Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
Metabolism. 2022 Aug;133:155223. doi: 10.1016/j.metabol.2022.155223. Epub 2022 May 29.
Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.
二甲双胍最初于 20 世纪 50 年代末用于治疗 2 型糖尿病，截至 2022 年，它仍是全球约 1.5 亿人日常使用的首选药物。大量的临床前和临床数据积累激发了人们将二甲双胍重新用于治疗包括 COVID-19 在内的各种疾病的兴趣。在多囊卵巢综合征中，二甲双胍可以提高胰岛素敏感性。在 1 型糖尿病中，二甲双胍可能有助于减少胰岛素剂量。荟萃分析和临床前及临床研究数据表明，二甲双胍可降低癌症发病率。MILES（二甲双胍在长寿研究中的应用）和 TAME（二甲双胍靶向衰老）等临床试验旨在确定二甲双胍是否可以延缓衰老并延长寿命。临床前和临床数据表明，二甲双胍通过抑制促炎途径、保护线粒体和血管功能以及对神经干细胞的直接作用，可能预防神经退行性疾病。二甲双胍还被研究用于其抗细菌、抗病毒和抗疟疾的功效。这些数据共同提出了一个问题：二甲双胍是否是一种适用于所有疾病的药物？目前尚不清楚这些潜在的有益作用是否是其作为降血糖和胰岛素增敏药物的作用的结果，还是来自于其他细胞作用，包括抑制雷帕霉素靶蛋白（mTOR）或直接的抗病毒作用。人们还在寻求澄清，基于使用高浓度二甲双胍的体外研究数据是否可以转化为临床益处，或者它们是否反映了“帕拉塞尔苏斯”效应。二甲双胍没有已知代谢物，对环境的影响也是一个新出现的问题，它与鱼类的内分泌干扰有关，在 2 型糖尿病中的广泛应用也引起了人们对其对人类生殖影响的担忧。本综述的目的是：1）评估二甲双胍的潜在作用机制；2）分析二甲双胍在治疗 2 型糖尿病以外疾病方面的有效性的有争议的证据；3）评估数据的可重复性；4）最终得出一个明智的结论，即二甲双胍是否是一种适用于所有疾病及其原因的药物。我们的结论是，二甲双胍的主要临床益处来自于其胰岛素增敏和降血糖作用，这间接降低了多种疾病的风险，从而延长了健康寿命。然而，像改善血管内皮功能等独立于葡萄糖稳态的益处也增加了二甲双胍的治疗作用。
