N. Wiernsperger
2000
Citations
3
Influential Citations
70
Citations
Quality indicators
Journal
Diabetes technology & therapeutics
Abstract
THE BIGUANIDE METFORMIN (dimethylbiguanide) (MET) is a leading drug in the therapy of noninsulin-dependent diabetes mellitus (NIDDM). Over several decades, intensive investigations in experimental and clinical pharmacology have progressively unraveled its modes of action to reduce hyperglycemia and combat insulin resistance.1–3 It has been far less recognized that this drug has multiple biological effects, among which vascular properties have now been discovered. Indeed, for a long time, biguanides were known to have fibrinolytic properties, and subsequently, reports on the vascular effects of MET were few, until a specific symposium was devoted to this subject in 1988 (International Workshop on Vascular Disease and Diabetes Mellitus. A New Approach, Diabete et Metabolisme 14.4bis, 1988). There, a series of exciting presentations underscored the potential interest of these partly unique properties, but it had to await the recent final analysis of the United Kingdom Prospective Diabetes Study (UKPDS) to confirm in-patients the promises set by the pharmacological rationale. Indeed the UKPDS has demonstrated that patients with diabetes receiving MET either as a single therapy or in combination with other treatments experienced an additional 40% reduction in their risk for developing vascular complications when compared with those treated with sulfonylureas or insulin alone.4 Because the glycemic control was similar among these treatment regimen, it is clear that MET obviously exerted a vasculoprotective action largely independent of its wellknown antihyperglycemic action. It is the aim of the present review to provide for the first time a complete overview of the pleiotropic vascular effects of MET, based on data obtained at relevant drug concentrations and limited (with very few exception) to full scientific articles (indeed, dozens of additional abstracts are available). This review updates the supportive arguments that allow the consideration of the potential of this molecule especially for preventing diabetic vascular complications. Importantly, the individual properties are, whenever possible, also described in nondiabetic situations in order to demonstrate intrinsic effects independent of any links with the reduction in glycemia. Indeed, reductions in glycemia and possibly insulinemia are expected to afford some protection against diabetic complications5–6 although this concept is still questioned.7–9 A distinction must also be made here between large and small vessel disease, because it appears that improvements in glycemic control per se have little effects on macrovascular events: indeed, as for strictly controlled type I diabetes in the Diabetes Control and Complications Trial (DCCT), a good achievement of glycemic control versus moderate control was not accompanied by further significant reductions in cardiovascular disease (CVD).10 In fact, in type 2 diabetes, many oral antidiabetic agents are reported to improve vascular defects but these are mostly subsequent to reduction in insulin resistance, in circulating lipids, or hyperglycemia. Data also exist for more recent agents such as glimepiride and some thiazolidinediones but most are in vitro findings that still await confirmation in vivo. However, even in-