Retatrutide

Retatrutide is an investigational triple receptor agonist developed by Eli Lilly under the code LY3437943. Where semaglutide activates one receptor and tirzepatide two, retatrutide adds glucagon receptor activation to GLP-1 and GIP. That third arm is the interesting and difficult part: glucagon signalling raises energy expenditure, but it can also raise glucose and heart rate, so the balance the molecule strikes is what the trials have been testing. It belongs in this library because it produces the largest average weight reductions reported in a randomised trial to date — and because that result is usually quoted online without the second half of the sentence. It is an unapproved investigational compound whose human safety database is measured in months, not years.

Retatrutide combines GLP-1, GIP and glucagon receptor activity in one peptide scaffold. GLP-1 and GIP signalling reduce appetite centrally and slow gastric emptying; glucagon receptor activation adds energy expenditure and shifts hepatic fat handling. The net effect in trials has been appetite suppression, a measurable increase in energy expenditure, and a disproportionate fall in liver fat.

• Average weight reduction of up to roughly 24% at 48 weeks in the highest dose group of its phase 2 trial
• Marked reductions in liver fat, with a dedicated MASH programme in progress
• Improvements in glycaemic markers in participants both with and without type 2 diabetes
• Once-weekly subcutaneous dosing in every published protocol

Reported benefits describe what the published literature and user reports suggest — not a promise of outcome for any individual.

The compound's public profile rests mainly on one large phase 2 trial published in the New England Journal of Medicine in 2023, in which 338 adults with obesity and without diabetes received weekly retatrutide or placebo for 48 weeks. Mean weight reduction reached roughly 24% in the 12 mg group. A parallel cohort of people with type 2 diabetes showed substantial reductions in HbA1c and body weight. The phase 3 TRIUMPH programme is running across obesity, obstructive sleep apnoea, knee osteoarthritis and MASH, with cardiovascular outcome work alongside it. Reported phase 2 safety findings were the gastrointestinal effects typical of the incretin class, small increases in resting heart rate, and — at higher doses — reports of altered skin sensation. That last signal is worth watching as phase 3 data mature, and it is a reminder that combining three receptor activities is not the same as adding two known drugs together.

• Nausea, vomiting and diarrhoea, concentrated in the dose-escalation period
• Constipation
• Increased resting heart rate
• Reduced skin sensation or tingling reported at higher doses in phase 2
• Injection-site reactions

Nobody has taken retatrutide under regulatory approval. Long-term safety is unknown: the incretin class carries a rodent thyroid C-cell tumour signal, and stacking GLP-1, GIP and glucagon pharmacology in one molecule is precisely the situation that needs several years of trial data before conclusions can be drawn. Anyone with a personal or family history of medullary thyroid carcinoma or MEN2, a history of pancreatitis, or who is pregnant or planning pregnancy should treat it as off-limits. Research-grade supply is unregulated in both identity and purity.

Not a compound to stack. It already combines three receptor activities, so adding other incretin or growth-hormone compounds compounds unknown effects rather than adding predictable ones.