Effects of Sitagliptin on Endothelial Function in Type 2 Diabetes on Background Metformin Therapy
Condition: Diabetes; Atherosclerosis
MeSH terms: Atherosclerosis; Diabetes Mellitus
Study type: Interventional
Phase: Phase 4

Summary: 
      The study is being performed to determine whether sitagliptin, a dipeptidyl peptidase-4
      inhibitor, both acutely and chronically improves blood vessel function. Patients with type 2
      diabetes who are on metformin will be enrolled in this study for up to 22 weeks in this
      double blinded cross over study where they will receive a sitagliptin pill once a day for 8
      weeks and during a separate 8 weeks receive a matching placebo pill. The treatment periods
      are divided by a 4 week period. Blood vessel function will be measured by ultrasound before
      and after a single dose of sitagliptin and placebo, as well as after 8 weeks of treatment
      with each. Blood will also be taken to measure blood markers of inflammation at each time the
      ultrasounds are performed.
    

Detailed description: 
      We plan to recruit 38 patients with T2DM for this single center, double blind randomized,
      interventional crossover trial comparing sitagliptin (100 mg/day) to matching placebo. We
      have chosen placebo over a comparator for this study as our goal is to determine whether
      sitagliptin both improves glycemic control and endothelial function, properties not shared by
      other popular classes of agents like sulfonylureas. Subjects will be randomized with a 1:1
      allocation ratio to either sitagliptin 1st or placebo 1st.

      The study have 5 total visits. Subjects who pass a phone screen will be invited to a
      screening visit for study eligibility (Visit 1) Informed consent will be reviewed; a unique
      study number will be assigned once written informed consent is obtained (no subject will be
      assigned more than 1 allocation number); relevant participant medical history will be
      recorded including currently prescribed medications; anthropometric measurements will be
      taken (height, weight, and waist circumference in metric units) and blood pressure will be
      recorded (measured in triplicate and averaged). Subjects will be allowed to take their blood
      pressure medication on the morning of their screening visit, but not the mornings of any of
      the other study visits to limit the acute influence of these medications on endothelial
      function. If the potential participant qualifies for the study, he/she will be randomized
      either to receive sitagliptin 1st (100 mg/day) or matching placebo. Prior to receiving either
      of set of pills, subjects will return to the study center within approximately 1-2 weeks of
      the screening visit to undergo initial tests of endothelial function and receive their pills.
      Prior to all study visits except screening, subjects will also be asked to refrain from any
      vigorous physical activity (no weight lifting, jogging or any activity vigorous than walking)
      24 hours to reduce the risk of fasting hypoglycemia during the study visits. Subjects will
      also be asked to fast for 6-8 hours prior to the visit to limit the acute dietary influences
      on vascular endothelial function. At Visit 2, endothelial function will determined by
      brachial artery reactivity testing prior to and following a single dose of 100 mg of
      sitagliptin or matching placebo depending on the arm to which the subject was randomized.
      Blood samples will also be taken at this visit for systemic measurements of endothelial cell
      activation/inflammation (VCAM-1 and ICAM-1) prior to and 2 hours following acute drug
      administration. These will be measured at the indicated time points using commercially
      available kits.

      Endothelial function, like the blood samples, will be measured just prior to medication
      administration and then 2 hours following medication administration by brachial artery
      reactivity testing as described in Section D.3. The 2 hour time from was chose in given the
      plasma levels of sitagliptin appear to peak 2 hours following dose administration.32 At the
      end of this visit, subjects will be given a 9 week supply of the study pills (sitagliptin or
      matching placebo) as dispensed by the Froedtert Hospital Investigational Pharmacy, and
      scheduled to return for Visit 3 approximately 8 weeks following Visit 2. Subjects will be
      asked to not take any study medication for the 24 hours prior to Visit 3. At Visit 3,
      subjects will undergo repeat testing of endothelial function. Following this study visit,
      subjects will remain off study pills until they return for Visit 4 approximately 4 weeks
      following Visit 3. Visit 4 repeats Visit 2 except subjects will receive the set of pills to
      which they had been randomized to receive second. Subjects will return to the study center
      for Visit 5 approximately 8 weeks after Visit 4. Visit 5 is identical to Visit 3. Subject
      adherence will be determined by pill counts performed by MCW Translational Research Unit
      nursing staff who will perform all pill accounting. All medication dispensation will be
      handled by the Froedtert Hospital Investigational Drug Pharmacy.
    

Intervention name(s): sitagliptin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 100 mg pill, administered once/day orally; Matching placebo in appearance given once/day orally
Other intervention name(s): Januvia
Intervention MeSH terms: Sitagliptin Phosphate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: dipeptidyl peptidase-4 inhibitor; endothelium, vascular; diabetes type 2; nitric oxide; inflammation