Improve Cardiovascular Outcomes with DPP4 Inhibitors

DPP4 inhibitors may restore the normal functioning of vascular endothelium in patients who require insulin treatment and are at risk for cardiovascular problems. 

Researchers believe they now understand the role of dipeptidyl peptidase IV (DPP4) inhibitors in human vasculature. Atherosclerosis is a significant cause of death in patients with diabetes. In addition, cardiovascular diseases such as cerebral vascular disease, ischemic heart disease, peripheral artery disease, and coronary artery disease may result from atherosclerosis. Because patients with diabetes have a significantly higher risk of developing cardiovascular diseases, finding treatment options that promote vascular health is essential. Mice models have shown beneficial antioxidant effects on the vascular wall after treatment with insulin. However, despite achieving intensive glycemic control with insulin in patients, clinicians have not seen a decrease in cardiovascular mortality. This suggests that glycemic control alone may not be sufficient to prevent vascular complications. In a new study, a team of researchers aimed to understand the mystery behind the sustained cardiovascular mortality of patients with T2DM diabetes treated primarily with insulin and the potential role of DPP4 inhibitors in restoring physiological insulin signaling in human vasculature. 

There are several factors involved in the progression of atherosclerosis in patients with diabetes. Hyperglycemia and insulin resistance are among the most critical of these reasons. The enzyme, DPP4, is a ubiquitous serine protease with dozens of substrates located throughout the body. Given the diversity of substrates that exist, many of the physiological actions of DPP4 inhibitors are still not understood. The most well-studied substrates include glucagon-like peptide 1 (GLP-1) and glucose-insulinotropic peptide (GIP), which increase insulin production and release while simultaneously decreasing hepatic glucose production. However, researchers believe they have found another benefit to treatment with DPP4 inhibitors.  

In a two-part study published in Science Translational Medicine, researchers explored the effects of insulin and DPP4 inhibitors on cardiovascular redox state and endothelial function in patients with atherosclerosis. Also, the ability of DPP4 inhibitors to modify insulin signaling in vessels was investigated. Five hundred and eighty patients with advanced atherosclerosis undergoing coronary artery bypass surgery (CABG) were enrolled in this study. In addition, the saphenous veins and internal mammary arteries of 94 patients were obtained for experimentation (ex vivo).  

Researchers first studied the effects of endogenous or circulating insulin on endothelial function. They administered acetylcholine (Ach), bradykinin (B.K.), and nitroprusside (SNP) onto the extracted vessels of non-diabetic patients. It was found that high serum insulin was associated with reduced vasorelaxations of human vessels in response to Ach and B.K. but not to SNP. They then exposed vessels from patients with and without diabetes with exogenous insulins using either long-acting or human insulin formulations. The results replicated those from the prior experiment regardless of insulin resistance status or insulin type confirming an inverse relationship between serum insulin concentration and nitric oxide (NO) bioavailability in the endothelium. While insulin had an antioxidant effect on the blood vessels of mice, this was not the case for human vessels. On the contrary, insulin had a pro-oxidant effect on the vessel wall regardless of diabetic status, contributing to plaque formation and resulting in an insulin signaling shift within the cells. 

To determine the mechanism behind the observed endothelial dysfunction, researchers measured the levels of superoxide ions in human vessels using Lucigenin chemical luminescence after administering various types of insulin and DPP4 inhibitors. Results showed that higher insulin levels resulted in increased activity of NADPH oxidase, as seen by increased levels of superoxide ions. The proposed mechanism of this shift is via the dysregulation of vascular redox signaling from the Akt pathway to the extracellular signal-regulated kinase 1 and 2 pathway. This signaling represents a state of insulin resistance, which also affects the activity of enzymes and the coupling status of endothelial nitric oxide synthase (eNOS). These effects were observed at concentrations of >10nM for human insulin and glargine and >100nM for insulin degludec. 

Another important finding is that DPP4 inhibitors may restore normal insulin signaling. In experimental models, DPP4 inhibitors have improved cellular insulin resistance. In the study, researchers observed only one patient who responded with the continued triggering of the AKT pathway, opposing what was seen in response to insulin. This patient was the only patient on a DPP4 inhibitor. Laboratory experiments were able to replicate this effect. The vessels that were pretreated with DPP4 inhibitors before insulin showed antioxidant and vasoprotective properties. The value of endogenous insulin or DPP4 activity in predicting cardiac mortality was explored over 3.9 years of follow-up. 

This study’s results may help clinicians select therapies that may prevent or improve cardiovascular disease in patients with diabetes. We now understand that higher insulin levels, whether endogenous or exogenous, are linked to lower bioavailability of NO and reduced vasorelaxations, regardless of diabetes status. With the addition of DPP4 inhibitors, we can restore the normal functioning of vascular endothelium and potentially lower the total daily dose of insulin required to keep a patient at target HbA1c levels. 

Practice Pearls: 

• This study suggests that reduced vasorelaxations may be a class action effect of insulin even in the absence of systemic insulin resistance. 
• DPP4 inhibitors may improve insulin resistance and have vasoprotective effects in patients. 
• Pre-treatment with DPP4 inhibitors before insulin treatment may reduce the risk of vascular oxidative stress and insulin resistance.  

Hampton T. Insulin Given With DPP4 Inhibitors Might Protect Blood Vessels in Patients With Diabetes. JAMA. 2020;324(1):15–16. doi:10.1001/jama.2020.10110 

Akoumianakis I, Badi I, Douglas G, et al. Insulin-induced vascular redox dysregulation in human atherosclerosis is ameliorated by dipeptidyl peptidase 4 inhibition. Sci Transl Med. 2020;12(541):eaav8824. doi:10.1126/scitranslmed.aav8824 

Katakami N. Mechanism of Development of Atherosclerosis and Cardiovascular Disease in Diabetes Mellitus. J Atheroscler Thromb. 2018;25(1):27-39. doi:10.5551/jat.RV17014 

Xia C, Goud A, D’Souza J, et al. DPP4 inhibitors and cardiovascular outcomes: safety on heart failure. Heart Fail Rev. 2017;22(3):299-304. doi:10.1007/s10741-017-9617-4 

Melinda Rodriguez, PharmD Candidate 2021, Lake Erie College of Osteopathic Medicine – L|E|C|O|M School of Pharmacy