Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.
J Intern Med. 2018 Dec;284(6):581-602. doi: 10.1111/joim.12837. Epub 2018 Oct 23.
Obesity and its comorbidities, such as type 2 diabetes, are pressing worldwide health concerns. Available anti-obesity treatments include weight loss pharmacotherapies and bariatric surgery. Whilst surgical interventions typically result in significant and sustained weight loss, available pharmacotherapies are far less effective, typically decreasing body weight by no more than 5-10%. An emerging class of multi-agonist drugs may eventually bridge this gap. This new class of specially tailored drugs hybridizes the amino acid sequences of key metabolic hormones into one single entity with enhanced potency and sustained action. Successful examples of this strategy include multi-agonist drugs targeting the receptors for glucagon-like peptide-1 (GLP-1), glucagon and the glucose-dependent insulinotropic polypeptide (GIP). Due to the simultaneous activity at several metabolically relevant receptors, these multi-agonists offer improved body weight loss and glucose tolerance relative to their constituent monotherapies. Further advancing this concept, chimeras were generated that covalently link nuclear acting hormones such as oestrogen, thyroid hormone (T ) or dexamethasone to peptide hormones such as GLP-1 or glucagon. The benefit of this strategy is to restrict the nuclear hormone action exclusively to cells expressing the peptide hormone receptor, thereby maximizing combinatorial metabolic efficacy of both drug constituents in the target cells whilst preventing the nuclear hormone cargo from entering and acting on cells devoid of the peptide hormone receptor, in which the nuclear hormone might have unwanted effects. Many of these multi-agonists are in preclinical and clinical development and may represent new and effective tools in the fight against obesity and its comorbidities.
肥胖及其合并症，如 2 型糖尿病，是全球紧迫的健康问题。现有的抗肥胖治疗方法包括减肥药物治疗和减肥手术。虽然手术干预通常会导致显著且持续的体重减轻，但现有的药物治疗效果要差得多，通常体重减轻不超过 5-10%。一种新兴的多激动剂药物类可能最终会填补这一空白。这种新型的特制药物将关键代谢激素的氨基酸序列融合到一个单一实体中，具有增强的效力和持续的作用。这种策略的成功例子包括针对胰高血糖素样肽-1 (GLP-1)、胰高血糖素和葡萄糖依赖性胰岛素释放肽 (GIP)受体的多激动剂药物。由于同时在几个与代谢相关的受体上发挥作用，这些多激动剂相对于其单一疗法提供了更好的体重减轻和葡萄糖耐量。进一步推进这一概念，产生了将核作用激素（如雌激素、甲状腺激素（T）或地塞米松）与肽激素（如 GLP-1 或胰高血糖素）共价连接的嵌合体。这种策略的好处是将核激素作用仅限于表达肽激素受体的细胞，从而最大限度地提高目标细胞中两种药物成分的组合代谢效果，同时防止核激素货物进入并作用于缺乏肽激素受体的细胞，其中核激素可能产生不良影响。许多这些多激动剂处于临床前和临床开发阶段，可能是对抗肥胖及其合并症的新的有效工具。
