Dipeptidyl Peptidase-4 Inhibitors and Their Effects on the Cardiovascular System

Abstract

It is well known that patients with type 2 diabetes mellitus (T2DM) are at increased risk of cardiovascular (CV) disease. Elevated plasma glucose levels that independently lead to increased cardiovascular risk, combined with associated co-morbidities such as obesity, hypertension, and dyslipidemia, further contribute to the development of CV complications. Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) are a relatively new class of drugs used for the treatment of diabetes and recently have been widely used in clinical practice. They exert their actions through degradation inhibition of endogenous glucagon-like peptides (GLP-1) and glucose-dependent insulinotropic peptides (GIP), with a resulting increase in glucose mediated insulin secretion and a suppression of glucagon secretion. Since GLP-1 is known to have an impact not only on plasma glucose levels but also to have cardiovascular protective effects there is increased speculation of whether DPP-4 inhibitors will have similar effects. Though many short-term studies have been encouraging, ongoing long-term clinical trials on humans are needed to provide further clarity to the complete safety profiles of these agents in terms of cardiovascular risk, and whether they may exert potential cardiovascular benefit. This review includes available data on the cardiovascular effects of DPP-4 inhibitors as well as their overall safety profile.

Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention

“…They are effective in the protection of pancreatic β cells and promotion of normal glucagon secretion, thus inhibiting the progression of T2DM. DPP-4 inhibitors are well tolerated because they play pivotal roles in cardiovascular protection and anti-arteriosclerotic action, with few gastrointestinal side effects and weight neutrality 131. So far, available DPP-4 inhibitors include vildagliptin, sitagliptin, saxagliptin and linagliptin, which have been assessed in a variety of clinical studies about their pharmacokinetics/pharmacodynamics, safety, efficacy, and tolerability 132.…”

Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

“…After DPP4 cleavage, NPY and PYY are generated and preferentially signal through the Y2R and Y5R. B, DPP4 cleaves SP [1][2][3][4][5][6][7][8][9][10][11], which signals through the NK1R receptor to generate SP [5][6][7][8][9][10][11], which can signal through (NK1R, -2R, -3R). doi: 10.1210/er.2014-1035 edrv.endojournals.org and cleaved PYY peptides have been detected in human plasma.…”

“…SP, or tachykinin, is an 11-amino acid neurotransmitter that signals predominantly through the neurokinin-1 receptor (NK1R). Plasma from wild-type (but not Fischer 344) rats cleaves recombinant SP [1][2][3][4][5][6][7][8][9][10][11] to generate SP [3][4][5][6][7][8][9][10][11] and SP [5][6][7][8][9][10][11], via mechanisms sensitive to the DPP4 inhibitor diprotin A (131). Dpp4 Ϫ/Ϫ mice exhibit approximately 2-fold higher levels of circulating SP, implicating an essential biological role for DPP4 in control of SP biology (132).…”

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

“…Not enough results of long‐term clinical trials have been yet available. Future and ongoing studies will offer more insight into cardiovascular safety and benefits of these agents …”