Williams David M, Nawaz Asif, Evans Marc
Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK.
Diabetes Ther. 2020 Jun;11(6):1199-1216. doi: 10.1007/s13300-020-00816-y. Epub 2020 Apr 15.
Whilst the prevalence of obesity continues to increase at an alarming rate worldwide, the personal and economic burden of obesity-related complications becomes ever more important. Whilst dietary and lifestyle measures remain the fundamental focus of the patient to counter obesity, more frequently pharmacological and/or surgical interventions are required. Nevertheless, these therapies are often limited by weight loss efficacy, side effects, surgical risks and frequently obesity relapse. Currently, only five drug therapies are approved for the specific treatment of obesity. However, our understanding of the pathophysiology of obesity and of gut hormones has developed precipitously over the last 20-30 years. As a result, there has been a recent movement to create and use analogues that manipulate these gut hormones to support weight loss. In this article we review the efficacy of the currently approved drug therapies and discuss future potential drug mechanisms and early clinical trial results exploring these budding avenues. We discuss the use of glucagon-like peptide-1 (GLP-1) analogues as monotherapy and unimolecular dual or triple agonists that exploit the GLP-1 receptor and/or the gastric inhibitory peptide (GIP) receptor and/or the glucagon receptor. We also explore the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, amylin mimetics, leptin analogues, ghrelin antagonists and centrally acting agents to suppress appetite [neuropeptide Y (NPY) antagonists, melanocortin-4 receptor (MC4R) agonists and cannabinoid-1 receptor antagonists]. Whilst further evidence is required to support their clinical use, preclinical and early clinical trial results are encouraging.
尽管全球肥胖症患病率仍在以惊人的速度持续上升，但肥胖相关并发症的个人和经济负担变得越来越重要。虽然饮食和生活方式措施仍然是患者对抗肥胖的基本重点，但药物和/或手术干预的需求却越来越频繁。然而，这些疗法往往受到减肥效果、副作用、手术风险以及肥胖症复发的限制。目前，仅有五种药物疗法被批准用于肥胖症的特定治疗。然而，在过去20至30年里，我们对肥胖症病理生理学和肠道激素的理解有了飞速发展。因此，最近出现了一种趋势，即研发和使用能够操纵这些肠道激素以辅助减肥的类似物。在本文中，我们回顾了目前已批准的药物疗法的疗效，并讨论了未来潜在的药物作用机制以及探索这些新兴途径的早期临床试验结果。我们讨论了胰高血糖素样肽-1（GLP-1）类似物作为单一疗法以及利用GLP-1受体和/或胃抑制肽（GIP）受体和/或胰高血糖素受体的单分子双靶点或三靶点激动剂的应用。我们还探讨了钠-葡萄糖协同转运蛋白-2（SGLT-2）抑制剂、淀粉样多肽类似物、瘦素类似物、胃饥饿素拮抗剂以及中枢作用药物（神经肽Y（NPY）拮抗剂、黑皮质素-4受体（MC4R）激动剂和大麻素-1受体拮抗剂）在抑制食欲方面的应用。尽管还需要更多证据来支持它们的临床应用，但临床前和早期临床试验结果令人鼓舞。
