Evaluating the Use of Exenatide in People With Type 2 Diabetes and Diastolic Heart Failure

Diastolic heart failure is a life-threatening condition that occurs when the ventricles of
the heart become stiff and do not fully relax, preventing the heart from properly filling
with blood. The circulation of blood then backs up, and blood collects in the body's organs,
primarily the lungs. However, people with diastolic heart failure may have a normal ejection
fraction, which is a measure of the amount of blood that the heart pumps out with each heart
beat. Having type 2 diabetes may increase the risk of diastolic heart failure. Also, people
with both heart failure and type 2 diabetes are more likely to experience poor health and
even death than are people with only heart failure. It is possible that diabetes leads to
increased stiffness of the ventricles and the aorta, which is the main blood vessel into
which the heart empties. Exenatide, part of a class of medications known as glucagon-like
peptide-1 (GLP-1) receptor agonists, is a new medication that is currently used to treat
elevated blood sugar levels in people with diabetes. Some studies have shown that this class
of medications may have a positive effect on the heart and blood vessels. The purpose of
this study is to determine the effect that exenatide has on aortic and left ventricular
stiffness in people who have type 2 diabetes and diastolic heart failure.

This 12-week study will enroll adults with type 2 diabetes and diastolic heart failure with
normal ejection fraction. At a baseline study visit, participants will undergo a physical
examination, blood pressure and heart rate measurements, a blood collection, an
echocardiogram to obtain images of the heart, and a non-invasive test that measures blood
flow in the aorta. Participants will then be randomly assigned to receive either exenatide
or usual care. Participants who receive exenatide will inject the medicine twice a day for
12 weeks. At Week 4, these participants will attend a study visit to adjust the medication
dosage and to report any problems, and at Week 6, study staff will follow up with
participants by phone. All participants will attend a study visit at Week 12 for repeat
baseline testing.

Inclusion Criteria:

- Stable New York Heart Association (NYHA) Class II-IV heart failure symptoms for at
least 4 weeks before study entry

- Diagnosis of diastolic heart failure with a normal ejection fraction

- Admitted to the hospital with a diagnosis of heart failure in the 12 months before
study entry

- Type 2 diabetes

Exclusion Criteria:

- Unstable angina, heart attack, coronary artery bypass surgery, or angioplasty in the
3 months before study entry

- Angina with exertion

- Technically inadequate echocardiogram

- Atrial fibrillation or atrial flutter

- Severe valvular heart disease

- Significant kidney insufficiency (serum creatinine greater than 2.0 mg/dL or require
hemodialysis)

- Conditions that may be associated with changes in markers of fibrosis or collagen
turnover (e.g., ongoing or active rheumatological disease, requiring significant
anti-inflammatory agents, immunosuppression, pulmonary fibrosis, active cancer)

- Significant history of active substance abuse

- Type 1 diabetes

- Type 2 diabetes requiring chronic insulin use before study entry

- Active thiazolidinedione (TZD) use, because TZDs have been shown to worsen volume
retention and may exacerbate signs and/or symptoms of heart failure

- Pregnant or breastfeeding

- Hypertrophic cardiomyopathy