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.

Keywords: Aging; COVID-19; Cancer; Diabetes; Metformin; Neurodegenerative diseases.

  1. Introduction
    1.1. Brief history
    Metformin, dimethyl biguanide, is a synthetic biguanide that combines two guanidine moieties together into one molecule. Its development as an anti-diabetic drug can be linked to Southern and Eastern European folk medicine knowledge dating back until the 17th Century when extracts from French lilac (Galega officinalis) were used to treat
    people with ‘sweet urine’. French Lilac is a widely distributed perennial found in temperate regions and is also known by a variety of names including goat’s rue, Italian fitch, and in the USA as Professor Weed and has been employed in folk medicine for a wide range of afflictions including diuretic and anti-diabetic actions as well as use in farm animals and humans as a galactogogue [1–3]. Arguably many of the benefits of French lilac, including its effects as a galactogogue, can be attributed to the insulin-sensitizing actions of guanidines. The history of the development of metformin from botanical origins to chemical synthesis has been well documented by others and is summarized in Table 1
    In brief, the primary active anti-diabetic chemical in the extracts from French Lilac is the alkaloid galegine (isoamylene guanidine); however, galegine is too toxic for chronic use and in the late 19th century German chemists, Adolph Strecker and Bernhard Rathke synthesized guanidine and biguanides. Studies with these synthetic guanidine derivatives provided the stimulus to develop an orally effective and less toxic anti-diabetic drug and guanidine hydrochloride was reported to
    lower blood glucose levels in rabbits [8]. Metformin was synthesized in 1922 [9] and reports of the ability of metformin and other synthetic guanidines to lower blood glucose in rabbits and dogs were published shortly thereafter [10–12]. Synthalin A (decamethylene diguanide) and Synthalin B (dodecamethylene diguanide) were biguanidines developed by Schering AG to treat diabetes. Synthalin B, with an aliphatic chain with 12 links was claimed to be safer than Synthalin A but reports of liver toxicity led to the withdrawal of Synthalin B from use in most countries in the 1930s and in Germany in the mid-1940s. There was little interest in metformin until the late 1950s when French physician, Jean Sterne, described its benefits in patients with diabetes [15]. However, it was Ciba’s more potent biguanide, phenformin (phenethylbiguanide), which was adopted into clinical use and reduced interest in metformin [22,23]. In 1978 as a result of increasing concerns with hepatotoxicity and lactic acidosis phenformin and another biguanide, buformin, were withdrawn from use in most countries. Positive data from the Multicenter Metformin Study in the USA was published in 1995 and provided renewed interest in the role of metformin as well as the importance of blood glucose control. The conclusions of this 1995 study were further enhanced by the results of the larger United Kingdom Prospective Diabetes Study (UKPDS) in 1998 [18,24]. Currently, metformin remains the first-choice drug for most patients with T2D [18,25], and as depicted in Fig. 1 subsequent to the completion of UKPDS in 1998 there has been a steady increase in publications focusing on the use of metformin to treat T2D.
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