Effects of Sitagliptin on Endothelial Function in Type 2 Diabetes on Background Metformin Therapy

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.

Inclusion Criteria:

1. Adult age 21-70 years of age.

2. Diagnosis of type 2 diabetes by a physician as defined by the American Diabetes
Association standard criteria: 1) Fasting Plasma glucose at or above 126 mg/dL 2) a
two-hour value in an oral glucose tolerance test at or above 200 mg/dL, or 3) a
random plasma glucose concentration 200 mg/dL in the presence of symptoms, or 4)
glycosylated hemoglobin greater than or equal to 6.5%.

3. On stable metformin therapy for at least 6 weeks prior to enrollment.

4. Glycosylated Hemoglobin ≥6.2% and ≤ 9.5%.

Exclusion Criteria:

1. History of stroke, peripheral arterial disease, or coronary artery disease (as
defined by the presence of at least one coronary stenosis ≥ 50% on angiography or by
confirmed history of myocardial infarction by standard criteria.)

2. Evidence of other evident major illness including chronic renal insufficiency
(creatinine clearance less than 60 mL/min),chronic liver disease (AST or ALT greater
than 2.5 x normal), or cancer currently undergoing systemic therapy or had systemic
therapy for cancer within 1 year of enrollment.

3. Pregnancy as determined by urinary beta-HCG test

4. Illicit drug use (heroin, cocaine etc) in the past 1 year.

5. Alcohol abuse, defined as the equivalent of 14 beers/week for a man or 7 beers/week
for a woman

6. History of allergy to DPP-4 inhibitors at the time of screening/enrollment

7. Prior history of pancreatitis

8. Patients currently on insulin or sulfonylurea therapy.

9. Patients currently on digoxin.