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Effects of SGLT2 Inhibition on the Mechanisms of Cardiac Damage in the Diabetic Patient With HFpEF (CARDIA-STIFF)

Primary Purpose

Diabetes Mellitus, Type 2, Heart Failure With Preserved Ejection Fraction

Status

Unknown status

Phase

Phase 4

Locations

Spain

Study Type

Interventional

Intervention

Dapagliflozin 10 MG [Farxiga]

Placebo

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 2 focused on measuring Diabetes mellitus, Heart Failure

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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/exclusion criteria for Descriptive Study will be the same as previously described without the diagnosis of DM2.

Sites / Locations

Hospital General Universitario Gregorio MaranonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

No Intervention

Arm Label

Clinical Trial: Experimental Arm

Clinical Trial: Placebo Arm

Descriptive Study

Arm Description

Patients with heart failure with preserved ejection fraction and type 2 diabetes mellitus treated with Dapagliflozin (Forxiga) 10 mg, one capsule per day orally.

Patients with heart failure with preserved ejection fraction and type 2 diabetes mellitus treated with Placebo in a similar pattern.

Patients with heart failure with preserved ejection fraction but with no type 2 diabetes mellitus (n=10).

Outcomes

Primary Outcome Measures

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.

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)

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 Outcome Measures

Changes in LV stiffness constants (S+ and S-).

LV stiffness constants will be obtained from invasive pressure-volume data analysis.

Changes in the slope, Emax, of the end-systolic pressure-volume relationship

Emax will be obtained from invasive pressure-volume data analysis.

Impact of iSGLT2 on myocardial remodeling.

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.

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.

Intraventricular flow patterns will be studied by Doppler echocardiography and phase contrast CMR, considering vorticity and blood transport parameters.

Changes in serum levels of collagen type I C-terminal telopeptide to matrix metalloproteinase ratio (CITP:MMP-1)

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 N-terminal pro brain natriuretic peptide (pg/mL)

We will measure the changes in N-terminal pro brain natriuretic peptide (pg/mL)

Changes in high sensitivity troponin T (pg/mL)

We will measure the changes in high sensitivity troponin T (pg/mL)

Full Information

NCT ID

NCT04739215

First Posted

January 15, 2021

Last Updated

February 1, 2021

Sponsor

Hospital General Universitario Gregorio Marañon

Collaborators

University of Navarra, Instituto de Salud Carlos III, Fundación para la Investigación Biomédica del Hospital Gregorio Maranon

1. Study Identification

Unique Protocol Identification Number

NCT04739215

Brief Title

Effects of SGLT2 Inhibition on the Mechanisms of Cardiac Damage in the Diabetic Patient With HFpEF

Acronym

CARDIA-STIFF

Official Title

Effects of Sodium-Glucose Cotransporter 2 Inhibition on the Mechanisms of Cardiac Damage in the Diabetic Patient With Heart Failure With Preserved Ejection Fraction

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Unknown status

Study Start Date

January 15, 2021 (Actual)

Primary Completion Date

December 30, 2022 (Anticipated)

Study Completion Date

December 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hospital General Universitario Gregorio Marañon

Collaborators

University of Navarra, Instituto de Salud Carlos III, Fundación para la Investigación Biomédica del Hospital Gregorio Maranon

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type 2, Heart Failure With Preserved Ejection Fraction

Keywords

Diabetes mellitus, Heart Failure

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

62 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Clinical Trial: Experimental Arm

Arm Type

Experimental

Arm Description

Patients with heart failure with preserved ejection fraction and type 2 diabetes mellitus treated with Dapagliflozin (Forxiga) 10 mg, one capsule per day orally.

Arm Title

Clinical Trial: Placebo Arm

Arm Type

Placebo Comparator

Arm Description

Patients with heart failure with preserved ejection fraction and type 2 diabetes mellitus treated with Placebo in a similar pattern.

Arm Title

Descriptive Study

Arm Type

No Intervention

Arm Description

Patients with heart failure with preserved ejection fraction but with no type 2 diabetes mellitus (n=10).

Intervention Type

Drug

Intervention Name(s)

Dapagliflozin 10 MG [Farxiga]

Intervention Description

Dapagliflozin 10 mg / day oral

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

One Placebo capsule daily oral

Primary Outcome Measure Information:

Title

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.

Description

Intrinsic diastolic properties will be analyzed by dynamic pressure-volume loop catheterization.

Time Frame

Baseline vs 12 months

Title

Main Structural Objective: Changes in serum levels of procollagen type I C-terminal propertied (PICP, ng/mL)

Description

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

Time Frame

Baseline vs 12 months

Secondary Outcome Measure Information:

Title

Changes in LV stiffness constants (S+ and S-).

Description

LV stiffness constants will be obtained from invasive pressure-volume data analysis.

Time Frame

Baseline vs 12 months

Title

Changes in the slope, Emax, of the end-systolic pressure-volume relationship

Description

Emax will be obtained from invasive pressure-volume data analysis.

Time Frame

Baseline vs 12 months

Title

Impact of iSGLT2 on myocardial remodeling.

Description

Time Frame

Baseline vs 12 months

Title

Correlation of myocardial remodeling patterns with the intrinsic diastolic properties of chamber VI with systolic function.

Description

Results from the pressure-volume analysis and CMR will be assess in common in order to search for association.

Time Frame

Baseline vs 12 months

Title

Relative contribution of the intrinsic diastolic properties of the LV and the flow patterns on filling pressures and their modulation under treatment with iSGLT2.

Description

Intraventricular flow patterns will be studied by Doppler echocardiography and phase contrast CMR, considering vorticity and blood transport parameters.

Time Frame

Baseline vs 12 months

Title

Changes in serum levels of collagen type I C-terminal telopeptide to matrix metalloproteinase ratio (CITP:MMP-1)

Description

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.

Time Frame

Baseline vs 12 months

Title

Changes in N-terminal pro brain natriuretic peptide (pg/mL)

Description

We will measure the changes in N-terminal pro brain natriuretic peptide (pg/mL)

Time Frame

Baseline vs 12 months

Title

Changes in high sensitivity troponin T (pg/mL)

Description

We will measure the changes in high sensitivity troponin T (pg/mL)

Time Frame

Baseline vs 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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/exclusion criteria for Descriptive Study will be the same as previously described without the diagnosis of DM2.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Javier Bermejo Thomas, MD, PhD

Phone

(34) 91 5868279

javier.bermejo@salud.madrid.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Javier Bermejo Thomas, MD, PhD

Organizational Affiliation

Hospital General Universitario Gregorio Marañón

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hospital General Universitario Gregorio Maranon

City

Madrid

ZIP/Postal Code

280007

Country

Spain

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Javier Bermejo Thomas, MD, PhD

Phone

(34) 91 5868815

javier.bermejo@salud.madrid.org

First Name & Middle Initial & Last Name & Degree

Javier Bermejo Thomas, MD, PhD

First Name & Middle Initial & Last Name & Degree

Adolfo Villa

First Name & Middle Initial & Last Name & Degree

Antonia Delgado Montero

First Name & Middle Initial & Last Name & Degree

Elena Rodríguez Gonzalez

First Name & Middle Initial & Last Name & Degree

Jaime Elízaga

First Name & Middle Initial & Last Name & Degree

Maria del Mar Desco

First Name & Middle Initial & Last Name & Degree

Juan Carlos del Álamo

First Name & Middle Initial & Last Name & Degree

Jose Carlos Antoranz

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

21329845

Citation

Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kuhl U, Schultheiss HP, Tschope C. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol. 2011 Feb 22;57(8):977-85. doi: 10.1016/j.jacc.2010.10.024.

Results Reference

result

PubMed Identifier

26378978

Citation

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.

Results Reference

result

PubMed Identifier

28402411

Citation

Perez Del Villar C, Savvatis K, Lopez B, Kasner M, Martinez-Legazpi P, Yotti R, Gonzalez A, Diez J, Fernandez-Aviles F, Tschope C, Bermejo J. Impact of acute hypertension transients on diastolic function in patients with heart failure with preserved ejection fraction. Cardiovasc Res. 2017 Jul 1;113(8):906-914. doi: 10.1093/cvr/cvx047.

Results Reference

result

PubMed Identifier

23743396

Citation

Bermejo J, Yotti R, Perez del Villar C, del Alamo JC, Rodriguez-Perez D, Martinez-Legazpi P, Benito Y, Antoranz JC, Desco MM, Gonzalez-Mansilla A, Barrio A, Elizaga J, Fernandez-Aviles F. Diastolic chamber properties of the left ventricle assessed by global fitting of pressure-volume data: improving the gold standard of diastolic function. J Appl Physiol (1985). 2013 Aug 15;115(4):556-68. doi: 10.1152/japplphysiol.00363.2013. Epub 2013 Jun 6.

Results Reference

result

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Effects of SGLT2 Inhibition on the Mechanisms of Cardiac Damage in the Diabetic Patient With HFpEF

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