Metabolic Modulation with Incretins: Is the Bloom off the Rose?

For the better part of a half century, cardiovascular physiologists have recognized that the failing heart is characterized by perturbations in myocardial metabolism whether or not heart failure is accompanied by myocardial ischemia. These metabolic derangements have long been a target of therapeutic intervention but with little or no evidence of therapeutic benefit. Attempts to drive substrate uptake, oxidation, or utilization have all proven ineffective in altering the natural history and clinical symptoms in heart failure. The shift in substrate preference from fatty acid to glucose oxidation as a means to achieve oxidative efficiency has led to a focus on driving glucose metabolism. Early efforts to employ supplemental insulin, glucose and potassium (GIK) inadvertently exacerbated heart failure due to the volume requirements. These early failure led to a consideration of agents which further impair fatty acid oxidation as an intrinsic means of driving glucose utilization but to no avail. Thus, the emergence of incretin based therapies as an intrinsic insulin dependent means to increase glucose uptake and disposal were heralded as a next generation of metabolic adjuvants. There emergence on the scene corresponded to a period in which modifying cardiovascular outcomes in diabetes has become an equally compelling clinical objective particularly given the occurrence of diabetes and heart failure in the world's population. Here we review what has been learned regarding the cardiovascular effects of incretin based therapies and their impact on the progression of heart failure. At this point, effective metabolic modulation with incretins in heart failure remains elusive.