Concept paper: antihyperglycemic therapy and the diabetic heart--do we really know enough?

The purpose of this article is to provide reasons to start looking more critically at the existing glucose-lowering therapies in diabetes, from the point of their effect on cardiac metabolism. The presented arguments begin with the description of major differences between metabolism in myocardium and the skeletal muscle and of examples of myocardial metabolic inflexibility observed in heart failure and Type 2 diabetes. It is proposed that the metabolic inflexibility of diabetic myocardium should be taken into consideration as a factor to explain causes of unexpected cardiovascular mortality observed in the recently published outcome studies such as Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Feasibility Trial. The same reasoning was applied to challenge the "legacy effect" of the UK Prospective Diabetes Study and Steno-2 trials. A striking paucity of data on the effects of antihyperglycemic therapies on cardiac metabolism is brought to attention in spite of the fact that the technology to study human cardiac metabolism in vivo is available. It is hoped that increased focus on research in this area could contribute to improved cardiovascular safety monitoring of various antihyperglycemic regimens and thereby enhance our ability to save more lives of patients with Type 2 diabetes.