GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Pharmacological agents that are based on the gut-derived hormone glucagon-like peptide (GLP)-1 are increasingly used for hyperglycemia management in type 2 diabetes mellitus. Both GLP-1 receptor agonists and inhibitors of the GLP-1–degrading enzyme dipeptidyl peptidase-4 (ie, DPP-4 inhibitors) increase insulin and reduce glucagon secretion, thereby lowering plasma glucose levels. Moreover, GLP-1 receptor agonists reduce appetite, gastric emptying rate, and bodyweight, whereas both antihyperglycemic drug classes improve blood pressure and (postprandial) lipid profiles in patients with type 2 diabetes mellitus. The microcirculation encompasses all vessels of <150 μm, which includes arterioles, capillaries, and venules, and is involved in regulation of tissue perfusion to optimize nutrient delivery. An increase in microvascular perfusion improves glucose and insulin supply to the muscle interstitium, thereby enhancing peripheral glucose disposal. In addition, the microcirculation regulates peripheral vascular resistance, which in conjunction with cardiac output determines arterial blood pressure. GLP-1 peptide has been shown to improve microvascular function. As such, GLP-1 infusion increased microvascular perfusion of skeletal muscle in rodents, leading to increased glucose disposal. Infusion of GLP-1 peptide has also been shown to improve microvascular perfusion in healthy humans, although this was not associated with glucose disposal in one study. Evidence about the effects of GLP-1 receptor agonists or dipeptidyl peptidase-4 inhibitors on the microcirculation,