Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat’s rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin’s future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.
This short biography of metformin (1,1-dimethylbiguanide hydrochloride) plots a chequered history from herbal ancestry in Europe to synthesis, and the discovery of its glucose-lowering activity in the 1920s: information that was disregarded and forgotten. In the 1940s, metformin was rediscovered in the search for antimalarial agents and repurposed to treat influenza, before its introduction, in 1957, for the treatment of adult-onset diabetes (Table 1). However, metformin was considered weaker than other glucose-lowering biguanides and received limited use. When the other biguanides (phenformin and buformin) were withdrawn in the late 1970s because of links to lactic acidosis, metformin was spared, but mostly rejected. However, ongoing research and minimal clinical use in the 1980s and early 1990s demonstrated a uniqueness and utility of metformin that fostered its rescue. The introduction of metformin into the USA in 1995 boosted research and clinical use and long-term evidence from the UK Prospective Diabetes Study (UKPDS) in 1998 set metformin on course for its current position as the preferred initial agent to manage hyperglycaemia in type 2 diabetes. Now exonerated, metformin is being assessed for further clinical indications. How could such a medicinal servant have received such a tempestuous journey?
The herbal lineage of metformin can be traced from the use of Galega officinalis (a.k.a. goat’s rue, French lilac, Italian fitch, Spanish sainfoin or professor weed; Fig. 1) as a traditional medicine in medieval Europe . Also known as Herba rutae caprariae in some herbals, G. officinalis was ascribed benefits against worms, epilepsy (‘falling-sickness’), fever and pestilence in Culpeper’s Complete Herbal of 1653, whilst in 1772, John Hill recommended Galega to treat conditions of thirst and frequent urination [2,3,4]. In Europe, wild G. officinalis was widely recognised as an animal galactagogue from which it gained its name (‘Galega’ being derived from the Greek for ‘milk stimulant’). The plant was introduced into North America in 1891 and is now classed as a noxious weed in many states of the USA . Chemical analyses of G. officinalis dating from the mid-1800s found the plant to be rich in guanidine and related compounds (shown in Fig. 2), especially the immature seed pods . In 1918, guanidine was reported to reduce blood glucose in animals, and during the 1920s several mono-guanidine derivatives, notably galegine (isoamylene guanidine) and diguanidines, such as synthalin (two guanidines separated by a methylene chain; see Fig. 2), were also shown to lower blood glucose in animals [6,7,8,9,10]. This led to the introduction of galegine and the more potent synthalin in diabetes treatment. However, initial optimism was tempered with disappointment as toxicity was observed, curtailing their use during the 1930s as insulin became more widely available [6, 11,12,13,14,15].
From Galega to biguanides
The chemical origins of metformin run in parallel with its herbal origins and date from the preparation of guanidine by Adolph Strecker (1840s–1860s) and the subsequent work of Bernhard Rathke in 1879, resulting in the fusion of two guanidines to form biguanide (Fig. 2) [6, 16]. These developments provide the background for the synthesis of metformin (dimethylbiguanide) by Werner and Bell in 1922 . Despite structural proximity to the glucose-lowering mono- and diguanidines, it was not until 1929 that metformin and other biguanides were reported to lower blood glucose levels in animals (rabbits and dogs) by Hesse and Taubmann and Slotta and Tschesche [18, 19]. Importantly, biguanides were deemed to be less toxic than mono- and diguanidines and, of the various methyl biguanides tested, metformin exerted the least toxicity . However, the real potential of these agents was underappreciated at the time because of the high doses required to achieve modest glucose-lowering effects in non-diabetic animals (compared with subsequent evidence in models of diabetes). Hence, the biguanides were not developed for diabetes therapy and were forgotten during the following decade, along with the other guanidine-based agents.
Rediscovery via malaria and influenza
A third strand in the history of metformin is the independent development of a guanidine-based antimalarial agent proguanil (Paludrine) in the mid 1940s. This drug was reported to cause a lowering of blood glucose in animal studies [20, 21]. In a search for other guanidine-based antimalarials, proguanil was modified to metformin, and tests for antimalarial activity by Eusebio Garcia in the Philippines, in 1949, found metformin to be helpful in treating a local influenza outbreak . This gave rise to the use of metformin hydrochloride as an anti-influenza agent called flumamine, and a tendency for metformin to lower blood glucose in some of the influenza patients was duly noted [6, 22].
Step forward Jean Sterne
The visionary who translated the blood-glucose lowering potential of metformin into a therapeutic reality was Jean Sterne, a physician at the Aron Laboratories in Suresnes, in the west of Paris, France (Fig. 3). In 1956, encouraged by laboratory owner, Jan Aron, Sterne critically assessed the evidence around flumamine, and recalled his involvement in a disappointing study of galegine as an intern with Professor Francis Rathery at Hôpital de la Pitié in Paris many years earlier . Maybe metformin would be better? Working at Aron Laboratories with his pharmacist colleague, Denise Duval, the duo embarked on an ambitious programme of research into the pharmacodynamics of several guanidine-based compounds, including metformin and phenformin, in normal and diabetic animal models. Unknowingly they duplicated and extended studies on guanidine-based compounds from the 1920s and noted afresh the issues of high dose, limited glucose-lowering properties and high toxicity. They singled out metformin for study in the diabetes clinic based on its glucose-lowering efficacy and minimal adverse effects in normal and diabetic animal models, coupled with the documented experience of flumamine use in humans .
Sterne had a position at Hôpital Laennec in Paris where he started metformin studies with his patients; he also persuaded Dr. Elie Azerad at Hôpital Beaujon in Clichy (northwestern Paris) to collaborate. Their initial studies, mostly in insulin-treated individuals, included a mix of juvenile-onset and maturity-onset presentations of diabetes. The studies indicated that metformin could replace the need for insulin in some individuals with maturity-onset diabetes and reduce the insulin dose required by others, but it did not eliminate the need for insulin in individuals with juvenile-onset diabetes . They also noted no occurrence of frank hypoglycaemia (as had recently been reported with sulfonylureas) and little or no effect of metformin use in individuals without diabetes. This was enough for Sterne to publish a brief account of his findings in a Moroccan medical journal in 1957 , a paper that is now recognised as a landmark paper for the emergence of metformin as a diabetes therapy. In his report, Sterne made the following prophetic remarks (translated from French): ‘LA6023 [metformin] is…well tolerated, which, even after very prolonged administration, does not damage the organism. At low doses, it is hypoglycaemic by mouth in the rabbit, chicken, rat, guinea pig, dog, alloxan-diabetic rabbit, and the diabetic human…and its ultimate place in the management of diabetes requires further study’. Later publications would elaborate details of these animal studies, revealing Sterne’s insight, skill and persistence [25,26,27,28,29,30,31].
Sterne suggested the name ‘glucophage’ (meaning glucose eater), which was adopted by Aron to market metformin, and Sterne played a prominent role in ongoing research and physician education to assist the introduction of metformin into clinical practice in Europe . History might be tempted to consider the diabetes indication of metformin as serendipitous, but we must gratefully acknowledge Sterne’s sharp enquiring mind, his prodigious experimentation and his perceptive clinical sixth sense.
The biguanide opportunity
During the 1950s, other groups investigated guanidine derivatives, and the glucose-lowering properties of phenformin were rediscovered and published in 1957 by Ungar and colleagues (based in the USA) . This was followed by reports of buformin’s ability to reduce blood sugar levels in 1958, by A. Beringer (Germany) [32, 33]. A vast selection of guanidine derivatives was then synthesised and evaluated, but enthusiasm was dampened by their lesser glucose-lowering efficacy in non-diabetic animals compared with agents that stimulate insulin secretion [34, 35]. However, studies in human maturity-onset diabetes indicated greater glucose-lowering efficacy of phenformin compared with other biguanides and this agent gained global popularity as an alternative to sulfonylureas, especially in the USA [36,37,38]. At this time, metformin and buformin were not introduced for use in the USA and received relatively minor use in Europe, although metformin became available in the UK in 1958 and in Canada in 1972 and was championed in several respected diabetes clinics. In the early 1960s, buformin became available across Europe (but not the UK), with its use particularly being adopted in Germany; nonetheless, it remained in the shadow of phenformin [39, 40].
Clinical experience with metformin use in small studies and anecdotal accounts from individuals with maturity-onset diabetes typically portrayed modest efficacy but generally good tolerability, accepting the gastrointestinal incommode experienced by some patients [6, 41]. Large comparative trials (notably in Edinburgh, UK) showed that metformin could achieve similar long-term glycaemic control as sulfonylureas, without significant hypoglycaemia or weight gain [42,43,44]. Later studies reported that basal insulin concentrations were often reduced with metformin use, consistent with the amelioration of insulin resistance, while lipid-lowering effects and improved haemodynamics were evident in some individuals [41, 45]. The requirement for renal monitoring was consolidated, contraindications were appreciated and a possible decrease of vitamin B12 absorption was recognised [41, 45].
The risk of lactic acidosis, especially with phenformin and buformin, was evident from the outset, and the controversy was fuelled when phenformin was withdrawn from the University Group Diabetes Program (UGDP) trial in the USA in 1971 [46,47,48]. Phenformin was removed from the market in the USA in 1978, and phenformin and buformin were discontinued in much of Europe around this time, although both agents can still be obtained in some countries . The incidence of lactic acidosis amongst users of metformin was much lower and most cases could be attributed to inappropriate use in contraindicated patients with chronically impaired renal function or in those with acute kidney disease [47, 50, 51]. Moreover, in some studies it was debatable whether incidence rates of lactic acidosis with metformin were higher than background rates amongst individuals with maturity-onset diabetes. Nevertheless, the reputation of metformin was tarnished by association with the other biguanides, causing metformin to teeter on the very brink of discontinuation .
Ironically, soon after withdrawal of phenformin it was noted that about 9% of Europids have a mutation in the CYP2D6 gene, encoding the cytochrome P450 2D6 (CYP2D6) hydroxylation enzyme, causing a build-up of unmetabolised phenformin, leading to lactic acidosis [52, 53]: a problem that modern pharmacogenomics could deal with.
How did metformin survive the biguanide cull?
Clinical experience with metformin, albeit limited compared with phenformin, generally suggested a more favourable safety profile, and there were pharmacokinetic data to indicate distinct differences between metformin and the other biguanides (Fig. 4; Table 2) [40, 41]. During the 1980s, ‘non-insulin-dependent diabetes’ (replacing the term ‘maturity-onset diabetes’), as a condition, became viewed as much from the perspective of insulin resistance as beta cell failure, and the ability of metformin to counter insulin resistance generated interest [54, 55]. New information in the 1980s and early 1990s indicated that the ability of metformin to reduce hepatic gluconeogenesis and increase peripheral glucose utilisation was not merely an anaerobic consequence of respiratory-chain disruption . Rather, metformin affected a raft of insulin-dependent and insulin-independent effects in ways that varied in different tissues because of the difference in the amount of drug exposure to these tissues and the activity of insulin, glucagon and pathways of nutrient metabolism within these tissues. In particular, it became evident that high levels of metformin in the intestinal wall exert insulin-independent effects that account for most of the excess lactate production associated with its use, whereas liver and muscle tissues are exposed to lower concentrations of metformin that alter post-receptor insulin signalling pathways and redirect energy-generating and storage pathways [56,57,58,59,60,61,62].
Metformin enters the USA
With reverberations from phenformin, the US Food and Drug Administration (FDA) was hesitant about metformin, but in 1986 an approach by Lipha Pharmaceuticals (having acquired Aron Laboratories) sparked an inordinately thorough reassessment of metformin by the FDA and the sponsor. The Lipha team was led by Dr. Gerard Daniel, an inspired, meticulous and pragmatic physician reminiscent of Jean Sterne. Daniel worked tirelessly alongside another very accomplished physician, Dr. Anita Goodman, to deliver answers to an avalanche of questions from the FDA . This involved a proliferation of studies by Lipha Europe plus input from a group of independent clinical scientists (initially Gerald Reaven, Ralph DeFronzo and Clifford Bailey, later joined by Robert Turner and Alan Garber) who engaged with the FDA to design the clinical trials, discuss the data and consider the implications for routine clinical use in the USA [6, 56]. The FDA approved metformin on 29 December 1994 and soon after its launch in the USA, in 1995, new key trial data were published in the New England Journal of Medicine . These and later clinical studies confirmed and extended the findings from the aforementioned comparative trials conducted in Edinburgh two decades earlier, and the design of the FDA registration trials for metformin has provided a template for phase 3 evaluation of subsequent glucose-lowering agents [63, 64]. Bristol Myers Squibb acquired US marketing rights to metformin and instigated an education programme of unprecedented proportion to facilitate safe introduction of the drug, emphasising its different mode of action to sulfonylureas and the necessary cautions associated with renal impairment and hypoxaemic conditions. The value of this safety-first approach accorded with the FDA’s ‘black box warning’ reminder that is inserted in the product label and played an important role in maintaining the acknowledged safety profile of the drug . As prescriber confidence grew, an extended-release formulation of metformin was approved in 2000 with reduced gastrointestinal side effects [65, 66]. Also, new fixed-dose combinations of metformin with sulfonylureas, and later with other classes of oral glucose-lowering agents, became available, taking advantage of additive efficacy when combining agents with different modes of action . The key difference from earlier European fixed-dose combinations was that the dosages were based around metformin as the primary component, with doses of the second agent tailored to complement the administration schedule for metformin and to minimise risk of hypoglycaemia .
The UKPDS and long-term retrospective studies
In 1998, the UKPDS revealed data from newly diagnosed type 2 diabetes individuals receiving glucose-lowering treatment for more than a decade. This epic study, which redefined the therapeutic strategy for the management of type 2 diabetes, noted that in addition to glucose-lowering effects, weight neutrality and low hypoglycaemia risk, long-term metformin therapy might reduce cardiovascular events and improve survival . Reduced cardiovascular risk appeared to be largely independent of glucose-lowering efficacy and attention is drawn to a substantial literature noting potentially advantageous effects of the drug on the macro- and microvasculature (Table 3) [70, 71]. Interrogation of large databases that captured long-term treatment of type 2 diabetes consistently confirmed the reduced cardiovascular risk with metformin, and a 10-year follow-up of the UKPDS in 2008 showed a continued cardiovascular benefit of early use of the drug [72,73,74].
First-line pharmacological choice
Many studies on the pharmacokinetics, pharmacodynamics, clinical efficacy and cellular mechanisms of metformin have informed a favourable benefit:risk ratio that, alongside cost-effectiveness, has elevated this agent to the preferred first-line glucose-lowering pharmacological therapy for type 2 diabetes in major national and international treatment guidelines and algorithms (for examples, see [75,76,77,78]). Metformin has become the most prescribed glucose-lowering therapy worldwide and it is now included in the World Health Organization’s (WHO’s) essential medicines list . A citizens’ petition in the USA prompted an update to the product label in 2016 to extend prescribing for individuals with mild renal impairment. Overall, the prominent position of metformin reflects judicious prescribing, emphasising that contraindications should not be over-relaxed if the safety profile is to be retained (Table 4).
Possible additional indications for metformin are under investigation; opportunities for its use in type 1 diabetes to improve glycaemic control and reduce required insulin dose have been appreciated since the very first clinical studies [6, 80]. Several studies have affirmed the value of metformin to slow or prevent progression of impaired glucose tolerance (IGT)/impaired fasting glucose (IFG) (‘prediabetes’) to type 2 diabetes and other studies have suggested a place for metformin in the treatment of gestational diabetes [81,82,83]. Various insulin-resistant states in which metformin has improved prognosis include polycystic ovary syndrome (PCOS), human immunodeficiency virus (HIV)-associated lipodystrophy, acanthosis nigricans and, possibly, dementia-type neurodegenerative disorders [84,85,86,87]. Reduced cancer risk was tentatively indicated in the UKPDS and has subsequently been identified in large database analyses, suggesting that metformin might protect against certain cancers in individuals with type 2 diabetes, notably in the bowel where drug exposure is high, and this has opened a whole new research arena [69, 88, 89]. Advances in pharmacogenomics may better inform responsiveness to metformin and effects on the gut microbiome, and animal studies have intriguingly noted anti-ageing effects of metformin [90, 91].
There are endless generic lessons for medical research thinly disguised within the history of metformin. With hindsight, we are reminded that time spent searching early original literature can save valuable laboratory time, effort and money: vital clues can be concealed amidst throw-away observations in other areas of research. We are also reminded that the selection and interpretation of experimental models is fundamental, scrutiny within a drug class can reveal important differences, and we don’t have to know exactly how a drug works to reap benefit, but we do need to appreciate how to use it safely.
The awesome voyage of metformin from herbal beginnings to respected therapeutic agent has been turbulent. It was discovered, forgotten, rediscovered, repurposed, rejected, rescued, exonerated and may have further secrets to reveal. Each chapter has a cast of champions who helped it on its way (Fig. 5), but the pivotal work of Jean Sterne stands aloft [6, 56]. Metformin is unusual amongst pharmacotherapies as it does not appear to have a single mechanistic target: rather it counters insulin resistance and impacts metabolic, vascular and other physiological functions through multiple effects that are individually modest but collectively substantial. The value of such a favourably versatile medication requires that the contraindications (especially renal and hypoxaemic restrictions) are respected and that further potential therapeutic opportunities are explored.
Food and Drug Administration
Impaired fasting glucose
Impaired glucose tolerance
UK Prospective Diabetes Study
Bailey CJ, Day C (2004) Metformin: its botanical background. Pract Diabetes Int 21:115–117
Culpeper N (1995) Culpeper’s complete herbal: a book of natural remedies for ancient ills. Wordsworth Editions Ltd, Ware, Hertfordshire p335. Available from https://books.google.co.uk/books?id=aGih_JZtPvoC&pg=PA335&lpg=PA335&dq=galega+culpeper+herbal&source=bl&ots=77gExCABa_&sig=wV0BcjUm_RS8F6ZRMjo8N8F6zgU&hl=en&sa=X&ved=0ahUKEwiPw_fJ6YzSAhUBJcAKHV4EB2kQ6AEIQTAH#v=onepage&q=galega%20culpeper%20herbal&f=false. Accessed 13 Feb 2017
Hill J (1772). The vegetable system. Or the internal structure and the life of plants; their parts, and nourishment, explained; their classes, orders, genera, and species, ascertained, and described; in a methods altogether new: comprehending an artificial index, and a natural system. With figures of all the plants; designed and engraved by the author. The whole from nature only. Vol. XXI, containing plants and four-petal’d irregular flowers. London, p54
Hadden DR (2005) Goat’s rue—French lilac – Italian fitch – Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection. J R Coll Physicians Edinb 35:258–260
Galega officinalis. Available from https://en.wikipedia.org/wiki/Galega_officinalis. Accessed 27 Feb 2017
Pasik C (1997) Diabetes and the biguanides: the mystery of each. In: Pasik C (ed) Glucophage: serving diabetology for 40 years. Groupe Lipha, Lyon, p79
Watanabe CK (1918) Studies in the metabolic changes induced by administration of guanidine bases. Influence of injected guanidine hydrochloride upon blood sugar content. J Biol Chem 33:253–265
Frank E, Nothmann M, Wagner A (1926) Über synthetisch dargestellte Körper mit insulinartiger Wirkung auf den normalen und diabetischen Organismus. Klin Wchnschr 5:2100–2107 [article in German]
Simonnet H, Tanret G (1927). Sur les proprietes hypoglycemiantes du sulfate de galegine. Bull Soc Chim Biol Paris, 8 [article in French]
Bischoff F, Sahyun M, Long ML (1928) Guanidine structure and hypoglycemia. J Biol Chem 81:325–349
Muller H, Reinwein H (1927) Zur Pharmakologie des Galegins. Arch Exp Path Pharmacol 125:212–228 [article in German]
Rabinowiz IM (1927) Observations on the use of synthalin in the treatment of diabetes mellitus. Can Med Assoc J 17:901–904
Leclerc H. Le galega. Presse Med 1928, 22 décembre [article in French]
Howlett HCS, Bailey CJ (2007) Galegine and antidiabetic plants. In: Bailey CJ, Campbell IW, JCN C et al (eds) Metformin—the gold standard: a scientific handbook. Wiley, Chichester, pp 3–9
Parturier H, Hugnot G (1935). Le galega dans le traitement du diabète. Massons, Paris [article in French]
Rathke B (1879) Uber Biguanid. Ber Dtsch Chem Ges 12:776–784 [article in German]
Werner EA, Bell J (1922) The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc Trans 121:1790–1794
Hesse G, Taubmann G (1929) Die Wirkung des Biguanids und seiner Derivate auf den Zuckerstoffwechsel. Arch Exp Path Pharmacol 142:290–308 [article in German]
Slotta KH, Tschesche R (1929) Uber Biguanide. Die blutzuckersenkende Wirkung der Biguanides. Ber Dtsch Chem Ges 62:1398–1405 [article in German]
Curd FHS, Davey DG, Rose FL (1945) Studies on synthetic antimalarial drugs. Some biguanide derivatives as new types of antimalarial substances with both therapeutic and causal prophylactic activity. Ann Trop Med Parasitol 39:208–216
Chen KK, Anderson RC (1947) The toxicity and general pharmacology of N1-p-chlorophenyl-N5-isopropyl biguanide. J Pharmacol Exp Ther 91:157–160
Garcia EY (1950) Flumamine, a new synthetic analgesic and anti-flu drug. J Philippine Med Assoc 26:287–293
Pasik C (1997) Jean Sterne: a passion for research. In: Pasik C (ed) Glucophage: serving diabetology for 40 years. Lyon, Groupe Lipha, pp 29–31
Sterne J (1957) Du nouveau dans les antidiabétiques. La NN dimethylamine guanyl guanidine (N.N.D.G.) Maroc Med 36:1295–1296 [article in French]
Sterne J (1958) Blood sugar-lowering effect of 1,1-dimethylbiguanide. Therapie 13:650–659 article in French
Sterne J (1959) Treatment of diabetes mellitus with N,N-dimethylguanylguanidine (LA. 6023, glucophage). Therapie 14:625–630 [article in French]
Sterne J (1963) Report on 5-years’ experience with dimethylbiguanide (metformin, glucophage) in diabetic therapy. Wien Med Wochenschr 113:599–602 [article in German]
Sterne J, Hirsch C (1964) Experimental basis for combined treatment of diabetes with the biguanide-sulfonamide association. Diabete 12:171–175 [article in French]
Sterne J (1964) Mechanism of action of antidiabetic biguanides. Presse Med 72:17–19 [article in French]
Sterne J (1969) Pharmacology and mode of action of the hypoglycemic guanidine derivatives. In: Campbell GD (ed) Oral hypoglycemic agents. Academic Press, London, pp 193–245
Sterne J, Duval D, Junien JL (1979). Aspects of pharmacology and mechanisms of action. In: Cudwoth AG (ed) Metformin: current aspects and future developments. Research and Clinical Forums, Vol. 1, Tunbridge Wells, pp 13–20
Ungar G, Freedman L, Shapiro SL (1957) Pharmacological studies of a new oral hypoglycemic drug. Proc Soc Exp Biol Med 95:190–192
Beringer A (1958) Zur Behandlung der Zuckerkrankheiten mit Biguaniden. Wien Med Wschr 108:880–882 [article in German]
Shapiro SL, Parrino VA, Freedman L (1959) Hypoglycemic agents. III.1—3N1-alkyl- and aralkylbiguanides. J Am Chem Soc 81:3728–3736
Beckmann R (1971) Biguanide (Experimenteller Teil). Handb Exp Pharmacol 29:439–596 [article in German]
Azerad E, Lubetzki J (1959) Treatment of diabetes with N,N-dimethyl diguanide (LA6023). Presse Med 67:765–767 [article in French]
McKendry JB, Kuwayti K, Rado PP (1959) Clinical experience with DBI (phenformin) in the management of diabetes. Can Med Assoc J 80:773–778
Mehnert H, Seitz W (1958) Weitere Ergebnisse der Diabetesbehandlung mit blutzuckersenkenden Biguaniden. Münch Med Wochenschr 100:1849–1851 [article in German]
Butterfield WJ (1968) The effects of phenformin on peripheral glucose utilization and insulin action in obesity and diabetes mellitus. Ann N Y Acad Sci 148:724–733
Schäfer G (1983) Biguanides: a review of history, pharmacodynamics and therapy. Diabete Metab 9:148–163
Hermann LS (1979) Metformin: a review of its pharmacological properties and therapeutic use. Diabete Metab 5:233–245
Clarke BF, Duncan LJP (1968) Comparison of chlorpropamide and metformin treatment on weight and blood-glucose response of uncontrolled obese diabetics. Lancet 291:123–126
Clarke B, Campbell IW (1977) Comparison of metformin and chlorpropamide in non-obese maturity-onset diabetic uncontrolled on diet. Br Med J 275:1576–1578
Campbell IW, Howlett HC (1995) Worldwide experience of metformin as an effective glucose-lowering agent: a meta-analysis. Diabetes Metab Res Rev 11(Suppl 1):S57–S62
Bailey CJ (1992) Biguanides and NIDDM. Diabetes Care 15:755–772
Walker RS, Linton AL (1959) Phenethylbiguanide: a dangerous side effect. Br Med J 2:1005–1006
Luft D, Schmulling RM, Eggstein M (1978) Lactic acidosis in biguanide-treated diabetics. Diabetologia 14:75–87
University Group Diabetes Program (1975) A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Evaluation of phenformin therapy. Diabetes 24(Suppl 1):65–184
Nattrass M, Alberti KGMM (1978) Biguanides. Diabetologia 14:71–74
Bailey CJ, Nattrass M (1988) Treatment—metformin. Ballière’s Clin Endocrinol Metab 2:455–476
Lalau JD (2010) Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf 33:727–740
Shah RR, Oates NS, Idle JR, Smith RL (1980) Genetic impairment of phenformin metabolism. Lancet 315:1147
Bosisio E, Kienle MG, Galli G et al (1981) Defective hydroxylation of phenformin as a determinant of drug toxicity. Diabetes 30:644–649
DeFronzo RA (1988) The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37:667–687
Reaven GM (1988) Role of insulin resistance in human disease. Diabetes 37:1595–1607
Howlett HCS, Bailey CJ (2007) Metformin: a chemical perspective. In: Bailey CJ, Campbell IW, Chan JCN et al (eds) Metformin, the gold standard. A scientific handbook. Wiley, Chichester, pp 23–28
Bailey CJ, Puah JA (1986) Effect of metformin on glucose metabolism in mouse soleus muscle. Diabete Metab 12:212–218
Wollen N, Bailey CJ (1988) Inhibition of hepatic gluconeogenesis by metformin: synergism with insulin. Biochem Pharmacol 37:4353–4358
Bailey CJ, Wilcock C, Day C (1992) Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 105:1009–1013
Wilcock C, Bailey CJ (1994) Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24:49–57
Bailey CJ, Mynett KJ, Page T (1994) Importance of the intestine as a site of metformin-stimulated glucose utilization. Brit J Pharmacol 112:671–675
Wiernsperger NF, Bailey CJ (1999) The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 58(Suppl 1):31–39
DeFronzo RA, Goodman AM, Multicenter Metformin Study Group (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:541–549
Bailey CJ, Turner RC (1996) Drug therapy: metformin. N Engl J Med 334:574–579
Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ (2004) Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets—results of a retrospective cohort study. Curr Med Res Opin 20:565–572
Davidson J, Howlett H (2004) New prolonged-release metformin improves gastrointestinal tolerability. Br J Diabetes Vasc Dis 4:273–277
Garber AJ, Larsen J, Schneider SH, Piper BA, Henry D (2002) Simultaneous glyburide/metformin therapy is superior to component monotherapy as an initial pharmacological treatment for type 2 diabetes. Diabetes Obes Metab 4:201–208
Bailey CJ, Day C (2009) Fixed-dose single tablet antidiabetic combinations. Diabetes Obes Metab 11:527–533
UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865
Wiernsperger NF (2007) 50 years later: is metformin a vascular drug with antidiabetic properties? Br J Diabetes Vasc Dis 7:204–210
Bailey CJ (2008) Metformin: effects on micro and macrovascular complications in type 2 diabetes. Cardiovasc Drug Ther 22:215–224
Johnson JA, Simpson SH, Toth EL, Majumdar SR (2005) Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabet Med 22:497–502
Eurich D, Majumdar SR, FA MA, Tsuyuki RT, Johnson JA (2005) Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 28:2345–2351
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589
International Diabetes Federation Clinical Guidelines Task Force (2012). Global guideline for type 2 diabetes. Available from www.idf.org/e-library/guidelines/79-global-guideline-for-type-2-diabetes. Accessed 10 May 2017
Inzucchi SE, Bergenstal RM, Buse JB et al (2015) Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of diabetes. Diabetologia 58:429–442
Garber AJ, Abrahamson MJ, Barzilay JI et al (2017) Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2017 executive summary. Endocr Pract 23:207–238
Qaseem A, Barry MJ, Humphrey LL, Forciea MA for the Clinical Guidelines Committee of the American College of Physicians (2017) Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med 166:279–290
World Health Organization (2015). WHO model list of essential medicines. Available from www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1. Accessed 10 Feb 2017
Ferguson AW, De La Harpe PL, Farquhar JW (1961) Dimethyl biguanide in the treatment of diabetic children. Lancet 1:1367–1369
Knowler WC, Barrett-Connor E, Fowler SE et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403
Hostalek U, Gwilt M, Hildemann S (2015) Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs 75:1071–1094
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP for the MiG Trial Investigators (2008) Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 358:2003–2015
Nestler JE (2008) Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 358:47–54
Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S (2000) Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 284:472–477
Tankova T, Koev D, Dakovska L, Kirilov G (2002) Therapeutic approach in insulin resistance with acanthosis nigricans. Int J Clin Pract 56:578–581
Moreira PI (2014) Metformin in the diabetic brain: friend or foe? Ann Transl Med 2:54
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305
Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777
Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (2016) Metformin as a tool to target aging. Cell Metab 23:1060–1065
McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract. Diabetologia 59:426–435
Scheen AJ (1996) Clinical pharmacokinetics of metformin. Clin Pharm 30:359–371
This work received no specific grant from any funding agency in the public, commercial or not-for-profit sectors’.
Duality of interest
The author declares that there is no duality of interest associated with this manuscript.
The author was the sole contributor to this paper.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Bailey, C.J. Metformin: historical overview. Diabetologia 60, 1566–1576 (2017). https://doi.org/10.1007/s00125-017-4318-z
- Galega officinalis
- Jean Sterne
- Type 2 diabetes