Treatment with Metformin
Metformin is an anti-hyperglycaemic agent widely used in the treatment of type 2 diabetes. It counters insulin resistance through insulin-dependent and -independent effects on cellular nutrient and energy metabolism, improving glycaemic control without we
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Treatment with Metformin Clifford J. Bailey
8.1
General Overview
Metformin (dimethylbiguanide) is a biguanide agent now used widely in the treatment of type 2 diabetes. As a guanidine derivative (Fig. 8.1), its history can be traced from the use of Galega officinalis (goat’s rue or French lilac) in mediaeval Europe as a treatment for symptoms of diabetes [1]. Galega officinalis is rich in guanidine, and the glucose-lowering properties of guanidine were noted early in the twentieth century, giving rise to the use of synthalin (decamethylene diguanidine) and galegine (isoamylene guanidine) as diabetes therapies [2, 3]. Although the synthesis and glucose-lowering effect of dimethylbiguanide was recorded in the late 1920s [4], the use of guanidine derivatives all but disappeared with increasing availability of insulin in the 1930s. It was not until the 1950s that Jean Sterne and Denise Duval, unaware of the previous studies, noted that guanidine derivatives used to treat malaria or influenza also lowered blood glucose. After extensive animal research they identified dimethylbiguanide as a low toxicity antihyperglycaemic agent [5]. Other more potent biguanides, notably phenformin and buformin, that were introduced as antidiabetic agents at or around this time were initially more popular, but were subsequently withdrawn due to associated lactic acidosis [3]. It was not until the introduction of metformin into the United States (1995) and the results of the United Kingdom Prospective Diabetes Study (UKPDS) (1998) that this agent became recognised as an important glucose-lowering therapy for type 2 diabetes [6, 7]. Metformin does not have an approved indication for use to treat metabolic syndrome, but it has been used “off-label” in many studies to determine its effect on the emergence, progression and treatment of features of the metabolic syndrome. We will first consider its approved indication for use in the treatment of type
C.J. Bailey (*) School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK e-mail: [email protected] H. Beck-Nielsen (ed.), The Metabolic Syndrome, DOI 10.1007/978-3-7091-1331-8_8, # Springer-Verlag Wien 2013
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NH
Guanidine
NH2
C
NH2
NH
Synthalin (decamethylene diguanidine)
NH NH2
C
NH2 C
(2-(3-methylbut-2-enyl)guanidine)
C
NH
C
NH
Biguanide Galegine
NH
NH
(dimethylbiguanide)
NH2
NH
CH3 CH3
C
CH
CH2 NH NH
Metformin
NH2
NH
CH3 CH3
N
C
C
NH2
NH NH
C
NH 2
Fig. 8.1 Structures of guanidine, synthalin, biguanide, galegine and metformin
2 diabetes and then return to its “off-label” use against other features of the metabolic syndrome. A substantial proportion of type 2 diabetes patients exhibit sufficient of these other features of metabolic syndrome to qualify for a diagnosis of metabolic syndrome by current criteria [8]. However, it is not possible from most of the published literature on type 2 diabetes patients to tease out data that specifically apply or refer to those patients with metabolic syndrome. Nevertheless,
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