Metformin, a principle biguanide antihyperglycemic agent used agent, represents a mainstay of today's therapy in the treatment of non-insulin-dependent diabetes mellitus and shows significant effectiveness in decreasing the risk of disease development. The discovery of this drug can be traced back to the pioneering work with extracts of the herb Galega officinalis, which led to the characterization of the blood-lowering effects of an active ingredient named galegine.
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Drug of a plant origin
Galega officinalis (also known by many other names including as goat's rue, false indigo, professor-weed, French lilac, Spanish sanfoin, and Italian fitch) is a summer-flowering perennial herb with white, blue, or purple flowers found in most temperate regions. It originated in southern Europe and western Asia, but in the last two centuries, it has spread to many countries around the globe.
In medieval times, a prescription of Galega officinalis was used in folklore medicine to relieve the frequent urination accompanying the disease that is today known as diabetes mellitus. The plant was also given as a medicine in plague epidemics to promote perspiration of the affected individuals and has been widely used to stimulate lactation in cows. Still, the plant was too toxic for widespread agricultural usage.
Traditional herbal remedies were poorly understood at the beginning of the 20th century. Although Galega officinalis successfully lowered blood glucose concentrations in diabetic patients, the quest for an active ingredient was slow in the early days of the last century. The main reasons were mild effects from the plant and the introduction of potent insulin, which was effective for both type 1 and type 2 diabetes.
The active ingredient in the French lilac that produced the lowering of blood glucose was shown to be galegine or isoamylene guanidine. Studies in the late 1800s indicated that goat's rue was rich in guanidine, but it was shown to be overly toxic for clinical use. Thus the attention turned to galegine, a less toxic extract, whose precise structure was confirmed in 1923 by a research group in Edinburgh, UK.
The history of clinical application
Early clinical experience with galegine sulfate was described by Muller and Reinwein in 1927. They experimented with self-administration of 109 mg of galegine sulfate, after which blood glucose levels were followed for 25 hours. They subsequently expanded the study on other healthy individuals, and finally on patients with diabetes. In all three subjects, a hypoglycaemic effect was noted (mild in the normoglycemic subjects, but significant in diabetic patients).
Further work by Leclerc and his research groups, as well as work by Parturier and Hugonot during the next ten years, yielded additional observations on the antidiabetic actions of extracts of Galega officinalis. These succeeded in improving the safety and delivery of galegine-based therapy, although its utility was limited by the variability of the responses and short duration of action.
In 1957, metformin (by then already dubbed Glucophage or "glucose eater") was studied in several trials in Paris and has shown to lower blood glucose in patients with type 2 diabetes, although not in healthy individuals. Unlike sulfonylureas (another class of oral antidiabetic drugs), metformin did not stimulate insulin release, but primarily reduced the release of glucose from the liver. In those studies, metformin showed adverse gastrointestinal effects.
In the same year, an American group published similar results for phenformin (phenylethyl biguanide). The marketing of that drug was energetic by Ciba-Geigy, but its association with lactic acidosis effectively curtailed the use of phenformin due to a myriad of reported cases of lactic acidosis. In contrast, metformin was manufactured by a small French company and initially, it was the preferred biguanide only in France and Scotland (among developed countries at the time).
As the number of lactic acidosis and deaths increased, phenformin was removed from the market in the USA in 1977, and withdrawn from many other countries as well. The Australian Drug Evaluation Committee recommended severe restrictions on both phenformin and metformin, not taking into account the different pharmacokinetics of the two drugs. Phenformin is metabolized by the liver and can accumulate in patients with certain genetic disorders, while metformin is excreted renally and only rarely results in lactic acidosis cases or death in patients who overdose or have an advanced renal failure.
Endocrinologists in France and Scotland with substantial experience of using metformin continued with its prescription. In 1968 and 1977, studies conducted in Scotland compared metformin with chlorpropamide and found that glucose control was similar with both drugs. Still, patients on metformin had less hypoglycemia and lost weight, while those on the sulfonylurea showed some weight gain.
In 1995 the benefits of metformin were rediscovered. Many studies were performed, and among them, the most influential has been the UK Prospective Diabetes Study. It was a randomized, multicenter clinical trial that followed 3867 patients over 10 years. Independently of blood glucose control, metformin reduced the risks of myocardial infarction and mortality of all causes.
As a result, metformin arose as the first-choice treatment for obese patients with type 2 diabetes. The drug's anti-atherosclerotic and cardioprotective effects have been confirmed in prospective and retrospective studies, but it took another decade for these findings to be translated into official recommendations. In 2012 diabetes experts in the USA and Europe declared that metformin is the drug of the first choice for all patients with type 2 diabetes.
Metformin
References
- Witters, L. (2001) "The blooming of the French lilac", Journal of Clinical Investigation, 108(8), pp. 1105-1107. doi: 10.1172/jci14178.
- Bailey, C. and Day, C. (2004) "Metformin: its botanical background", Practical Diabetes International, 21(3), pp. 115-117. doi: 10.1002/pdi.606.
- Drug Discovery: metformin and the control of diabetes (2011). Available at: https://edu.rsc.org/feature/drug-discovery-metformin-and-the-control-of-diabetes/2020127.article (Accessed: 30 September 2021).
- (2021) Media.wiley.com. Available at: https://media.wiley.com/product_data/excerpt/19/04707254/0470725419.pdf (Accessed: 30 September 2021).
- "Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group" (1998), (9131), p. Available at: https://pubmed.ncbi.nlm.nih.gov/9742976/ (Accessed: 30 September 2021).
- Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P. Metformin - The Gold Standard: A Scientific Handbook. Chichester: Wiley, 2008; 1-36.
Further Reading
Healthy eating, physical activity, and medication: Type 2 diabetes patients' willingness to engage varies