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

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

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.

Study Overview

• Status: Unknown
• Conditions: Diabetes Mellitus, Type 2; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Dapagliflozin 10 MG [Farxiga]; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 62
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 280007
    • Recruiting
    • Hospital General Universitario Gregorio Maranon
    • Contact: Javier Bermejo Thomas, MD, PhD; Phone Number: (34) 91 5868815; Email: javier.bermejo@salud.madrid.org
    • Principal Investigator: Javier Bermejo Thomas, MD, PhD
    • Sub-Investigator: Adolfo Villa
    • Sub-Investigator: Antonia Delgado Montero
    • Sub-Investigator: Elena Rodríguez Gonzalez
    • Sub-Investigator: Jaime Elízaga
    • Sub-Investigator: Maria del Mar Desco
    • Sub-Investigator: Juan Carlos del Álamo
    • Sub-Investigator: Jose Carlos Antoranz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Clinical Trial: Experimental Arm; Patients with heart failure with preserved ejection fraction and type 2 diabetes mellitus treated with Dapagliflozin (Forxiga) 10 mg, one capsule per day orally.	Drug: Dapagliflozin 10 MG [Farxiga]; Dapagliflozin 10 mg / day oral
PLACEBO_COMPARATOR: Clinical Trial: Placebo Arm; Patients with heart failure with preserved ejection fraction and type 2 diabetes mellitus treated with Placebo in a similar pattern.	Drug: Placebo; One Placebo capsule daily oral
NO_INTERVENTION: Descriptive Study; Patients with heart failure with preserved ejection fraction but with no type 2 diabetes mellitus (n=10).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline vs 12 months
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	Baseline vs 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in LV stiffness constants (S+ and S-).	LV stiffness constants will be obtained from invasive pressure-volume data analysis.	Baseline vs 12 months
Changes in the slope, Emax, of the end-systolic pressure-volume relationship	Emax will be obtained from invasive pressure-volume data analysis.	Baseline vs 12 months
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.	Baseline vs 12 months
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.	Baseline vs 12 months
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.	Baseline vs 12 months
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.	Baseline vs 12 months
Changes in N-terminal pro brain natriuretic peptide (pg/mL)	We will measure the changes in N-terminal pro brain natriuretic peptide (pg/mL)	Baseline vs 12 months
Changes in high sensitivity troponin T (pg/mL)	We will measure the changes in high sensitivity troponin T (pg/mL)	Baseline vs 12 months

Collaborators and Investigators

• Sponsor: Hospital General Universitario Gregorio Marañon
• Collaborators: Instituto de Salud Carlos III; University of Navarra; Fundación para la Investigación Biomédica del Hospital Gregorio Maranon

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 15, 2021
• Primary Completion (ANTICIPATED): December 30, 2022
• Study Completion (ANTICIPATED): December 30, 2022

Study Registration Dates

• First Submitted: January 15, 2021
• First Submitted That Met QC Criteria: February 1, 2021
• First Posted (ACTUAL): February 4, 2021

Study Record Updates

• Last Update Posted (ACTUAL): February 4, 2021
• Last Update Submitted That Met QC Criteria: February 1, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Heart Failure; Diabetes mellitus
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: FIBHGM-CARDIA-STIFF; 2019-002046-20 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No