Dipeptidyl peptidase IV (DPP4) inhibitors are orally available antidiabetic agents that decrease blood glucose by preventing the degradation of incretins such as glucagon-like peptide 1 and gastric inhibitory peptide. The global market for DPP4 inhibitors has been forecast to reach $10.1 billion by the year 2017. Diabetics are at increased risk of cardiovascular death. Interruption of the renin-angiotensin system (RAS) reduces cardiovascular events in patients with diabetes and risk of heart disease. In clinical trials examining the cardiovascular effects of DPP4 inhibitors, over eighty percent of patients were taking angiotensin- converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Understanding the interactive cardiovascular effects of DPP4 inhibitors and RAS inhibiting drugs is of the utmost importance. In addition to preventing degradation of incretins, DPP4 inhibitors prevent degradation of other peptides with a penultimate amino-terminus arginine or proline, including the ACE substrate substance P. During ACE inhibition, an increased proportion of substance P is degraded by DPP4. Inhibition of both DPP4 and ACE potentiates effects of substance P in rodents. Substance P causes vasodilation and vascular permeability, but also stimulates release of norepinephrine and the DPP4 substrate neuropeptide Y (NPY) from nerve terminals. Sympathetic activation by substance P could have deleterious effects in hypertension and heart failure. We have discovered a hemodynamic interaction between DPP4 inhibition and ACE inhibition that may reduce the beneficial cardiovascular effects of ACE inhibitors. Specifically, we have found that DPP4 inhibition decreases the blood pressure response to acute maximal ACE inhibition and increases heart rate and circulating norepinephrine in individuals with the metabolic syndrome. In addition, we have found that intra- arterial substance P stimulates vascular release of norepinephrine when both DPP4 and ACE are inhibited. We propose to test the overarching hypothesis that DPP4 inhibition attenuates the antihypertensive effect of chronic ACE inhibition by increasing activation of the sympathetic nervous system by endogenous substance P.
In Aim 1, we will test the hypothesis that DPP4 inhibition decreases the anti-hypertensive effect of chronic ACE inhibition, but not angiotensin receptor blockade, in patients with type 2 diabetes. We will assess the contribution of endogenous substance P to the effects of combined DPP4 and ACE inhibition using the substance P (NK1) receptor blocker aprepitant.
In Aim 2, we will test the hypothesis that substance P increases norepinephrine spillover and net vascular release of NPY through an NK1 receptor-dependent mechanism during combined DPP4 and ACE inhibition in individuals with type 2 diabetes.
In Aim 3, we will test the hypothesis that DPP4 inhibition also prevents the degradation of NPY, leading to increased vasoconstriction and forearm norepinephrine spillover in diabetics. Results of these studies could affect treatment of millions of people with diabetes and high blood pressure.

Public Health Relevance

Worldwide 336 million people suffer from diabetes. Many patients with diabetes take drugs called angiotensin- converting enzyme (ACE) inhibitors to reduce their risk of heart disease, stroke and kidney injury. This project investigates the possibility that a widely used new class of diabetes drugs called dipeptidyl peptidase IV inhibitors reduces the beneficial effects of ACE inhibitors on blood pressure, a risk factor for heart and kidney disease, and will suggest treatment strategies to reduce the risk of heart disease while controlling blood sugar.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125426-05
Application #
9463519
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Mcdonald, Cheryl
Project Start
2015-07-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Hubers, Scott A; Wilson, Jessica R; Yu, Chang et al. (2018) DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition. Hypertension 72:712-719
Wasserman, David H; Wang, Thomas J; Brown, Nancy J (2018) The Vasculature in Prediabetes. Circ Res 122:1135-1150
Hubers, Scott A; Kohm, Kevin; Wei, Shouzuo et al. (2018) Endogenous bradykinin and B1-B5 during angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 142:1636-1639.e5
Wilson, Jessica R; Shuey, Megan M; Brown, Nancy J et al. (2017) Hypertension and Type 2 Diabetes Are Associated With Decreased Inhibition of Dipeptidyl Peptidase-4 by Sitagliptin. J Endocr Soc 1:1168-1178
Straka, Brittany T; Ramirez, Claudia E; Byrd, James B et al. (2017) Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema. J Allergy Clin Immunol 140:242-248.e2
Wilson, Jessica R; Brown, Nancy J (2016) Examining EXAMINE for an Interaction With Angiotensin-Converting Enzyme Inhibition. Hypertension 68:549-51
Toh, Sengwee; Hampp, Christian; Reichman, Marsha E et al. (2016) Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs: A Retrospective Cohort Study. Ann Intern Med 164:705-14
Hubers, Scott A; Brown, Nancy J (2016) Response by Hubers and Brown to Letter Regarding Article, ""Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition"". Circulation 134:e11-2
Luther, James M; Brown, Nancy J (2016) Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat 125:2-7
Hubers, Scott A; Brown, Nancy J (2016) Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation 133:1115-24

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