Effect of DPP4 Inhibition on Vasoconstriction

Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition

The purpose of this study is to understand how dipeptidyl peptidase IV (DPP4) inhibition in diabetics affects hemodynamic parameters and sympathetic activation in the setting of increasing concentrations of neuropeptide Y, an endogenous peptide. The central hypothesis is that DPP4 inhibition decreases degradation of neuropeptide Y, resulting in increased vasoconstriction and sympathetic activation.

Dipeptidyl peptidase IV (DPP4) inhibitors are routinely used for the treatment of type II diabetes mellitus (T2DM). Since the prevalence of hypertension is 1.5-3 times greater in diabetics compared to sex-aged matched controls, the use of antihypertensives such as ACE inhibitors is also common in diabetics. DPP4 is involved in the degradation of multiple vasoactive peptides, one of which is neuropeptide Y. This peptide is thought to play a role in blood pressure regulation and sympathetic nervous system activation. The aim of this study is to investigate how DPP4 inhibition affects vasoconstriction in response to increasing neuropeptide Y concentrations. Additionally, the investigators want to understand how the combination of DPP4 inhibition and ACE inhibition affects vasoconstriction and sympathetic activation. Understanding the hemodynamic and neurohumoral changes associated with DPP4 and ACE inhibitors has important implications for the millions of patients with T2DM who take these drugs concurrently.

Inclusion Criteria:

Type 2 Diabetes Mellitus, as defined by one or more of the following,

• Hgb A1C ≥6.5%, or
• Fasting plasma glucose ≥126mg/dL, or
• Two hour plasma glucose ≥200 mg/dL following 75gr oral glucose load

For female subjects the following conditions must be met:

• Postmenopausal status for at least 1 year, or
• Status post-surgical sterilization, or
• If of childbearing potential, utilization of some form of birth control and willingness to undergo β-HCG testing prior to drug treatment and on every study day

Exclusion Criteria:

• Type 1 diabetes.
• Poorly controlled T2DM, defined as Hgb A1C>8.7%.
• Use of anti-diabetic medications other than metformin.
• Hypertension.
• Subjects who have participated in a weight-reduction program during the last 6 months and whose weight has increased or decreased more than 5 kg over the preceding 6 months.
• Pregnancy. Breast-feeding.
• Treatment with any of the following drugs: cisapride, pimozide, terfenadine, astemizol
• Clinically significant gastrointestinal impairment that could interfere with drug absorption
• Cardiovascular disease that would pose risk for the subject to participate in the study, such as: myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second- or third-degree AV block, mitral valve stenosis, or hypertrophic cardiomyopathy.
• Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >2 x upper limit of normal range)
• Impaired renal function (eGFR< 60mL/min/1.73m2 as determined by the MDRD equation).
• History or presence of immunological or hematological disorders.
• History of pancreatitis or known pancreatic lesions.
• History of angioedema or cough while taking an ACE inhibitor.
• Hematocrit <35%.
• Treatment with anticoagulants.
• Growth hormone deficiency.
• Diagnosis of asthma requiring use of an inhaled β-2 agonist more than 1 time per week.
• Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
• Treatment with systemic glucocorticoids within the last 6 months.
• Treatment with lithium salts
• Ongoing tobacco use or recreational drug use.
• Treatment with any investigational drug in the 1 month preceding the study
• Mental conditions rendering the subject unable to understand the nature, scope, or possible consequences of the study
• Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study