Interestingly, and despite this popularity, there still remains controversy about the drug’s precise mechanism of action, although most data point to a reduction in hepatic glucose production being predominately involved (described further by Rena et al in this issue of Diabetologia) although, recent data suggests that some of the drug’s effect may involve the stimulation of intestinal release of incretin hormones. Based on these important characteristics, there continues to be extensive interest in this compound, even now, many years after its incorporation into the diabetes pharmacopeia. The drug’s efficacy has been demonstrated in monotherapy as well as in combination with other glucose-lowering medications for type 2 diabetes mellitus. Its popularity increased after eventual approval in the USA in 1994, although it was used extensively in Europe and other regions of the world prior to that. A derivative of guanidine, which was initially extracted from the plant Galega officinalis or French lilac, metformin was first synthesised in 1922 and introduced as a medication in humans in 1957, after the studies of Jean Sterne. This reputation has resulted from its effective glucose-lowering abilities, low cost, weight neutrality, overall good safety profile (especially the lack of hypoglycaemia as an adverse effect), and modest evidence for cardioprotection.
Metformin hydrochloride, a biguanide, is the most popular oral glucose-lowering medication in most countries, widely viewed as ‘foundation therapy’ for individuals with newly diagnosed type 2 diabetes mellitus. With no long-term studies comparing it against newer glucose-lowering drugs, some of which have more robust evidence for cardioprotection, metformin’s established role as ‘foundation therapy’ in type 2 diabetes may justifiably be challenged. Regulations guiding its use in patients with stable, modest renal dysfunction have, as a result, become more lenient in recent years. Data have emerged questioning the previous reluctance to use this agent in those with mild to moderate chronic kidney disease. Other benefits have also been described, including improvements in certain lipids, inflammatory markers, and a reduction in cardiovascular events, apparently independent from the drug’s glucose-lowering effect.
Its favoured status lies in its efficacy, low cost, weight neutrality and good safety profile. It is now recommended as first-line treatment in various guidelines, including that of the EASD and ADA. Interestingly, there still remains controversy regarding the drug’s precise mechanism of action, which is thought to involve a reduction in hepatic glucose production. Metformin is one of the most popular oral glucose-lowering medications, widely considered to be the optimal initial therapy for patients with type 2 diabetes mellitus.
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