Effect of Saxagliptin Treatment on Myocardial Fat Content, and Monocyte Inflammation

Obese, insulin resistant individuals have an excess of fat in the liver which is not
attributable to alcohol or other known causes of liver disease, a condition defined as
nonalcoholic fatty liver disease (NAFLD). The fatty liver is insulin resistant. Individuals
with a fatty liver are more likely to have excess intra-abdominal fat as well as a reduction
in circulating plasma adiponectin levels. A new class of antidiabetes medications known as
dipeptidyl peptidase 4 (DPP-4) inhibitors (sitagliptin, saxagliptin) which enhance the
circulating half life of Glucagon-like peptide-1 (GLP-1), an incretin hormone that enhances
insulin secretion/ lowers glucose levels, have been approved to treat type 2 diabetes. More
recently, it has been shown that these dipeptidyl peptidase 4 inhibitors can also decrease
liver fat and inflammation in animal models of obesity by increasing circulating levels of
GLP-1. It has been shown that GLP-1 enhances liver fat oxidation, reduces liver fat
synthesis, and increases adiponectin levels in animal models in vivo.

Recent reports suggest that NAFLD is associated with an increased risk of cardiovascular
disease independent of associated cardiovascular risk factors. Furthermore type 2 diabetics
and subjects with impaired glucose tolerance are characterized by an increase in both hepatic
and myocardial fat and left ventricular (LV) dysfunction, particularly diastolic dysfunction.
Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes
mellitus as well as impaired glucose tolerance. However, the effect of saxagliptin therapy on
liver and myocardial fat content, as well as LV systolic and diastolic function in patients
with impaired glucose tolerance (IGT) or type 2 diabetes has not been previously studied.
Recently, it has been demonstrated that myocardial triglyceride content is increased in type
2 diabetic patients and is associated with impaired left ventricular diastolic function,
independently of age, body mass index (BMI), heart rate, visceral fat, and diastolic blood
pressure. More recently, it has been shown that that obese normal glucose tolerant subjects,
obese subjects with IGT, and type 2 diabetic subjects have increased myocardial fat compared
to lean subjects. Thus, both IGT and type 2 diabetic subjects have increased myocardial
steatosis and defects in LV function. GLP-1 has been shown to improve myocardial function and
cardiac output in conscious chronically instrumented canine models of cardiac injury or heart
failure. GLP-1 increased cardiac output and reduced left ventricular end diastolic pressure
in association with reduced systemic vascular resistance, and it improved myocardial insulin
sensitivity and myocardial glucose uptake in dogs with rapid pacing-induced dilated
cardiomyopathy. However, no previous study has examined the effect of saxagliptin on
myocardial fat or LV function in IGT or type 2 diabetic patients. Finally, the effect of
saxagliptin on vascular inflammation and monocyte Nuclear Factor-KappaB (NFkappaB) remains to
be studied. Patients with Impaired Glucose Tolerance (IGT)/ Impaired Fasting Glucose (IFG)
have insulin resistance as a well established defect. Furthermore, as stated previously, both
myocardial and hepatic steatosis as well as defects in LV function are well characterized in
obese, insulin resistant patients with IGT. However, the effect of DPP IV inhibitors on
hepatic and myocardial steatosis and monocyte inflammation in insulin resistant patients with
IGT have not been previously studied.

Inclusion Criteria:

- Men and women with a diagnosis diagnosis of Impaired Glucose Tolerance i.e. fasting
plasma glucose less than or equal to 125 mg/dl, 2 hour post 75 gram oral glucose
tolerance test (OGTT) plasma glucose between 140-199 mg/dl, glycosylated hemoglobin
A1c (HbA1c) less than 6.5% as per American Diabetes Association (ADA) criteria.

- Women of childbearing potential (WOCBP) and men must be using an acceptable method of
contraception to avoid pregnancy throughout the study in such a manner that the risk
of pregnancy is minimized.

Exclusion Criteria:

- Patients must not be on anti-diabetes therapy for treatment of Impaired Glucose
Tolerance (IGT) and must have a fasting plasma glucose concentration less or equal to
125 mg/dl.

- Type 1 or Type 2 diabetes mellitus (fasting plasma glucose greater than 125 mg/dl).

- Patients must not be on or have received metformin, thiazolidinediones, sulfonylureas,
DPP IV inhibitor, or exenatide/liraglutide treatment for treatment of IGT at any time.
Patients must not be receiving any of the following medications: thiazide or
furosemide diuretics, beta-blockers, or other chronic medications such as hormone
replacement therapy with known adverse effects on glucose tolerance levels. Patients
taking systemic glucocorticoids will also be excluded.

- Subjects with a history of clinically significant heart disease, peripheral vascular
disease, or pulmonary disease.

- Subjects must have a Body Mass Index between 30-35 kg/m2 and stable body weight.

- Subjects must not have clinically significant liver disease (aspartate
aminotransferase (AST) < 2.5 times upper limit of normal, Alanine transaminase (ALT) <
2.5 times upper limit of normal, Alkaline phosphatase< 2.5 times upper limit of
normal), kidney disease (Serum creatinine < 1.5 mg/dl in men and 1.4 mg/dl in women)
or significant anemia (Hematocrit < 34 vol%).

- Subjects with a history of any serious hypersensitivity reaction to saxagliptin or a
dipeptidyl peptidase 4 (DPP-IV) inhibitor.

- Concomitant treatment with systemic cytochrome P450 3A4 inducers.

- Women who are pregnant or breastfeeding