Diabetes Mellitus, Type 2, Heart Failure, Systolic
Conditions
Keywords
Systolic Heart Failure, Canagliflozin, Sitagliptin Phosphate, Type 2 Diabetes, SGLT2 inhibitor, DPPIV inhibitor
Brief summary
Investigator Initiated Study to study the effects of Canagliflozin 100 milligrams (mg) vs Sitagliptin 100 mg on parameters of aerobic exercise capacity (peak oxygen consumption \[VO2\]) and ventilator efficiency (minute ventilation \[VE\]/carbon dioxide production \[VCO2\] slope) at cardiopulmonary exercise test (CPET) after 12 weeks of active treatment (primary endpoints). Blood pressure (BP), body water content, body composition, cardiac function, and diet will be also measured (secondary endpoints).
Detailed description
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.
Interventions
DRUGCanagliflozin
DRUGSitagliptin
Sponsors
Janssen Scientific Affairs, LLC
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Aerobic Exercise Capacity at 12 Weeks | baseline and 12 weeks | Peak oxygen consumption (VO2) measured by maximal cardiopulmonary exercise test |
| Change From Baseline Ventilatory Efficiency at 12 Weeks | baseline and 12 weeks | Minute ventilation (VE) relative to CO2 production (VCO2) slope measured by cardiopulmonary exercise test |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Canagliflozin Canagliflozin will be administered orally in pill form at 100 mg, daily for 12 weeks.
Canagliflozin | 17 |
| Sitagliptin Sitagliptin will be administered orally in pill form at 100 mg, daily for 12 weeks.
Sitagliptin | 19 |
| Total | 36 |
Baseline characteristics
| Characteristic | Total | Canagliflozin | Sitagliptin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 15 Participants | 19 Participants |
| Age, Continuous | 56.0 years STANDARD_DEVIATION 7.8 | 58.0 years STANDARD_DEVIATION 6.1 | 54.3 years STANDARD_DEVIATION 8.8 |
| Peak Oxygen Consumption | 15.7 mL/kg/min STANDARD_DEVIATION 3.4 | 16.2 mL/kg/min STANDARD_DEVIATION 3.4 | 15.3 mL/kg/min STANDARD_DEVIATION 3.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 10 Participants | 7 Participants |
| Region of Enrollment United States | 36 participants | 17 participants | 19 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 28 Participants | 13 Participants | 15 Participants |
| Ventilator Efficiency | 33.3 Unitless STANDARD_DEVIATION 6.7 | 34.1 Unitless STANDARD_DEVIATION 6.1 | 32.6 Unitless STANDARD_DEVIATION 7.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 19 |
| other Total, other adverse events | 7 / 17 | 6 / 19 |
| serious Total, serious adverse events | 3 / 17 | 1 / 19 |
Outcome results
Primary
Change From Baseline Aerobic Exercise Capacity at 12 Weeks
Peak oxygen consumption (VO2) measured by maximal cardiopulmonary exercise test
Time frame: baseline and 12 weeks
Population: Unadjusted p values were reported throughout, with statistical significance set at the 2-tailed 0.05 level. Only cases with available data used to compute the primary endpoint will be included in the analyses (16 subjects for canagliflozin group and 18 subjects for sitagliptin group).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Change From Baseline Aerobic Exercise Capacity at 12 Weeks | 0.67 mL/kg/min | Standard Deviation 2.1 |
| Sitagliptin | Change From Baseline Aerobic Exercise Capacity at 12 Weeks | -0.53 mL/kg/min | Standard Deviation 1.75 |
Comparison: We expected a baseline peak oxygen consumption (VO2) of 14.5 mL/kg/min. A sample size of 40 patients per group (total of 80 patients) provided sufficient power to detect a mean difference in the interval change in peak VO2 of 1.50±1.76 mL/kg/min (primary endpoint) expected with Canagliflozin compared to Sitagliptin, which we predict to have no significant effect on peak VO2 (0±1.76 mL/kg/min).p-value: 0.083ANOVA
Primary
Change From Baseline Ventilatory Efficiency at 12 Weeks
Minute ventilation (VE) relative to CO2 production (VCO2) slope measured by cardiopulmonary exercise test
Time frame: baseline and 12 weeks
Population: Unadjusted p values were reported throughout, with statistical significance set at the 2-tailed 0.05 level. Only cases with available data used to compute the primary endpoint will be included in the analyses (16 subjects for canagliflozin group and 18 subjects for sitagliptin group).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Change From Baseline Ventilatory Efficiency at 12 Weeks | -0.3 Unitless | Standard Deviation 4.1 |
| Sitagliptin | Change From Baseline Ventilatory Efficiency at 12 Weeks | -0.3 Unitless | Standard Deviation 5.1 |
p-value: 0.51ANOVA