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Molecular action and pharmacogenetics of metformin: current understanding of an old drug

Graham Rena, Ewan R Pearson& Kei Sakamoto

Metformin is the most commonly used diabetes therapy, with over 100 million patients prescribed this drug per year globally. This popularity stems from a number of factors: it is weight neutral, or in some studies associated with weight loss; and the UK Prospective Diabetes Study (UKPDS) established its cardiovascular benefit and improved mortality compared with nonintensive treatment. Metformin is a very safe drug with over 50 years of clinical use; indeed, metformin has recently been shown to have beneficial off-target effects including a reduction in cancer incidence. Metformin, however, remains an intriguing drug with multiple physiological and molecular effects that remain incompletely understood. In this review we address what is known and unknown about the mechanisms of action of metformin, and how an individual’s genotype may be expected to alter the efficacy of action or the severity of side effects of this drug.