Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial

Jastreboff, Ania M.; Kaplan, Lee M.; Frías, Juan P.; Wu, Qiwei; Du, Yu; Gurbuz, Sirel; Coskun, Tamer; Haupt, Axel; Miličević, Zvonko; Hartman, Mark L.

doi:10.1056/nejmoa2301972

Cited by 305 publications

(138 citation statements)

References 28 publications

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“…Concurrent targeting of more than one receptor is now a major focus for drug development. Within this field, the GLP‐1R/GIPR co‐agonist tirzepatide is the most advanced, with highly promising results also seen with the GLP‐1R/GIPR/GCGR triple agonist retatrutide 51 . Two possible drawbacks with the unimolecular dual agonist approach are that (a) the activation profile for each receptor may be sub‐optimal because of conflicting requirements for two targets, and (b) the relative contribution of each receptor component cannot be fine‐tuned for individual patients.…”

Section: Discussionmentioning

confidence: 99%

Abolishing β‐arrestin recruitment is necessary for the full metabolic benefits of G protein‐biased glucagon‐like peptide‐1 receptor agonists

Hinds,

Peace,

Chen

et al. 2023

Diabetes Obesity Metabolism

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AimEarlier studies have shown that peptide glucagon‐like peptide‐1 receptor (GLP‐1R) agonists with reduced β‐arrestin recruitment show enhanced anti‐hyperglycaemic efficacy through avoidance of GLP‐1R desensitization. However, the ligand modifications needed to decrease β‐arrestin recruitment usually also reduces GLP‐1R affinity, therefore higher doses are needed. Here we aimed to develop new, long‐acting, G protein‐biased GLP‐1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios.Materials and MethodsNew GLP‐1R agonist peptides were assessed using a variety of in vitro and in vivo assays.ResultsFirst, we show that very substantial reductions in β‐arrestin recruitment efficacy are required to realize fully the benefits of GLP‐1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist‐specific GLP‐1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP‐1R agonist pharmacogenomics.ConclusionsCompletely abolishing β‐arrestin recruitment improves the anti‐hyperglycaemic effects of GLP‐1R agonists in mice.

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Section: Discussionmentioning

confidence: 99%

Abolishing β‐arrestin recruitment is necessary for the full metabolic benefits of G protein‐biased glucagon‐like peptide‐1 receptor agonists

Hinds,

Peace,

Chen

et al. 2023

Diabetes Obesity Metabolism

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“…To date, there have been no attempts to establish voluntary licensing for AOMs [49]. A recent phase II trial showed up to −24.2% weight loss for retadrutide at 48 weeks compared with −2.1% for placebo [50 ▪ ]. Promising results are also seen for Oflorglipron with up to −14.7% vs. −2.3% for placebo [51 ▪ ].…”

Section: Antiobesity Medicationsmentioning

confidence: 99%

Intersections between HIV and obesity in emerging economies

Levi,

Fairhead,

Hill

2023

Current Opinion in HIV and AIDS

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Purpose of review HIV epidemics are increasing in many emerging economy countries, whilst the very process of ‘economic emergence’ is obesogenic. Annual deaths related to obesity and overweight are now four times more than for HIV globally. We describe the intersections between HIV and obesity in emerging economies, and highlight potential mitigation options, including antiobesity medications (AOMs), which are safe and effective, but inaccessibly priced. Recent findings We summarize what is known about weight-change in HIV and review strategies including public health policies and clinical interventions for emerging economy countries to fight obesity. We also illustrate the landscape from a selection of ‘emerging economy’ countries with available data from UNAIDS, World Bank and World Obesity Federation to visualize the developing challenges faced. AOM course prices are high in many countries, but could be manufactured and sold profitably for much less. We present lessons from the early HIV/AIDS movements on how to improve access and pricing for AOMs for people with HIV with obesity in emerging economy countries. Summary We illustrate the complex intersectional issues that ‘emerging economy countries’ may experience, with a ‘double burden’ of increasing HIV and obesity epidemics, and explore potential mitigation options, focussing on AOM access and pricing.

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“…Neben den Ko-Agonisten, ist aktuell auch ein Triple-Agonist Gegenstand klinischer Studien. So sind kürzlich Ergebnisse einer Phase II klinischen Studie zu Retatrutide, einem Triple-Agonisten für GIP, GLP-1 und dem Glukagon-Rezeptor, veröffentlicht worden [68]. In dieser Studie wurde ein dosisabhängiger Gewichtsverlust detektiert.…”

Section: Retatrutideunclassified

“…Nach 48 Wochen wurde ein Gewichtsverlust von durchschnittlich 24 % erreicht. Auch bei Retatrutide kam es vermehrt zu gastroin-Review testinalen Problemen und einer erhöhten Herzfrequenz, die jedoch nach 24 Wochen der Behandlung abnahm [68].…”

Section: Retatrutideunclassified

Genetische Ursachen der Adipositas und ihre therapeutischen Implikationen

Rajcsanyi,

Schmidt,

Düerkop

et al. 2023

Adipositas - Ursachen, Folgeerkrankungen, Therapie

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ZusammenfassungAdipositas ist eine komplexe Störung, die von Umweltfaktoren und genetischen Varianten beeinflusst wird. Basierend auf den genetischen Grundlagen wird zwischen zwei Formen der Adipositas unterschieden. Die monogene (und syndromale) Adipositas ist selten und wird von Mutationen in jeweils einem Gen bedingt. Zur Manifestation einer extremen Adipositas mit Hyperphagie kommt es bereits in den ersten Lebensjahren. Abhängig vom betroffenen Gen können zudem weitere phänotypische Ausprägungen hinzukommen. Die polygene Adipositas dagegen ist weitaus häufiger. Ursächlich für diese Form ist eine Vielzahl von genetischen Varianten, die jeweils einen geringen, aber additiven Effekt auf das Körpergewicht haben. Frühzeitige genetische Diagnostik kann die vorliegende Form der Adipositas identifizieren und die Wahl einer geeigneten Therapieoption, ob Lebensstilintervention, bariatrische Chirurgie oder pharmakologische Behandlung, unterstützen. Wir stellen aktuelle Erkenntnisse der Forschung über die genetischen Ursachen der Adipositas dar. Zudem werden therapeutische und diagnostische Optionen, die teils auf genetischen Befunden basieren, beleuchtet.

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Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial

Cited by 305 publications

References 28 publications

Abolishing β‐arrestin recruitment is necessary for the full metabolic benefits of G protein‐biased glucagon‐like peptide‐1 receptor agonists

Abolishing β‐arrestin recruitment is necessary for the full metabolic benefits of G protein‐biased glucagon‐like peptide‐1 receptor agonists

Intersections between HIV and obesity in emerging economies

Genetische Ursachen der Adipositas und ihre therapeutischen Implikationen

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