Clinical trial NCT02130687: Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure
Official title: Contribution of Substance P to Blood Pressure Regulation in the Setting of Dipeptidyl Peptidase IV (DPP4) and Angiotensin-Converting Enzyme (ACE) Inhibition
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Hypertension
Keywords: Type 2 Diabetes Mellitus
Hypertension
Angiotensin Converting Enzyme Inhibitors
Dipeptidyl Peptidase IV Inhibitors
Sitagliptin
Aprepitant
Ramipril
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2014-05-05
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: In this study the investigators will test the hypothesis that dipeptidyl peptidase IV (DPP4) inhibition attenuates the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibition but not angiotensin receptor blockade or calcium channel blockade. The investigators further hypothesize that this effect is mediated by substance P.

Detailed description: The use of dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes (T2DM) is growing rapidly. The majority of patients with T2DM are also taking ACE inhibitors or angiotensin receptor blockers (ARBs) in order to reduce cardiovascular and renal morbidity and mortality. DPP4 and ACE inhibitors share the common vasoactive substrate substance P. Substance P acts as a vasodilator but also activates the sympathetic nervous system. Understanding the interactive effects of DPP4 and ACE inhibitors on blood pressure and neurohumoral activation has important implications for the millions of patients with T2DM who take these drugs concurrently.

Eligibility criteria: Inclusion Criteria:

Age 18 to 80 years old

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 barrier methods of birth control and willingness to undergo urine β-HCG testing prior to drug treatment and on every study day

T2DM, as defined by 1 or more of the following at the time of screening visit:

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

Hypertension, as defined by:

* Seated SBP ≥130 mm Hg on three occasions documented in medical record, or
* Seated DBP ≥80 mm Hg on three occasions documented in medical record, or
* Treatment with antihypertensive medications for a minimum of 6 months

Exclusion Criteria:

* Type 1 diabetes
* Poorly controlled T2DM, defined as Hgb A1C\>8.7%
* Use of anti-diabetic medications other than metformin for at least 12 months prior to initiation of the study
* Secondary 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 drugs primarily metabolized through CYP3A4 (e.g. cisapride, pimozide)
* Clinically significant gastrointestinal impairment that could interfere with drug absorption
* Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy and diastolic dysfunction 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 \[ALT\] \>3 x upper limit of normal range)
* Impaired renal function (eGFR\< 50mL/min/1.73m2 as determined by the MDRD equation)
* History or presence of immunological or hematological disorders.
* History of pancreatitis or know pancreatic lesion
* History of angioedema while taking an ACE inhibitor
* Hematocrit \<35%
* Treatment with anticoagulants
* Diagnosis of asthma requiring use of 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
* 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

Primary outcomes:
measure: Mean Arterial Blood Pressure
timeFrame: 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant)
measure: Heart Rate
timeFrame: 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant)
measure: Norepinephrine (NE) Concentrations
timeFrame: 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant)
Secondary outcomes:
measure: Low Frequency Variability of Blood Pressure Activity
timeFrame: for 5 minutes on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
measure: Glucose
timeFrame: fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
measure: Insulin
timeFrame: fasting insulin measured at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitatliptin+aprepitant)
measure: Dipeptidyl Peptidase IV (DPP4) Activity
timeFrame: for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
measure: Angiotensin Converting Enzyme (ACE) Activity
timeFrame: for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
measure: Mean Arterial Blood Pressure
timeFrame: Value provided is the AVERAGE of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal.
measure: Heart Rate
timeFrame: Value provided is the average of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal.
measure: Neuropeptide Y
timeFrame: Neuropeptide Y concentration prior to ingestion of the mixed meal.
measure: 24hr Urinary Testing for Sodium
timeFrame: Urine was collected for sodium for 24 hrs prior to each of the study days listed below. Study days occurred after each 7-day treatment arm (placebo/placebo, sitagliptin/placebo, or sitagliptin/aprepitant) within 3 anti-hypertensive groups.
Other outcomes:
measure: Aldosterone, Angiotensin II, and Plasma Renin Activity (PRA)
timeFrame: for 4.5 hours on the 7th day of each intervention
Locations:
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
Study officials:
affiliation: Vanderbilt University
name: Nancy J Brown, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mashayekhi M, Wilson JR, Jafarian-Kerman S, Nian H, Yu C, Shuey MM, Luther JM, Brown NJ. Association of a glucagon-like peptide-1 receptor gene variant with glucose response to a mixed meal. Diabetes Obes Metab. 2021 Jan;23(1):281-286. doi: 10.1111/dom.14216. Epub 2020 Oct 22.