Diabetes Mellitus, Type 2, Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
Diabetes mellitus, Heart Failure
Brief summary
The main aim of this study is to identify the underlying mechanisms of Sodium-glucose co-transporter-2 (SGLT2) inhibitors which are associated to better outcomes in patients with Diabetes mellitus type 2 and Heart Failure with preserved Ejection Fraction.
Detailed description
Double design study including a clinical trial and a nested case-control study. A) Experimental study (clinical trial): Phase IV, prospective, randomized, double-blind placebo-controlled with 12 months follow-up. Inclusion criteria are: 1) diagnosis of DM2, 2) HF with preserved EF with a hospital admission in the previous 6 months with demonstration of diastolic dysfunction. 3) Stable clinical situation at inclusion. 4) Clinical indication of cardiac catheterization. Patients will be randomized 1:1 to received Dapagliflozin 10 mg/day or placebo. The main objective is to compare the impact of the drug on LV diastolic properties at the peak of effort and in levels of plasma deposit and cross-linking biomarkers of type I collagen between the two treatment groups at baseline and after 12 months. 52 patients will be recruited. B) Descriptive study: Nested case-control study, considering patients from the experimental study as cases and 10 additional patients with HF with preserved EF but no type 2 DM as controls. The main aim will be compare the histological, molecular, biochemical and biomechanical features of the HFpEF patients with and without DM2.
Interventions
Dapagliflozin 10 mg / day oral
DRUGPlacebo
One Placebo capsule daily oral
Sponsors
University of Navarra
Instituto de Salud Carlos III
Fundación para la Investigación Biomédica del Hospital Gregorio Maranon
Hospital General Universitario Gregorio Marañon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of DM2 based on the established criteria: HbA1c ≥ 6.5% (48 mmol / mol) and fasting plasma glucose ≥ 7.0 mmol / L (≥126 mg / dL) or 2-h after overload ≥ 11.1 mmol / L ( ≥ 200 mg / dL). * LVEF ≥ 50%. * Diagnosis of ICFEP according to clinical criteria, with a hospital admission in the previous 6 months with demonstration of diastolic dysfunction according to the echocardiographic criteria. * Stable clinical situation (\> 1 month after hospitalization due to IC decompensation). * Clinical indication of cardiac catheterization. * Signature of informed consent.
Exclusion criteria
* Previous treatment with iSGLT2. * Significant coronary disease. * Aortic or mitral valve disease ≥ moderate (grades 3 or 4/4 for valve regurgitations) * Contraindications for dapagliflozin treatment according to the data sheet (hereditary galactose intolerance, Lapp lactase insufficiency or glucose-galactose malabsorption, moderate-severe renal failure -CrCl \<60 ml / min or eGFR \<60 ml / min / 1 , 73 m2-, severe hepatic insufficiency). The inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional Main Objective: Impact of iSGLT2 on LV diastolic properties in terms of the change in LV stiffness constant (S+) at the peak of exercise. | Baseline vs 12 months | Intrinsic diastolic properties will be analyzed by dynamic pressure-volume loop catheterization. |
| Main Structural Objective: Changes in serum levels of procollagen type I C-terminal propertied (PICP, ng/mL) | Baseline vs 12 months | We will measure the changes in serum levels of procollagen type I C-terminal propertied (PICP, ng/mL), a validated biomarker of collagen type I deposition |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Impact of iSGLT2 on myocardial remodeling. | Baseline vs 12 months | Reverse cardiac remodeling will be studied by cardiac magnetic resonance (CMR). CMR studies will be performed on 1.5 T scanners and will include short-axis cine steady-state free-precession images from base to apex, and standard long axis views for the analysis of mass, volume and ventricular function. CMR study will require the administration of a gadolinium contrast medium to study myocardial fibrosis, unless contraindicated. |
| Correlation of myocardial remodeling patterns with the intrinsic diastolic properties of chamber VI with systolic function. | Baseline vs 12 months | Results from the pressure-volume analysis and CMR will be assess in common in order to search for association. |
| Relative contribution of the intrinsic diastolic properties of the LV and the flow patterns on filling pressures and their modulation under treatment with iSGLT2. | Baseline vs 12 months | Intraventricular flow patterns will be studied by Doppler echocardiography and phase contrast CMR, considering vorticity and blood transport parameters. |
| Changes in LV stiffness constants (S+ and S-). | Baseline vs 12 months | LV stiffness constants will be obtained from invasive pressure-volume data analysis. |
| Changes in N-terminal pro brain natriuretic peptide (pg/mL) | Baseline vs 12 months | We will measure the changes in N-terminal pro brain natriuretic peptide (pg/mL) |
| Changes in high sensitivity troponin T (pg/mL) | Baseline vs 12 months | We will measure the changes in high sensitivity troponin T (pg/mL) |
| Changes in serum levels of collagen type I C-terminal telopeptide to matrix metalloproteinase ratio (CITP:MMP-1) | Baseline vs 12 months | We will measure the changes in serum levels of collagen type I C-terminal telopeptide to matrix metalloproteinase ratio (CITP:MMP-1), biomarker of the degree of collagen type cross-linking. |
| Changes in the slope, Emax, of the end-systolic pressure-volume relationship | Baseline vs 12 months | Emax will be obtained from invasive pressure-volume data analysis. |
Countries
Spain
Contacts
Primary ContactJavier Bermejo Thomas, MD, PhD
Outcome results
None listed