This is a 24 week, multicenter, randomized, double-blind, parallel group, placebo-controlled study to investigate the effects of saxagliptin and sitagliptin on cardiac dimensions and function in patients with type 2 diabetes (T2DM) mellitus and heart failure (HF).

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