ESPEYB21 15. Editors’ Choice New Treatments (4 abstracts)
15.3. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial
Jastreboff AM , Kaplan LM , Frias JP , Wu Q , Du Y , Gurbuz S , Coskun T , Haupt A , Milicevic Z , Hartman ML & for the Retatrutide Phase 2 Obesity Trial Investigators.
N Engl J Med 389(6): 514–526 (2023). PubMed: 37366315
In Brief: This phase 2 trial randomized 338 adults with overweight or obesity to once-weekly subcutaneous Retatrutide (LY3437943), a ‘triple agonist’ for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1), and glucagon receptors, or placebo. Mean % change in body weight at 24 weeks was −7.2%, −12.9%, −17.3% and −17.5% in the 1-mg, 4-mg, 8-mg and 12-mg Retatrutide groups, compared with −1.6% in the placebo group.
GLP1 analogues have remarkably good effectiveness in the treatment of Type 2 diabetes and other comorbidities of obesity. Indeed, many of us are hoping for wider funding approvals to enable such therapies to reach more of our Paediatric patients. Meanwhile, drug companies are developing even more potent treatments by combining additional incretin receptor targets, such as the dual-agonist Tirzepatide (GIP and GLP1) and Retatrutide (GIP, GLP1 and Glucagon).
The results are impressive. After 48 weeks treatment, 75%, 91%, and 93% of adults had lost 10% or more body weight on 1-mg, 4-mg, and 8-mg Retatrutide, and 60%, 75% and 83% had lost 15% or more body weight. Larger % reductions in body weight were seen in women, and in those with higher baseline BMI. Similar to other incretin receptor agonists, gastrointestinal side effects were only of mild to moderate severity, were dose-related, and partially mitigated by starting on a low dose.
There will no doubt be many more future incretin-based drugs. Even if they don’t combine even more receptor targets, there may be differing combinations of receptor potency. Compared to the endogenous (natural) ligands, Retatrutide shows much higher potency for the GIP receptor (8.9-fold higher), and only half the natural potency for GLP1 and Glucagon receptors. The optimal combination of receptor potencies may be different to this, or might even vary between individuals, e.g. depending on sex, age, health, physical or genetic characteristics.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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