Retatrutide explained: how the triple agonist differs from semaglutide and tirzepatide
Retatrutide (LY3437943) is Eli Lilly's investigational triple agonist of the GLP-1, GIP and glucagon receptors. In its 48-week phase 2 trial the highest dose produced about 24% mean body-weight reduction, more than semaglutide (~15%) or tirzepatide (~21%) achieved in their pivotal trials. It is not approved anywhere; phase 3 trials are ongoing.
6 September 2026 · SiamesePeptides
Three drugs define the current incretin landscape. Semaglutide acts on one receptor. Tirzepatide acts on two. Retatrutide acts on three, and that is the whole reason the research market is fixated on it.
The three receptors
- GLP-1 receptor. Slows gastric emptying, increases insulin secretion, suppresses appetite centrally. Semaglutide is a pure GLP-1 agonist.
- GIP receptor. Also enhances insulin secretion and appears to improve the tolerability of GLP-1 agonism. Tirzepatide adds this to GLP-1.
- Glucagon receptor. Increases energy expenditure and hepatic fat oxidation. On its own it raises blood glucose, which is why it was long avoided in obesity drugs. Paired with GLP-1 and GIP, the glucose effect is offset and the energy-expenditure effect remains.
Retatrutide is a single 39-amino-acid peptide, engineered from the glucagon backbone with a C20 fatty diacid for once-weekly half-life, that hits all three.
What the phase 2 trial showed
Jastreboff et al., New England Journal of Medicine, June 2023: 338 adults with obesity, 48 weeks, once-weekly injections.
| Dose | Mean weight change at 48 weeks |
|---|---|
| Placebo | −2.1% |
| 1 mg | −8.7% |
| 4 mg | −17.1% |
| 8 mg | −22.8% |
| 12 mg | −24.2% |
Weight loss had not plateaued at 48 weeks in the higher-dose arms. A parallel phase 2 trial in type 2 diabetes (Rosenstock et al., Lancet, 2023) showed HbA1c reductions of up to 2.0 percentage points. A substudy in participants with fatty liver reported liver-fat reductions above 80% at the higher doses.
For comparison, semaglutide 2.4 mg produced about 15% loss at 68 weeks in STEP 1, and tirzepatide 15 mg about 21% at 72 weeks in SURMOUNT-1. The trials differ in population and duration, so the comparison is indicative, not head-to-head.
Adverse effects
Gastrointestinal, dose-dependent, and consistent with the class: nausea, diarrhoea, vomiting, constipation, mostly during dose escalation. Two signals specific to glucagon agonism were watched: heart rate rose by up to about 6 beats per minute at higher doses, and a small number of participants showed skin hyperaesthesia or dysaesthesia. Neither stopped the programme.
Where it stands
The TRIUMPH phase 3 programme began in 2023 across obesity, type 2 diabetes, obstructive sleep apnoea, knee osteoarthritis and cardiovascular outcomes, with readouts expected from 2026 onward. Retatrutide is not approved by any regulator. Any vial sold outside a trial is a research reagent, synthesised by a third party, with no connection to Lilly’s clinical supply.
Why researchers care
The glucagon component is the scientific novelty. It is the first time a glucagon agonist has been carried into late-stage obesity trials without the glucose penalty, and it is the reason the weight-loss curve looks different from the two-receptor drugs. That makes retatrutide a reference compound for anyone studying energy expenditure, hepatic lipid handling, or multi-receptor incretin pharmacology.
Key references
- Jastreboff AM et al. “Triple-Hormone-Receptor Agonist Retatrutide for Obesity.” NEJM 2023;389:514-526.
- Rosenstock J et al. “Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes.” Lancet 2023;402:529-544.
- Sanyal AJ et al. “Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease.” Nature Medicine 2024.
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