Retatrutide

Retatrutide is a novel triple receptor agonist peptide that targets the glucagon receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor, and the glucagon-like peptide-1 (GLP-1) receptor. ^{[1] [2]} It is an investigational drug being developed for the treatment of obesity and type 2 diabetes. ^[1] It is administered as a once-weekly subcutaneous injection. ^[3]

Retatrutide's mechanism of action involves a synergistic interaction among the GLP-1, GIP, and glucagon receptors, resulting in increased insulin secretion, improved glucose homeostasis, and appetite modulation. ^[2] In animal studies retatrutide delays gastric emptying, reduces food intake, and promotes weight loss. ^[4]

Evidence for retatrutide is currently limited to phase 2 studies, with a comprehensive phase 3 programme, including the TRIUMPH studies, ongoing to further evaluate its long-term safety and efficacy. ^{[1] [4]} In a phase 2 trial the drug reported an average weight loss of 17.5% and 24.4% at 24 and 48 weeks, respectively, in overweight and obese adults. ^[1] In a phase 2 trial in people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists. ^[5] In a systematic review of adults without diabetes, retatrutide at 12 mg once weekly produced weight loss of up to 22.1% after 48 weeks, greater than tirzepatide, semaglutide, or liraglutide. ^[6] A network meta-analysis found retatrutide 12 mg was the most efficacious of seven GLP-1 receptor agonists

The most common adverse effects are gastrointestinal and dose-related, including mild-to-moderate nausea, diarrhoea, vomiting, and constipation. ^{[5] [4]} In the phase 2 type 2 diabetes trial there were no reports of severe hypoglycaemia and no deaths during the study. ^[5] As with other incretin-based agents that induce roughly 15 to 24% weight loss, a substantial portion of the weight lost is fat-free mass including skeletal muscle, which can increase the risk of sarcopenia. ^[9] Meta-analyses caution that additional large and long-term phase 3 trials are required to establish retatrutide's efficacy and safety. ^{[8] [3]}