DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits

Abstract

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.

Keywords: Cardiovascular outcome; Dipeptidyl peptidase-4 inhibitors; Glucagon-like peptide-1 receptor agonists; Type 2 diabetes mellitus.

Fig. 1

Molecular basis of incretin axis: DPP-4 proteins consist of a short intracellular domain (6 amino acids), a transmembrane domain, and a large extracellular domain. The extracellular domain is responsible for the enzymatic cleavage of the substrates and binding to its ligands including fibronectin and ADA. DPP-4 inactivates GLP-1 by removing N-terminal dipeptide His7Ala8 from active form of GLP-1, which results in the loss of its affinity to GLP-1R. GLP-1R is a G-protein coupled receptor and its biding with active GLP-1 activates PI3K and PKA pathway by increasing intracellular cAMP concentration. DPP-4 dipeptidyl peptidase-4, sDPP-4 soluble DPP-4, AA amino acid, ADA adenosine deaminase, GLP-1 glucagon-like peptide-1, GLP-1R glucagon-like peptide-1 receptor, cAMP cyclic adenosine monophosphate, PKA protein kinase A, PI3K phosphoinositide 3-kinase

Fig. 2

Incretin axis and incretin-based therapies: GLP-1 is produced by the enteroendocrine L-cells in response to meal ingestion. The active form of GLP-1 is rapidly inactivated by DPP-4. GLP-1 acts on pancreas, liver, gastrointestinal tract, adipose tissue, cardiovascular system, and brain to exert a variety of functions. The rapid inactivation by DPP-4 in vivo limits the application of GLP-1 in clinic. The development of DPP-4 resistant analogues (GLP-1RAs) and DPP-4i overcame the instability shortcoming of GLP-1 and became an important class of glycemic lowering drugs that are safe or beneficial to cardiovascular disease. GLP-1RAs reduce multiple cardiovascular risks such as hypertension, hyperglycemia, dyslipidemia, overweight, and insulin resistance via various mechanisms. DPP-4 dipeptidyl peptidase-4, DPP-4i DPP-4 inhibitors, GLP-1 glucagon-like peptide-1, ApoB48 apolipoprotein B48, VLDL very low-density lipoprotein, LDL low-density lipoprotein