Abstract
The management of T2DM requires aggressive treatment to achieve glycemic and cardiovascular risk factor goals. In this setting, metformin, an old and widely accepted first line agent, stands out not only for its antihyperglycemic properties but also for its effects beyond glycemic control such as improvements in endothelial dysfunction, hemostasis and oxidative stress, insulin resistance, lipid profiles, and fat redistribution. These properties may have contributed to the decrease of adverse cardiovascular outcomes otherwise not attributable to metformin’s mere antihyperglycemic effects. Several other classes of oral antidiabetic agents have been recently launched, introducing the need to evaluate the role of metformin as initial therapy and in combination with these newer drugs. There is increasing evidence from in vivo and in vitro studies supporting its anti-proliferative role in cancer and possibly a neuroprotective effect. Metformin’s negligible risk of hypoglycemia in monotherapy and few drug interactions of clinical relevance give this drug a high safety profile. The tolerability of metformin may be improved by using an appropiate dose titration, starting with low doses, so that side-effects can be minimized or by switching to an extended release form. We reviewed the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits beyond its glycemic effect. We also discuss its potential role for a variety of insulin resistant and pre-diabetic states, obesity, metabolic abnormalities associated with HIV disease, gestational diabetes, cancer, and neuroprotection.
Highlights
The discovery of metformin began with the synthesis of galegine-like compounds derived from Gallega officinalis, a plant traditionally employed in Europe as a drug for diabetes treatment for centuries [1]
Results of the Metformin in Gestational Diabetes (MiG) TOFU reported that infants of diabetic mothers exposed to metformin in utero and examined at 2 years of age may present a reduction in insulin resistance, probably related to an increase in subcutaneous fat [48]
Metformin use in childhood and adolescence Type 2 diabetes mellitus has dramatically increased in children and adolescents worldwide to the extent that has been labeled an epidemic [49]
Summary
The discovery of metformin began with the synthesis of galegine-like compounds derived from Gallega officinalis, a plant traditionally employed in Europe as a drug for diabetes treatment for centuries [1]. In 1950, Stern et al discovered the clinical usefulness of metformin while working in Paris They observed that the dose–response of metformin was related to its glucose lowering capacity and that metformin toxicity displayed a wide security margin [1]. Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, muscle These effects are mediated by the activation of an upstream kinase, liver kinase B1 (LKB-1), which in turn regulates the downstream kinase adenosine monophosphatase. Metformin’s efficacy, security profile, benefic cardiovascular and metabolic effects, and its capacity to be associated with other antidiabetic agents makes this drug the first glucose lowering agent of choice when treating patients with type 2 diabetes mellitus (TDM2). One of the main contributing factors to this burden is the Western lifestyle which promotes obesity and sedentarism [5]
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