Type 2 Diabetes Mellitus, Heart Failure
Conditions
Keywords
SGLT2 inhibtion, Ertugliflozin, Type 2 Diabetes, Heart Failure
Brief summary
This study aims to elucidate the mechanisms whereby the SGLT2i ertugliflozin modifies cardiorenal interactions that regulate fluid volume and neurohormonal activation in patients with type 2 diabetes and heart failure (T2D-HF).
Detailed description
Newer agents called sodium glucose co-transporter-2 inhibitors (SGLT2i) have been developed to improve glycemic control and lower hemoglobin A1c by increasing glycosuria. SGLT2i also reduce blood pressure and albuminuria in T2D - possibly through natriuresis. Importantly, a landmark trial EMPA-REG OUTCOME demonstrated that the SGLT2i empagliflozin is the first anti- hyperglycemic agent to reduce mortality and HF risk, and also to decrease the risk of progressive diabetic nephropathy. Similar benefits were also recently reported in the CANVAS Program trial with canagliflozin. Despite the benefits observed in these two pivotal trials, the mechanisms responsible for beneficial effects of SGLT2i in patients with T2D with respect to the development and/or worsening of HF are not currently known. In light of the results of EMPA-REG OUTCOME, the investigators aim to elucidate the mechanisms whereby the SGLT2i ertugliflozin modifies cardiorenal interactions that regulate fluid volume and neurohormonal activation in patients with T2D and HF (T2D-HF). The investigators will test the hypothesis that ertugliflozin increases proximal tubular natriuresis, thereby reducing plasma volume, without inducing significant renal vasoconstriction or activation of the sympathetic nervous system (SNS) (see below, Figure 1). The systematic understanding of the effects of SGLT2i in the setting of HF will enable the design of rational physiology based strategies to decrease the burden of HF, which could have major clinical and research implications internationally.
Interventions
DRUGErtugliflozin
Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks
DRUGPlacebo
Placebo once daily for 12 weeks
Sponsors
University Medical Center Groningen
Merck Sharp & Dohme LLC
University of Toronto
Toronto General Hospital
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind study
Intervention model description
Patients will be randomized to 15 mg (10mg + 5mg tablets) PO ertugliflozin daily or a matched placebo.
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects diagnosed with T2D ≥12 months prior to informed consent; 2. eGFR ≥30 ml/min/1.73m2; 3. Age \>18 years; 4. HbA1c 6.5%-10.5%; 5. Body Mass Index (BMI) 18.5-45.0 kg/m2; 6. Blood pressure ≤160/110 and ≥90/60 at screening, 7. Heart failure with New York Heart Association (NYHA) class 2-3 symptoms and ejection fraction ≥20% 8. Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 30 days 9. Stable diuretic dose for at least 30 days at the time of baseline physiological assessment 10. BNP levels at baseline ≥100 pg/ml (no atrial fibrillation), ≥200 pg/ml if in atrial fibrillation
Exclusion criteria
1. Type 1 Diabetes; 2. Leukocyte and/or nitrite positive urinalysis that is untreated; 3. Severe hypoglycaemia within 2 months prior to screening; 4. History of brittle diabetes or hypoglycaemia unawareness based on investigator judgement; 5. Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months; 6. Clinically significant valvular disease; 7. Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example amyloid) or pericardial constriction; 8. Uncontrolled systemic hypertension (systolic blood pressure \>160 mmHg and/or diastolic blood pressure \>110) or systemic hypotension (systolic blood pressure \< 90/60 mmHg); 9. Bariatric surgery or other surgeries that induce chronic malabsorption; 10. Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening; 11. Treatment with systemic corticosteroids; 12. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells; 13. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control; 14. Participation in another trial with an investigational drug within 30 days of informed consent; 15. Alcohol or drug abuse within three months prior to informed consent that would interfere with trial participation or any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement; 16. Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase \>3 x upper limit of normal as determined during screening; 17. Active malignancy at the time of screening;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fractional Excretion of Lithium (FELi) | Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values) | The difference in fractional excretion of lithium (FELi) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before lithium excretion was measured in urine and blood. |
| Fractional Excretion of Sodium (FENa) | Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values) | The difference in fractional excretion of sodium (FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood. |
| Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa) | Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values) | The difference in fractional excretion of lithium and fractional excretion of sodium (calculated by the difference between FELi and FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure (SBP) | chronic (12 weeks) | The difference in seated SBP with ertugliflozin vs. placebo |
| Diastolic Blood Pressure (DBP) | chronic (12 weeks) | The difference in seated DBP with ertugliflozin vs. placebo |
| Heart Rate (HR) | chronic (12 weeks) | The difference in seated HR with ertugliflozin vs. placebo |
| LV Ejection Fraction | chronic (12 weeks) | Echocardiography for markers of systolic and diastolic function |
| Carotid-femoral Pulse Wave Velocity | chronic (12 weeks) | Arterial Stiffness using SphygmaCor software. Pulse points measured at carotid and femoral arteries. |
| Plasma Volume | chronic (12 weeks) | Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution) |
| Urinary Adenosine | chronic (12 weeks) | Neurohormones/biomarkers |
| Cardiac Output | chronic (12 weeks) | Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM) |
| Systemic Vascular Resistance | chronic (12 weeks) | Systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM) |
| Blood Angiotensin II | chronic (12 weeks) | Neurohormones/biomarkers |
| BNP | chronic (12 weeks) | Neurohormones/biomarkers |
| Norepinephrine | chronic (12 weeks) | Neurohormones/biomarkers |
| Extracellular Water | chronic (12 weeks) | Extracellular water will be measured non-invasively using bioimpedence spectroscopy |
| Glomerular Filtration Rate (GFR) | Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 12 weeks | The difference in iohexol-measured GFR with ertugliflozin vs. placebo. 5ml bolus iohexol (Omnipaque 300mg) was infused intravenously over 2 minutes while participants were supine. Iohexol disappearance curve was used to measure GFR over from 2-4 hours after infusion. |
| Effective Renal Plasma Flow (ERPF) | Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 12 weeks | The difference in ERPF with ertugliflozin vs. placebo. Paraaminohippurate (PAH) was intravenously administered to measured ERPF. |
Countries
Canada, Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ertuglifozin Treatment Arm Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks. | 17 |
| Placebo Arm Placebo Matching Ertugliflozin Tablet for 12 weeks. | 17 |
| Total | 34 |
Baseline characteristics
| Characteristic | Ertuglifozin Treatment Arm | Placebo Arm | Total |
|---|---|---|---|
| Age, Continuous | 69.8 years STANDARD_DEVIATION 8.7 | 69.4 years STANDARD_DEVIATION 7.5 | 69.6 years STANDARD_DEVIATION 7.4 |
| eGFR | 63.5 mL/min/1.73 m2 STANDARD_DEVIATION 23.3 | 66.4 mL/min/1.73 m2 STANDARD_DEVIATION 22.4 | 65 mL/min/1.73 m2 STANDARD_DEVIATION 22.9 |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 13 Participants | 12 Participants | 25 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment Canada | 8 participants | 8 participants | 16 participants |
| Region of Enrollment Netherlands | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 0 / 17 | 0 / 17 |
| serious Total, serious adverse events | 3 / 17 | 1 / 17 |
Outcome results
Primary
Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa)
The difference in fractional excretion of lithium and fractional excretion of sodium (calculated by the difference between FELi and FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood.
Time frame: Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ertuglifozin Treatment Arm | Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa) | Week 1 | 0.8 percentage of total sodium reabsorption | Standard Error 7 |
| Ertuglifozin Treatment Arm | Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa) | Week 12 | 1.4 percentage of total sodium reabsorption | Standard Error 10.6 |
| Placebo Arm | Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa) | Week 1 | -2.6 percentage of total sodium reabsorption | Standard Error 16.7 |
| Placebo Arm | Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa) | Week 12 | -5 percentage of total sodium reabsorption | Standard Error 16.1 |
p-value: 0.26Wilcoxon (Mann-Whitney)
p-value: 0.56Wilcoxon (Mann-Whitney)
Primary
Fractional Excretion of Lithium (FELi)
The difference in fractional excretion of lithium (FELi) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before lithium excretion was measured in urine and blood.
Time frame: Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ertuglifozin Treatment Arm | Fractional Excretion of Lithium (FELi) | Week 1 | 0.3 percentage of filtered lithium excreted | Standard Error 6.9 |
| Ertuglifozin Treatment Arm | Fractional Excretion of Lithium (FELi) | Week 12 | 0.8 percentage of filtered lithium excreted | Standard Error 11 |
| Placebo Arm | Fractional Excretion of Lithium (FELi) | Week 1 | -2.3 percentage of filtered lithium excreted | Standard Error 16.8 |
| Placebo Arm | Fractional Excretion of Lithium (FELi) | Week 12 | -4.9 percentage of filtered lithium excreted | Standard Error 16.6 |
p-value: 0.36Wilcoxon (Mann-Whitney)
p-value: 0.56Wilcoxon (Mann-Whitney)
Primary
Fractional Excretion of Sodium (FENa)
The difference in fractional excretion of sodium (FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood.
Time frame: Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ertuglifozin Treatment Arm | Fractional Excretion of Sodium (FENa) | Week 1 | -0.6 percentage of sodium excretion | Standard Error 1.9 |
| Ertuglifozin Treatment Arm | Fractional Excretion of Sodium (FENa) | Week 12 | -0.6 percentage of sodium excretion | Standard Error 1.6 |
| Placebo Arm | Fractional Excretion of Sodium (FENa) | Week 1 | 0.3 percentage of sodium excretion | Standard Error 1.7 |
| Placebo Arm | Fractional Excretion of Sodium (FENa) | Week 12 | 0.1 percentage of sodium excretion | Standard Error 1.3 |
p-value: 0.53Wilcoxon (Mann-Whitney)
p-value: 0.89Wilcoxon (Mann-Whitney)
Secondary
Blood Angiotensin II
Neurohormones/biomarkers
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Blood Angiotensin II | 89.2 pg/ml | Standard Error 7.1 |
| Placebo Arm | Blood Angiotensin II | 86.5 pg/ml | Standard Error 7.3 |
p-value: 0.802Wilcoxon (Mann-Whitney)
Secondary
BNP
Neurohormones/biomarkers
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | BNP | 1311.1 pg/ml | Standard Error 400.5 |
| Placebo Arm | BNP | 576.6 pg/ml | Standard Error 405.3 |
p-value: 0.327Wilcoxon (Mann-Whitney)
Secondary
Cardiac Output
Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM)
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Cardiac Output | 5.8 L/min | Standard Error 0.3 |
| Placebo Arm | Cardiac Output | 5.8 L/min | Standard Error 0.3 |
p-value: 0.844Wilcoxon (Mann-Whitney)
Secondary
Carotid-femoral Pulse Wave Velocity
Arterial Stiffness using SphygmaCor software. Pulse points measured at carotid and femoral arteries.
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Carotid-femoral Pulse Wave Velocity | 11.50 m/s | Standard Error 1.5 |
| Placebo Arm | Carotid-femoral Pulse Wave Velocity | 12.14 m/s | Standard Error 1.42 |
p-value: 0.443Wilcoxon (Mann-Whitney)
Secondary
Diastolic Blood Pressure (DBP)
The difference in seated DBP with ertugliflozin vs. placebo
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Diastolic Blood Pressure (DBP) | 77 mmHg | Standard Error 3 |
| Placebo Arm | Diastolic Blood Pressure (DBP) | 76 mmHg | Standard Error 3 |
p-value: 0.92Wilcoxon (Mann-Whitney)
Secondary
Effective Renal Plasma Flow (ERPF)
The difference in ERPF with ertugliflozin vs. placebo. Paraaminohippurate (PAH) was intravenously administered to measured ERPF.
Time frame: Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Effective Renal Plasma Flow (ERPF) | 399.1 mL/min/1.73 m2 | Standard Error 46.8 |
| Placebo Arm | Effective Renal Plasma Flow (ERPF) | 335.6 mL/min/1.73 m2 | Standard Error 41.5 |
p-value: 0.438Wilcoxon (Mann-Whitney)
Secondary
Extracellular Water
Extracellular water will be measured non-invasively using bioimpedence spectroscopy
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Extracellular Water | 20.1 L | Standard Error 0.9 |
| Placebo Arm | Extracellular Water | 21.8 L | Standard Error 1 |
p-value: 0.013Wilcoxon (Mann-Whitney)
Secondary
Glomerular Filtration Rate (GFR)
The difference in iohexol-measured GFR with ertugliflozin vs. placebo. 5ml bolus iohexol (Omnipaque 300mg) was infused intravenously over 2 minutes while participants were supine. Iohexol disappearance curve was used to measure GFR over from 2-4 hours after infusion.
Time frame: Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Glomerular Filtration Rate (GFR) | 48.6 mL/min/1.73 m2 | Standard Error 4 |
| Placebo Arm | Glomerular Filtration Rate (GFR) | 50.1 mL/min/1.73 m2 | Standard Error 4.2 |
p-value: 0.303Wilcoxon (Mann-Whitney)
Secondary
Heart Rate (HR)
The difference in seated HR with ertugliflozin vs. placebo
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Heart Rate (HR) | 74 bpm | Standard Error 3 |
| Placebo Arm | Heart Rate (HR) | 72 bpm | Standard Error 3 |
p-value: 0.405Wilcoxon (Mann-Whitney)
Secondary
LV Ejection Fraction
Echocardiography for markers of systolic and diastolic function
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | LV Ejection Fraction | 49.2 percentage of output | Standard Error 4.4 |
| Placebo Arm | LV Ejection Fraction | 43.6 percentage of output | Standard Error 5.4 |
p-value: 0.536Wilcoxon (Mann-Whitney)
Secondary
Norepinephrine
Neurohormones/biomarkers
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Norepinephrine | 2.6 nM | Standard Error 0.3 |
| Placebo Arm | Norepinephrine | 2.6 nM | Standard Error 0.3 |
p-value: 0.618Wilcoxon (Mann-Whitney)
Secondary
Plasma Volume
Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution)
Time frame: chronic (12 weeks)
Population: The plasma volume was calculated from the laboratory-measured indocyanine green dye values in n=18 participants who had measurements performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Plasma Volume | 3470.9 ml | Standard Error 438 |
| Placebo Arm | Plasma Volume | 3158.2 ml | Standard Error 491.9 |
p-value: 0.849Wilcoxon (Mann-Whitney)
Secondary
Systemic Vascular Resistance
Systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM)
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Systemic Vascular Resistance | 1346.7 dynes·s·cm5 | Standard Error 99.1 |
| Placebo Arm | Systemic Vascular Resistance | 1437.1 dynes·s·cm5 | Standard Error 99.9 |
p-value: 0.262Wilcoxon (Mann-Whitney)
Secondary
Systolic Blood Pressure (SBP)
The difference in seated SBP with ertugliflozin vs. placebo
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Systolic Blood Pressure (SBP) | 132 mmHg | Standard Error 5 |
| Placebo Arm | Systolic Blood Pressure (SBP) | 128 mmHg | Standard Error 5 |
p-value: 0.599Wilcoxon (Mann-Whitney)
Secondary
Urinary Adenosine
Neurohormones/biomarkers
Time frame: chronic (12 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertuglifozin Treatment Arm | Urinary Adenosine | 0.25 mM/μmol Cr | Standard Error 0.05 |
| Placebo Arm | Urinary Adenosine | 0.39 mM/μmol Cr | Standard Error 0.05 |
p-value: 0.946Wilcoxon (Mann-Whitney)