Mechanistic Evaluation of Glucose-lowering Strategies in Patients With Heart Failure

INCLUSION CRITERIA:

1. Provision of informed consent prior to any study specific procedure (Pre-screening ICF
and Informed Consent collected at screening)

2. Male or female, aged ≥18 years at the time of consent

3. Documented, controlled T2DM, as defined by:

- Diagnosis of Type 2 DM based on current ADA guidelines (Appendix C) Treatment
with stable doses of antidiabetic medications that have not increased or
decreased for ≥8 weeks before screening

- For patients taking insulin, the investigator must query the patient at
prescreening or screening regarding his/her usual total daily insulin dose (all
types combined) during the previous 8 weeks. Insulin dosages during pre-screening
and screening should not vary by more than ±20% on more than two occasions

- Dosage reductions of insulin and sulfonylurea agents may be considered at
randomization to minimize the possibility of hypoglycemia

- Any reductions in the dosage of insulin and sulfonylurea agents will be at
the discretion of the investigator

- For patients treated with insulin, consider a reduction in dose of 20% at
randomization

- For patients receiving sulfonylurea agents, consider a reduction in dose of
50% or discontinue if on a dosage that is considered low at randomization

4. HFrEF demonstrated by all 3 of the following criteria:

- History of HF and LVEF ≤45% within the last 6 months (echocardiogram, MRI, left
ventriculography, or other accepted methodology). Patients without a recent
assessment of LV function will undergo a local echocardiogram at the time of
screening to determine ejection fraction

- Elevated NT-proBNP (>300 pg/mL) during screening

- Patients should receive background standard of care for HFrEF and be treated
according to locally recognized guidelines as appropriate. Guideline-recommended
medications should be used at recommended doses unless contraindicated or not
tolerated. Therapy should have been individually optimized and stable for >or = 4
weeks (this does not apply to diuretics-see NB below) before screening visit and
include (unless contraindicated or not tolerated):

- an ACE inhibitor, or ARB, or sacubitril/valsartan

- and

- a beta-blocker

- and

- if considered appropriate by the patient's treating physician; a
mineralocorticoid receptor antagonist (MRA)

- NB: Most patients with heart failure require treatment with a diuretic to control
sodium and water retention leading to volume overload. It is recognized that
diuretic dosing may be titrated to symptoms, signs, weight, and other information
and may thus vary. Each patient should, however, be treated with a diuretic
regimen aimed at achieving optimal fluid/volume status for that individual

5. Stable HF, with no evidence of volume overload (no rales, jugular venous distention,
peripheral edema) at screening

6. Women of childbearing potential (WOCBP):

- Must be using appropriate birth control to avoid pregnancy throughout the study
and for up to 4 weeks after the last dose of investigational product

- Must have a negative serum or urine pregnancy test within 72 hours prior to the
start of investigational product

- Must not be breastfeeding.

EXCLUSION CRITERIA:

1. MRI contraindications: all implanted defibrillators; implanted pacemakers and other
devices/implants that in the judgment of the investigator preclude an MRI evaluation

2. Patients with atrial fibrillation/flutter, or any rhythm that would impact on MRI
imaging quality would be excluded. Patients with a prior history of atrial
fibrillation or paroxysmal atrial fibrillation may be eligible for entry into the
study based on the investigator's judgment related to the frequency of AF events and
the patient's overall condition

3. Body mass index >45 kg/m2 or any condition, including, but not limited to known
claustrophobia, that may preclude the ability to perform an MRI scan of acceptable
quality, or unwillingness to undergo MRI imaging

4. Receiving incretin therapy (DPP4 inhibitors, GLP-1 mimetics), or having received
incretin therapy within the previous 8 weeks of randomization

5. Receiving therapy with a TZD or having received TZD therapy within the previous 8
weeks of randomization

6. Type 1 diabetes mellitus

7. History of unstable or rapidly progressing renal disease

8. A central lab eGFR value <30 mL/min/1.73 m2 on pre-screening or screening

9. New York Heart Association (NYHA) Class IV HF

10. Myocardial infarction, stroke, transient ischemic attack, or coronary
revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass
graft [CABG]) within the past 3 months of screening

11. Inoperable aortic or mitral valvular heart disease. Recent (within 3 months) or
planned valvular heart procedure

12. Heart failure secondary to restrictive cardiomyopathy, active myocarditis,
constrictive pericarditis, and hypertrophic obstructive cardiomyopathy

13. Previous cardiac transplantation or transplantation indicated or expected within 6
months of randomization

14. Contraindications to saxagliptin therapy as outlined in the saxagliptin Investigator's
Brochure, or to sitagliptin therapy as outlined in the sitagliptin prescribing
information

15. Current treatment with strong cytochrome P450 (CYP) 3A4/5 inhibitors

16. Involvement in the planning and/or conduct of the study (applies to both AZ staff
and/or staff at the study site)

17. Previous enrollment which disqualifies patient from re-enrollment based on the rules
in Section 4.1 of the protocol, or previous randomization in the study

18. Participation in another clinical study with an investigational product during the
last 30 days

19. Patients either employed by or immediate relatives of the Sponsor

20. Known human immunodeficiency virus (HIV) infection

21. Severe hepatic disease, including chronic active hepatitis. Positive serologic
evidence of current infectious liver disease, including patients who are known to be
positive for hepatitis B viral antibody IgM, hepatitis B surface antigen, or hepatitis
C virus antibody; or aspartate transaminase (AST) or alanine transaminase (ALT) >3X
the upper limit of normal; or total bilirubin (TB) >2 mg/dL

22. Active malignancy requiring treatment at the time of Visit 1(with the exception of
successfully treated basal cell or treated squamous cell carcinoma).

23. Pregnant, positive pregnancy test, planning to become pregnant during clinical trial
or breast feeding

24. History of any clinically significant disease or disorder which, in the opinion of the
investigator, may put the patient at risk because of participation in the study, may
influence the results, or may limit the patient's ability to participate in or
complete the study

25. Unable or unwilling to provide written informed consent