Retatrutide

Also known as: LY3437943, Triple G agonist

Evidence: Clinical

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Overview

Investigational once-weekly agonist of GIP, GLP-1 and glucagon receptors; in the 80-week TRIUMPH-1 phase 3 trial (n=2339), 12 mg gave 25.0% weight loss versus 3.9% with placebo.

Retatrutide (LY3437943) is a 39-residue lipidated peptide from Eli Lilly that activates GIP, GLP-1 and glucagon receptors (Coskun 2022). Its half-life of about 6 days supports weekly dosing (Urva 2022). In phase 2, 48 weeks at 12 mg gave 24.2% weight loss in obesity (Jastreboff 2023) and lowered HbA1c in type 2 diabetes (Rosenstock 2023). In the phase 3 TRIUMPH-1 trial (n=2339, 80 weeks), 4, 9 and 12 mg gave 17.6%, 23.7% and 25.0% weight loss versus 3.9% with placebo, and reduced knee osteoarthritis pain and sleep apnea events (Jastreboff 2026). In TRIUMPH-2 (n=1152, obesity with type 2 diabetes), losses were 11.9 to 18.8% versus 5.1% (Bellido 2026). It is not approved by any regulator as of October 2026.

Benefits

Weight loss up to 25% at 80 weeks (human phase 3 RCT), weight loss and HbA1c reduction in type 2 diabetes (human phase 3 RCT), less knee osteoarthritis pain and sleep apnea events (human phase 3 RCT)

Dosing reference

Research dose: 1 to 12 mg once weekly subcutaneously (phase 2 range; phase 3 used 4, 9 and 12 mg)
Range: 1000 to 12000 mcg, 1x weekly
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 5 mg, 10 mg

Investigational, not approved. Subcutaneous, once weekly. Phase 2 used 1 to 12 mg with escalation from 2 mg or lower (Jastreboff 2023); phase 3 TRIUMPH-1 and TRIUMPH-2 used 4, 9 or 12 mg for 80 weeks (Jastreboff 2026; Bellido 2026).

Mechanism

Retatrutide is a single peptide that activates the GIP, GLP-1 and glucagon receptors (Coskun 2022). GLP-1 and GIP receptor activation lower appetite and raise glucose-dependent insulin secretion; retatrutide also delays gastric emptying (Urva 2022). Glucagon receptor activation is proposed to raise energy expenditure and liver fat oxidation (Coskun 2022). A fatty-acid moiety binds albumin and extends the half-life to about 6 days (Urva 2022).

Evidence

Clinical: at least one published human trial or an approved drug

TRIUMPH-1 phase 3 (n=2339, 80 weeks, obesity without diabetes): 17.6%, 23.7% and 25.0% weight loss at 4, 9 and 12 mg versus 3.9% with placebo; less knee osteoarthritis pain and fewer apnea events (Jastreboff et al., 2026)
TRIUMPH-2 phase 3 (n=1152, obesity with type 2 diabetes, 80 weeks): 11.9%, 16.8% and 18.8% weight loss versus 5.1% with placebo (Bellido et al., 2026)
Phase 2 (n=338, 48 weeks): 24.2% weight loss at 12 mg versus 2.1% with placebo (Jastreboff et al., 2023)
Phase 1b in type 2 diabetes: dose-proportional PK, half-life about 6 days (Urva et al., 2022)
Human-trial status: phase 3 TRIUMPH programme reporting from 2026; not approved by FDA or EMA

References

Side effects

Gastrointestinal effects dominate and are dose-related: in TRIUMPH-2, diarrhoea affected 27 to 34% versus 13% on placebo and nausea 14 to 28% versus 8%. Hypotension (1 to 6% versus under 1%) and dysesthesia (4 to 7% versus 1%) were more frequent than placebo, and discontinuation for adverse events reached 12% at 9 mg (Bellido 2026). Phase 2 trials showed a dose-dependent heart rate rise (Jastreboff 2023). Delayed gastric emptying was measured in a dedicated study. Class risks of approved incretin drugs (pancreatitis, gallbladder disease, aspiration under anaesthesia) are expected but retatrutide has no label.

Storage

Storage: Refrigerated (2-8°C); general lyophilised-peptide guidance, no compound-specific CoA located
Lyophilized: 24+ months refrigerated
Reconstituted: 28 days refrigerated

Pharmacology

Half-life: ~6 days (type 2 diabetes, subcutaneous; Urva 2022)
Bioavailability: Subcutaneous; absolute bioavailability not reported in located sources
Molecular weight: 4731.3 Da
Sequence: Y[Aib]QGTFTSDYSILLDKKAQ[Aib]AFIEYLLEGGPSSGAPPPS [one Lys lipidated with a fatty diacid; other non-coded residues per KEGG D12430]

Stacks with

Cagrilintide