The medicinal properties of the French Lilac, Galega Officinalis, also known as Goat's Rue, were already known in medieval Europe, when it was observed to reduce the diuresis associated with diabetes. Research on derivatives of guanidine, its main active principle, began in the early part of the twentieth century, but the discovery of insulin and the gastro-intestinal side effects and hepatotoxicity of these agents delayed further development until the 1950s when the biguanides phenformin, buformin and metformin were introduced into clinical use. By 1978 increasing reports of lactic acidosis associated with the use of phenformin led to the withdrawal of phenformin and buformin from the market. Metformin did not become available in the USA until 1995, but was widely used elsewhere, and became increasingly popular when UKPDS showed it to reduce macrovascular morbidity and mortality. Since then many studies have demonstrated its excellent clinical utility which currently makes it the first-line drug of choice for the treatment of type 2 diabetes. The actions of metformin are still somewhat obscure, and its apparent benefits in cardiovascular disease and cancer have prompted further investigation of this fascinating drug.
History of the biguanides
Fig 1. Galega officinalis.
Galega officinalis (as the term "officinalis" implies) was recognised as a medicinal herb in the middle ages, and used to treat a variety of illnesses. It was claimed to alleviate the diuresis associated with diabetes, and is still listed as a treatment for this condition in modern herbal pharmacopoeias. It contains large amounts of guanidine which has toxic side effects when eaten by cattle; the plant is classed as a noxious weed in 35 US states. Guanidine was shown to have hypoglycaemic effects in 1918, and two synthetic diguanides known as Synthalin A and B went into clinical use in the 1920s (one was tested in Oskar Minkowski's clinic in Breslau) but they were soon withdrawn because of their toxicity. A less toxic extract known as galegine (isoamylene guanidine) was also tried unsuccessfully. Dimethyl biguanide (metformin) was first synthesised in 1922, followed by many other chemicals in this group, but interest in oral therapies for diabetes languished until the introduction of the sulfonylureas in the 1950s. Phenformin, the most potent hypoglycaemia agent in this class, was introduced into clinical use in 1957, shortly followed by commercial development of buformin and metformin. Phenformin and buformin were withdrawn because of lactic acidosis in the 1970s. Phenformin was also associated with increased mortality in the University Group Diabetes Program (UGDP), and guilt by association meant that metformin did not reach the USA until 1995, although widely used in other parts of the world.
Both parasites and cancer cells rely upon a plentiful supply of glucose from the host, and synthalin was found to have some benefit in trypanosomiasis, an observation which led on to the development of the related drug pentamidine, which is still in clinical use. Coincidentally paludrine, an antimalarial with a biguanide structure, was found to have hypoglycaemic properties.
It is fascinating to note that this class of agent has twice fallen out of favour, and twice risen again. As Joslin's textbook said in 1985, "the biguanides, like the legendary phoenix, keep rising from their own ashes".
Chemistry of the biguanides
While many biguanides have been synthesized, only a few exert a glucose-lowering effect. As can be seen in figure 2, the biguanides have a shared basis, originating from two linked guanidines (in blue). The pharmacological differences between the biguanides are determined by differences in their non-polar hydrocycarbon side chains (in red). As a result of these non-polar side chains the biguanides bind to membrane phospholipids and other biological structures.
Actions of the Biguanides
Administration of metformin lowers plasma glucose, and reduces the requirement for insulin in insulin-treated individuals. It is therefore classed as an insulin sensitizer, and can be combined effectively with almost any other treatment used for diabetes. Its glucose-lowering effect is primarily due to inhibition of hepatic gluconeogenesis and thus of hepatic glucose output, which is increased two-fold or more in type 2 diabetes. Its glucose-lowering effect is directly proportional to the degree of elevation (Figure 3).
Figure 3. The glucose lowering effect of metformin is proportional to glucose elevation In addition metformin inhibits the the intracellular energy-sensing enzyme AMPK indirectly via an effect upon the electron transport chain in the mitochondria, and this and other properties suggested that it might have useful antineoplastic properties. A series of observational studies strongly suggest that metformin users experience protection against both heart disease and a range of cancers, and this agent is now in clinical trial as an adjunct to other anti-cancer therapy.
Biguanides and lactic acidosis
Differences in the side-chains of metformin and phenformin may also explain the differences in effects and side-effects of these drugs. As noted, phenformin was eventually banned from medical use because of a very high incidence of (fatal) lactic acidosis. However, lactic acidosis occurs much more frequently with phenformin than with metformin. This difference in the incidence of lactic acidosis between phenformin can be related to their different chemical structure. Firstly, in contrast to metformin, modestly raised phenformin concentrations may reduce peripheral glucose oxidation and enhance peripheral lactate production, leading to lactate accumulation. In line with this, phenformin levels correlate with plasma lactate, whereas metformin levels do not. Secondly, the route of metabolism of phenformin involves a hydroxylation step in the liver. About 10% of the Caucasian population has a genetic polymorphism that affects this step and which leads to a reduced clearance of phenformin, thus increasing the risk for side effects such as lactic acidosis. Finally, the higher lipophilicity of phenformin may lead to its accumulation in the mitochondrion, where it will exert its detrimental effects on lactate turnover.
Clinical use of biguanides
The popularity of metformin was enormously enhanced by the United Kingdom Prospective Diabetes Study (UKPDS), which showed a persistent reduction in cardiovascular mortality which could not be fully explained by its glucose-lowering properties.
Clinicians have long been aware that some patients respond much more favourably to metformin than others. It has recently been shown that the ataxia telangiectasia mutated (ATM) gene, which has a role in DNA repair and cell cycle control, influences the phosphorylation and activation of AMP-activated protein kinase in response to metformin. Further studies may permit more carefully targeted use of this agent.
^ Bailey CJ, Day C. Metformin - its botanical background. Practical Diabetes International 2004;21(3):115-117
^ Witters LA. The blooming of the French Lilac. JCI 2001;108(8):1105-7
^ Bailey CJ et al. Metformin - The Gold Standard. John Wiley and Sons, 2007.
^ GoDARTs and UKPDS Diabetes Pharmacogenetics Group. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature Genetics 2011;43(2):117-120