Vial | vial | 1 vial● In Stock | $380.00 | $7.600 | ||
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GLP-Reta (Retatrutide) 5mg | vial | 5mg vial● In Stock | $79.99 | $15.998 | ||
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GLP-Reta (Retatrutide) 10mg | vial | 10mg vial● In Stock | $119.99 | $11.999 | ||
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GLP-Reta (Retatrutide) 15mg | vial | 15mg vial● In Stock | $159.99 | $10.666 | ||
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GLP-Reta (Retatrutide) 30mg | vial | 30mg vial● In Stock | $279.99 | $9.333 |
Tracking since Mar 13, 2026 · 22 data points
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Related Compounds
View AllAOD-9604
Metabolic & Weight LossPhase 3AOD-9604 (Anti-Obesity Drug 9604) is a synthetic 16-amino-acid peptide fragment of human growth hormone (hGH) corresponding to residues 177-191 of the hGH molecule plus a tyrosine addition at the N-terminus (sequence: Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe).
Cagrilintide
Metabolic & Weight LossPhase 3Cagrilintide (also known as AM833, development code NN9838) is a long-acting amylin analog developed by Novo Nordisk as a next-generation weight-management therapy, designed to be co-administered with the GLP-1 receptor agonist semaglutide in a fixed-ratio combination known as CagriSema.
HGH Fragment 176-191
Metabolic & Weight LossPhase 2HGH Fragment 176-191 (also written HGH Frag 176-191, hGH Fragment 176-191, and frequently appearing in clinical literature as AOD-9604 — "Anti-Obesity Drug 9604") is a synthetic peptide corresponding to the C-terminal 15-amino-acid region of the 191-amino-acid human growth hormone (hGH) molecule, with an additional N-terminal tyrosine residue added for stability and biological activity.
Semaglutide
Metabolic & Weight LossFDA ApprovedSemaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a molecular weight of 4113.58 Da and CAS number 910463-68-2.
Tirzepatide
Metabolic & Weight LossFDA ApprovedTirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist with a molecular weight of 4813.45 Da and CAS number 2023788-19-2.
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5/19/2026Research Score
135 PubMed studies
Quality Indicators
Data Completeness
100%COA Verification
10
Verified COAs
2
Vendors w/ COA
High verification rate (83%)
Latest test: 3/1/2026
Research Credibility
Well-researched compound
Quick Facts
Half-Life
~6 days (plasma, albumin-bound)
Molecular Weight
4731 g/mol
Administration
subcutaneous
CAS Number
2381294-46-4
Trial Phase
Phase 3
Safety Profile
Moderate RiskCommon Side Effects
- • Nausea
- • Vomiting
- • Diarrhea
- • Constipation
- • Decreased appetite
Stop Use If
- Phase 3 trials ongoing — long-term safety profile still being established
- Thyroid tumor history
- Severe GI events
Research Disclaimer
This information is for educational and research purposes only. Not intended as medical advice. Consult a healthcare professional before use.
Frequently Asked Questions
What is retatrutide (LY3437943)?
Retatrutide is an investigational triple hormone receptor agonist developed by Eli Lilly that simultaneously activates GLP-1, GIP, and glucagon receptors. It is the first drug to target all three metabolic pathways, producing the largest weight loss ever recorded in a clinical trial — up to 24.2% at 48 weeks.
How does retatrutide differ from tirzepatide and semaglutide?
Semaglutide targets GLP-1 only. Tirzepatide targets GLP-1 + GIP (dual agonist). Retatrutide targets GLP-1 + GIP + glucagon (triple agonist). The glucagon receptor activation uniquely drives hepatic energy expenditure, fat oxidation, and thermogenesis — mechanisms unavailable to single or dual agonists.
What were the retatrutide Phase 2 trial results?
The Phase 2 trial (n=338) showed up to 24.2% mean body weight reduction with the 12mg dose at 48 weeks. 26% of participants lost ≥30% of body weight. Liver fat was reduced by up to 86%. These results significantly exceeded semaglutide (~15%) and tirzepatide (~21%) at comparable timepoints.
What are retatrutide's side effects?
Common side effects include nausea, vomiting, diarrhea, constipation, and decreased appetite — similar to other GLP-1 agonists. Additional effects include increased heart rate, injection site reactions, and fatigue. Preclinical thyroid concerns have been noted. Most GI side effects were dose-dependent and improved with titration.
What is the retatrutide dosing protocol?
Per the Phase 2 trial protocol: start at 1mg subcutaneous once weekly for 2 weeks, then titrate up through 2mg, 4mg, 8mg, and potentially 12mg over 24 weeks. The ~6-day half-life supports weekly dosing. Slow titration minimizes GI side effects.
Is retatrutide FDA approved?
No. Retatrutide is currently in Phase 3 clinical trials (TRIUMPH program) for obesity and MASLD/NASH. It is available only as a research compound. FDA approval is not expected before 2026–2027 at the earliest.
Can I stack retatrutide with semaglutide or tirzepatide?
No. Retatrutide already includes GLP-1 agonism. Stacking with semaglutide or tirzepatide would produce dangerous overlapping GLP-1 activity and is strongly contraindicated.
Research Tools
Related Compounds
View AllAOD-9604
Metabolic & Weight LossPhase 3AOD-9604 (Anti-Obesity Drug 9604) is a synthetic 16-amino-acid peptide fragment of human growth hormone (hGH) corresponding to residues 177-191 of the hGH molecule plus a tyrosine addition at the N-terminus (sequence: Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe).
Cagrilintide
Metabolic & Weight LossPhase 3Cagrilintide (also known as AM833, development code NN9838) is a long-acting amylin analog developed by Novo Nordisk as a next-generation weight-management therapy, designed to be co-administered with the GLP-1 receptor agonist semaglutide in a fixed-ratio combination known as CagriSema.
HGH Fragment 176-191
Metabolic & Weight LossPhase 2HGH Fragment 176-191 (also written HGH Frag 176-191, hGH Fragment 176-191, and frequently appearing in clinical literature as AOD-9604 — "Anti-Obesity Drug 9604") is a synthetic peptide corresponding to the C-terminal 15-amino-acid region of the 191-amino-acid human growth hormone (hGH) molecule, with an additional N-terminal tyrosine residue added for stability and biological activity.
Semaglutide
Metabolic & Weight LossFDA ApprovedSemaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a molecular weight of 4113.58 Da and CAS number 910463-68-2.
Tirzepatide
Metabolic & Weight LossFDA ApprovedTirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist with a molecular weight of 4813.45 Da and CAS number 2023788-19-2.
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