Abstract
Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits.
Highlights
Type 2 diabetes (T2D) is a key global health issue with rising prevalence [1]
Improvements in glycemic control only have modest effects on macrovascular outcomes, with only a subset of anti-hyperglycemic agents being associated with a beneficial effect on cardiovascular outcomes in T2D, including sodium glucose linked transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, along with metformin [2]
In the UKPDS trial, metformin use was associated with a moderate reduction in the incidence of various cardiovascular end-points and all-cause mortality, relative to both diet-only therapy and intensive glucose-lowering with alternate treatments, in overweight T2D patients [4,5]
Summary
Type 2 diabetes (T2D) is a key global health issue with rising prevalence [1]. T2D is associated with a two-to-three-fold risk of cardiovascular disease, which represents the most common cause of death. In the UKPDS trial, metformin use was associated with a moderate reduction in the incidence of various cardiovascular end-points and all-cause mortality, relative to both diet-only therapy and intensive glucose-lowering with alternate treatments, in overweight T2D patients [4,5]. Fluctuations in postprandial blood glucose, in particular, are strongly associated with the macrovascular complications of T2D [13], while a rapid rise in postprandial blood glucose is associated with endothelial injury and initiation of a pro-atherogenic cascade [14,15] It is generally considered, that the cardiovascular benefits of metformin are primarily related to extra-glycemic mechanisms. This review summarizes the gastrointestinal actions of metformin and their potential relevance to its cardiovascular effects in T2D
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