Treatment of Diabetes in Patients With Systolic Heart Failure

Investigator Initiated Study: Randomized, double-blinded, active-control clinical trial to
determine the safety and efficacy of Canagliflozin and Sitagliptin in patients with type 2
diabetes and systolic heart failure (HF).

The investigators propose to study the effects of Canagliflozin 100 mg vs Sitagliptin 100 mg
(both administered once daily for 12 weeks) on parameters of aerobic exercise capacity and
ventilator efficiency by CPET after 12 weeks of active treatment. BP, body water content
(Bioelectrical Impedance Analysis [BIA]), body composition (Dual-energy X-ray absorptiometry
[DEXA]), cardiac function, diet and biomarkers will be also measured. Subjects with evidence
of left ventricular hypertrophy will undergo cardiac magnetic resonance (CMR) imaging.

Major Inclusion Criteria:

- Symptomatic stable heart failure (New York Heart Association (NYHA) functional
classification II-III) with reduced left ventricular ejection fraction (LVEF) ≤40%

- Peak exercise limited by shortness of breath and associated with a respiratory
exchange ratio (RER) >1.00 (reflecting maximal aerobic effort);

- Poorly controlled Type 2 Diabetes Mellitus (T2DM)(HbA1c levels between 7.0% and 10.0%
if on a treatment regimen including insulin, or between 6.5% and 10.0% if not on an
insulin regimen);

- Eighteen years of age or older.

Major Exclusion Criteria:

- Type I diabetes;

- Open label treatment with Sodium-GLucose coTransporter (SGLT)-2 inhibitors (within the
past 3 months);

- Current treatment with thiazolidinedione (within the past 3 months);

- Chronic Renal Disease defined as Glomerular Filtration Rate (GFR) <50 ml•min-1/1.73m2
according to local laboratory

- Pregnancy or of child-bearing potential or lactating;

- Active or recent (within 2 weeks) genital/urinary infection;

- Concomitant conditions or treatment which would affect completion or interpretation of
the study (i.e, physical inability to walk or run on a treadmill

- Inability to give informed consent.

Exclusion criteria specific to the cardiac magnetic resonance (CMR) substudy.

- Estimated GFR <60 ml•min-1/1.73m2

- Implantable cardioverter defibrillator, pacemaker or other implantable metal device
not compatible with CMR scanning;

- Severe claustrophobia, inability to lay flat for up to 60 minutes, or other
contraindication to CMR scanning.