Mechanistic Evaluation of Glucose-lowering Strategies in Patients With Heart Failure
Condition: Type 2 Diabetes Mellitus; Heart Failure
MeSH terms: Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Saxagliptin; Sitagliptin; Placebo to match saxagliptin; Placebo to match sitagliptin
Intervention description: 5 mg or 2.5 mg, plain, yellow, biconvex, round, film-coated tablet; 50 mg or 100 mg, gray capsule; 2.5 mg or 5 mg, plain, yellow, biconvex, round, film-coated tablet; 50 mg or 100 mg, gray capsule
Intervention MeSH terms: Sitagliptin Phosphate; Saxagliptin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 348.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Type 2 Diabetes Mellitus; Heart Failure; Saxagliptin; Sitagliptin

Summary:

      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).
    

Eligibility criteria:

        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