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.
ID
Source
Brief title
Condition
- Heart failures
- Glucose metabolism disorders (incl diabetes mellitus)
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Our primary goal is to determine if SGLT2i causes a persistent proximal renal
tubular natriuretic effect (see below). We will capture acute (1 week) and
chronic (12 weeks) responses, since physiological effects of SGLT2i agents may
change over time. As an extension of our primary aim, we will assess whether
ertugliflozin-related effects on proximal tubule natriuresis lead to a
reduction in plasma volume and extracellular body water (see below). FENa and
FELi excretion were calculated according to FE(electrolyte) = 100 X
([(electrolyte urine) X (creatinine plasma)]/[(electrolyte plasma) X
(creatinine urine)]). FELi will used as a surrogate to measure proximal tubular
sodium reabsorption, whereas FENa assesses total overall (proximal and distal)
tubular sodium handling. Distal sodium handling is calculated by total-proximal
sodium reabsorption, as described elsewhere. As in previous work, plasma and
urine lithium levels will be measured using inductively with coupled
spectroscopy.
Secondary outcome
Secondary:
1. We will determine if volume contraction leads to a decline in hormones that
are activated in HF patients such as B*type natriuretic peptides
(BNP/NT-pro-BNP), without activating the SNS7;
2. We will determine the impact of ertugliflozin on: renal hemodynamic function
(GFRiohexol/ERPFpah) measured at 1 week and 12 weeks as a measure of safety;
3. Blood pressure, echocardiographic measures of cardiac output (and derived
systemic vascular resistance) arterial stiffness and systemic vascular
resistance to better understand the blood pressure lowering effect in this
patient population;
4. Heart rate and heart rate variability, to assess effects on SNS activation;
5. Urinary natriuretic modulators, such as angiotensin converting enzyme-29 and
adenosine10;
6. To characterize the safety of ertugliflozin vs. placebo by determining the
number of hypoglycemic episodes between groups, and serious adverse events.
Background summary
Patients with T2D-HF have >50% 5-year mortality, leading to substantial
societal and financial costs to Canadians. The identification of new therapies
is essential to improve the quality of life and survival of T2D-HF patients. In
EMPA-REG OUTCOME there was a significant decrease in the rate of
hospitalization for HF after therapy for only 3 months. Despite this beneficial
effect, the impact of SGLT2i in patients with overt HF remains unknown. The
current gap in knowledge around SGLT2i effects in patients with existing HF
highlights the urgent need for human mechanistic studies in this area. The
renal and cardiovascular function effects of SGLT2i on natriuresis-related
endpoints in patients with T2D and HF is not known. Our study will provide
needed insights into physiological effects of SGLT2i agents on natriuresis,
hemodynamic function and neurohormones in HF patients.
Study objective
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.
Study design
This study will use a double blind, stratified randomization trial approach
involving 36 T2D-HF patients taking standard HF therapies.
Measurements:
• During the double blind treatment period, patients will collect a 24-hour
urine collection at each visit for measurement of 24-hour protein, albumin,
glucose, sodium, potassium, creatinine, and urea excretion. Twenty-four hour
urine collections will be performed at: Visits 3, 4 and 8. Routine biochemistry
and safety labs will be drawn at screening, during each physiological
assessment and at each the specified office safety visits (see visit schedule
table below).
• Office systolic and diastolic blood pressure measurements, heart rate,
weight, and waist circumference will be performed at screening and at each
subsequent physiological testing day and at each office visit (see visit
schedule table below).
• Blood will be drawn for measurement of renal function tests, HbA1c, glucose,
complete blood count, plasma albumin, RAAS biomarkers, natriuretic peptides,
and neurohormones on visits 3, 4 and 8.
• Blood and urine samples will be stored for future exploratory biomarker
analyses to study the effect of ertugliflozin in this study population.
Intervention
Patients will be randomized to 15 mg (1x 15mg tablets) PO ertugliflozin daily
or a matched placebo.
Study burden and risks
Patients visit the outpatient clinic on a more regular basis than standard
patient care -
i.e. at study inclusion and at each study visit for clinical assessment. Blood
work for physiological assessments, renal function tests and cardiovascular
assessments will be obtained as described in the protocol. 24hr urine will be
collected one day prior to the hospital visit. No other invasive measurements
will be executed. Patients receive restitution of all travel costs. Patients
receive no priority in treatment of other diseases in the clinic during this
study. There are no direct benefits for the patients to be included and
participation is on a voluntary basis.
University Avenue 585
Toronto Ontario M5G 2N2
CA
University Avenue 585
Toronto Ontario M5G 2N2
CA
Listed location countries
Age
Inclusion criteria
Men and women with type 2 diabetes > 12 months, eGFR > 30 ml/min/1.73m2, age >
18 years, HbA1c 6.5 - 10.5%, BMI 18.5-45.0 kg, blood prssure < 160/110 and >
90/60 at screening, heart failure NYHA 2-3 with ejection fraction > 20%,
ACE/ARB-inhibition > 30 days, if diuretics are use then > 30 days before
baseline, BNP levels at baseline >100 pg/ml (no atrial fibrillation), >200
pg/ml if in atrial fibrillation, if NT-pro-BNP is used then a cut-off baseline
of >300ng/L (no atrial fibriallation) or >600 ng/L (in atrial fibrillation)
should be used
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 childbearing potential and not practicing an
acceptable method of birthcontrol;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 clinicalcondition 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 ofnormal as
determined during screening;17. Active malignancy at the time of screening;18.
Allergy to iodine-based substances if receiving iohexol for GFR measureseen
stenose > 30% vertoont;
6. De doellae
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001840-37-NL |
| ClinicalTrials.gov | NCT03416270 |
| CCMO | NL66121.029.18 |