Happy anniversary, metformin!

Diabetes and Primary Care, Autumn, 2007 by Roger Gadsby

2007 is the 50th Anniversary of the launch of metformin in Europe (Campbell et al, 1996). This article reviews its progress from humble beginnings to its place today as the initial monotherapy of choice for the oral treatment of type 2 diabetes.

Key words

- Metformin

- Sustained release

- Guidelines

- Adverse events

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In Medieval times the plant Galega officinalis (commonly called Goat's rue, French lilac or Italian fitch) was found to relieve the prolific urination that can accompany diabetes. Later the active ingredient was found to be galegine, also known as isoamylene guanidine (Witters, 2001). In 1918 it was shown that an infusion of guanidine produced a lowering of blood glucose (Watanabe, 1918). While guanidine itself was too toxic to be used as a therapy, substances containing two linked guanidine rings, the biguanides, were found to lower blood glucose levels and be less toxic than the single-ring form (Witters, 2001).

In 1957, bimethylbiguanide (metformin) was introduced as an agent to lower blood glucose levels in people with type 2 diabetes (Campbell et al, 1996). Two other biguanides, phenformin and buformin, also available in the 1950s, were withdrawn from the market worldwide in the late 1970s owing to an elevated risk of lactic acidosis (Bailey and Turner, 1996).

Overall, metformin was found to be a much safer drug and thus became widely used in Europe, usually as an add-on therapy to a sulphonylurea. However, it received its license in the US in 1995 (Bailey and Turner, 1996). Preparation for this launch necessitated another round of research into the safety and effectiveness of metformin, the favourable results of which supported FDA approval. Within a few years it became the most widely prescribed glucose-lowering agent in the USA (Hundal and Inzucchi, 2003).

Metformin therapy improves insulin sensitivity, as shown by a reduction in fasting plasma glucose and insulin concentrations, and is not effective in the absence of insulin (Bailey and Turner, 1996). In people with type 2 diabetes the glucose-lowering effect is attributed mainly to decreased hepatic glucose output and enhanced peripheral glucose uptake. Several other actions may contribute, such as increased intestinal use of glucose and decreased fatty acid oxidation (Bailey and Turner, 1996).

Metformin in diabetes guidelines today

In the UK, the National Institute for Health and Clinical Excellence (NICE) guidelines on glycaemic control in type 2 diabetes recommend metformin as the initial monotherapy of choice in all people who are overweight (BMI >25kg/[m.sup.2]). The document also advises that metformin should be considered as the initial monotherapy for type 2 diabetes in those with a BMI below 25 kg/[m.sup.2] (NICE, 2002).

The International Diabetes Federation (IDF) recommend metformin monotherapy unless there is evidence of renal impairment (IDF, 2005). NICE state that metformin should not be prescribed if serum creatinine levels are greater than 130[micro]m/l and should be stopped if they rise above 150[micro]m/l (NICE, 2002). Now that serum creatinine levels arc being translated into estimated glomerular filtration rates (eGFR) the equivalent eGFR figures are likely to be 30 and 45 ml/min, respectively.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) joint guidelines on hyperglycaemia in type 2 diabetes recommend, in the absence of specific contraindications, that metformin be introduced along with lifestyle interventions immediately after diagnosis of type 2 diabetes (Nathan et al, 2006). Metformin is recommended as the intitial pharmacological therapy owing to: its ability to lower Hb[A.sub.1c] by approximately 1.5%; the absence of associated weight gain or hypoglycaemia; low levels of side effects; high levels of patient acceptance; and relatively low cost (Nathan et al, 2006).

Further evidence comes from the UK Prospective Diabetes Study (UKPDS), in which a group of obese people newly diagnosed with type 2 diabetes were randomised to either receive metformin monotherapy or manage their diabetes through diet alone. Compared with the group treated by conventional means, the metformin group had a 32% risk reduction for diabetes-related end points (including myocardial infarction and stroke; P=0.002) and a 42% reduction in risk for diabetes-related deaths (UKPDS, 1998).

Metformin improves glycaemia as effectively as other oral medication and on the evidence of the UKPDS it reduces cardiovascular outcomes (DeFronzo and Goodman, 1993; UKPDS, 1998). The precise mechanism by which metformin achieves this reduction of adverse cardiovascular outcomes remains to be clarified.

In the Diabetes Prevention Study several thousand people with impaired glucose tolerance (IGT) were divided into three groups (Diabetes Prevention Programme Research Group, 2002). One group received a diet and exercise programme that was aimed at achieving a weight reduction of 7% and moderate physical activity, for example, brisk walking for 150 minutes per week. People in the active arm of the study had regular one-to-one sessions with their case manager in the first 24 weeks and then monthly sessions for the remaining period of the study. Fifty per cent of people in this group achieved the weight reduction target at 24 weeks and 74% achieved the exercise target. A control group received 'general advice' and another group received general advice plus metformin therapy. Those in the lifestyle plus exercise group reduced their risk of developing diabetes by 58% and those in the metformin group reduced their risk of developing diabetes by 31%, both compared with the control group. Metformin is therefore now being used off license by some prescribers in selected individuals with IGT who are unable to adhere to lifestyle change.