GLP-1 & incretin
Retatrutide
An investigational triple agonist acting on GIP, GLP-1 and glucagon receptors, with the largest weight loss reported for any peptide in an early trial. Not approved and not available outside studies.
What it is
Retatrutide is a synthetic 39-amino-acid peptide engineered to activate three receptors at once: GIP, GLP-1 and glucagon. Adding glucagon-receptor activity is intended to raise energy expenditure as well as reduce appetite. It is an investigational drug with no approved product anywhere, available only in registered clinical trials, and it is prohibited in sport.
How it works
- 1
Activates GIP and GLP-1 receptors, which together reduce appetite, slow gastric emptying and improve glucose-dependent insulin release.
- 2
Adds glucagon-receptor activation, which increases energy expenditure and fat oxidation — the main difference from dual agonists such as tirzepatide.
- 3
Glucagon activity also drives hepatic glucose output, which is why the net effect on blood glucose depends on the balance between the three receptors.
- 4
Liver fat falls measurably in imaging sub-studies, consistent with increased hepatic fat oxidation.
What it's studied for
Reported and studied effects
- Mean weight loss of up to about 24% at 48 weeks with the 12 mg dose in a phase 2 trial
- HbA1c reductions of up to about 2 percentage points in type 2 diabetes
- Large reductions in liver fat in imaging sub-studies
- Dose-related increases in resting heart rate
- High rates of gastrointestinal side effects, with more discontinuations at higher doses
Research protocol notes
Research context onlyResearch context only — retatrutide is not available outside clinical trials. The published phase 2 trial escalated weekly subcutaneous doses through 2 mg, 4 mg, 8 mg and 12 mg over 48 weeks with a maintenance period. Results from later-stage trials have not yet been reported.
These figures are described so you can understand what researchers did. They are not a dose, a schedule, or a suggestion — and they are not a substitute for a doctor.
Possible side effects and contraindications
Safety profile
Possible side effects
- Nausea, vomiting, diarrhoea and constipation — the most common reason for stopping
- Reduced appetite and food intake
- Increased resting heart rate
- Gallbladder events
- Pancreatitis and thyroid effects are class-level concerns but not yet characterised for this drug
- Injection-site reactions
Contraindications and cautions
- Not established — no approved product exists
- Personal or family history of medullary thyroid carcinoma and MEN2 are class-level cautions
- Pregnancy and breastfeeding should be treated as unknown
- Prohibited in competitive sport
A side-effect list is never complete, and these are not the only situations that warrant caution. Anything unexpected, or anything you are unsure about, should be discussed with a doctor before use.
Evidence assessment
One randomised phase 2 trial and phase 1 pharmacokinetic work in humans. Results are striking but not yet replicated at scale, and no phase 3 outcome data have been published.
References
- 01Jastreboff et al., Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial, NEJM 2023
- 02Retatrutide clinical trials — PubMed literature search
References link to published literature, regulator pages or literature indexes. Where a link points to a search, it collects the peer-reviewed work on that molecule rather than a single study.
Related
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GLP-1 & incretin
Cagrilintide
A long-acting amylin analogue that slows digestion and reduces appetite, studied alone and combined with semaglutide for obesity.
GLP-1 & incretin
Dulaglutide
A once-weekly GLP-1 receptor agonist approved for type 2 diabetes, with proven cardiovascular benefit in people at high risk.
GLP-1 & incretin
Exenatide
A GLP-1 receptor agonist derived from Gila monster saliva, approved for type 2 diabetes in twice-daily and once-weekly forms.