Official Title: “Effect of Sitagliptin on the Blood Pressure Response to ACE Inhibition on the Metabolic Syndrome”

This study will measure the effect of the anti-diabetic agent sitagliptin on blood pressure in individuals with the metabolic syndrome. We will also measure the effect of sitagliptin on blood pressure in people already taking a blood pressure medication called an ACE inhibitor.

Study Type: Interventional

Study Design: Basic Science, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Pharmacodynamics Study

Study Primary Completion Date: March 2009

The prevalence of metabolic syndrome and Type 2 diabetes mellitus (T2DM) has reached epidemic proportions in developed countries and is closely associated with hypertension. As new oral hypoglycemic agents become available for clinical use, practitioners wishing to treat both hyperglycemia and hypertension will use varieties of combinations of medications. In this setting, understanding interactions and additive effects of these medications becomes essential. Sitagliptin, a selective dipeptidyl peptidase-IV (DPP-4) inhibitor, improves glycemic control in patients with T2DM by decreasing the degradation of the incretin hormones. The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) augment nutrient mediated insulin release. To date there have been two reports of a blood pressure lowering effect of the DPP-4 inhibitor vildagliptin, but no mechanism for this effect has been proposed.

Specific Aim 1: To test the hypothesis that the DPP-4 inhibitor sitagliptin lowers blood pressure compared to placebo therapy in subjects with the metabolic syndrome. Specific Aim 2:

To test the hypothesis that the DPP-4 inhibitor sitagliptin potentiates the blood pressure response to acute ACE-inhibition.

Intervention(s) in this Clinical Trial

• Drug: Enalapril 5mg x 1 versus matching placebo.
  • Enalapril 5mg x 1 versus matching placebo.
• Drug: Sitagliptin 100mg p.o. x 5 days versus matching placebo.
  • Sitagliptin 100mg p.o. x 5 days versus matching placebo.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Enalapril and placebo versus enalapril and sitagliptin.
• Placebo Comparator: 2
  • Placebo and placebo versus sitagliptin and placebo.

Primary Measures

• Blood Pressure
  • Time Frame: Eight hours
    Safety Issue?: Yes

Secondary Measures

• Markers of vasoactive substances, and DPP-4 activity in the blood
  • Time Frame: Eight hours
    Safety Issue?: No

Inclusion Criteria:

• Ambulatory subjects, 18 to 70 years of age, inclusive
• For female subjects, the following criteria must be met:
• Postmenopausal for at least 1 year, or
• Status-post surgical sterilization, or
• If of childbearing potential, utilization of barrier contraceptive and willingness to undergo beta-hcg testing prior to drug treatment and on every study day
• Metabolic syndrome as defined by 3 or more of the following:
• Fasting plasma glucose of at least 100 mg/dL (5.6 mmol/L)
• Serum triglycerides of at least 150 mg/dL (1.7 mmol/L)
• Serum HDL less than or equal to 40 mg/dL in men or less than 50 mg/dL in women or on cholesterol-lowering medications
• Blood pressure of at least 130/85 mmHg or on blood-pressure lowering medications
• Waist girth of more than 102 cm in med or 88 cm in women
• Statin therapy for hypercholesterolemia must be a steady dose for 6 months prior to study day

Exclusion Criteria:

• Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater or the use of anti-diabetic medication
• History of reported or recorded hypoglycemia (plasma glucose less than 70 mg/dL)
• Use of hormone replacement therapy
• In hypertensive patients, a seated systolic blood pressure greater than 179 mmHg or a seated diastolic blood pressure greater than 110 mmHg
• Pregnancy
• Breast-feeding
• Cardiovascular disease 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 heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
• Treatment with anticoagulants
• History of serious neurological disease such as cerebral hemorrhage, stroke, or transient ischemic attack
• History or presence of immunological or hematological disorders
• Diagnosis of current asthma
• History of angioedema associated with use of ACE-I
• Clinically significant gastrointestinal impairment that could interfere with drug absorption
• Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transferase [ALT] > 2.0 x upper limit of normal range)
• Impaired renal function (serum creatinine > 1.5 mg/dl)
• Hematocrit <35%
• 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 chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
• Treatment with lithium salts
• History of alcohol or drug abuse
• Treatment with any investigational drug in the 1 month preceding the study
• Mental conditions rendering the subject unable to understand the nature, scope and 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
• Oral contraceptives

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Vanderbilt University

Overall Clinical Trial Officials and Contacts

Nancy J Brown, M.D. Principal Investigator Vanderbilt University  

Overall Contact: Loretta Byrne, RN 615-322-2105 loretta.byrne@vanderbilt.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00666848

Study ID Number: 070977

ClinicalTrials.gov Identifier: NCT00666848

Health Authority: United States: Institutional Review Board