Clinical trial NCT04739215: Effects of SGLT2 Inhibition on the Mechanisms of Cardiac Damage in the Diabetic Patient With HFpEF
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
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Heart Failure With Preserved Ejection Fraction
Keywords: Diabetes mellitus
Heart Failure
Lead sponsor: Hospital General Universitario Gregorio Marañon
Sponsor class: OTHER
Collaborators: name: University of Navarra
name: Instituto de Salud Carlos III
name: Fundación para la Investigación Biomédica del Hospital Gregorio Maranon
First posted: 2021-02-04
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: 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.
timeFrame: Baseline vs 12 months
measure: Main Structural Objective: Changes in serum levels of procollagen type I C-terminal propertied (PICP, ng/mL)
timeFrame: Baseline vs 12 months
Secondary outcomes:
measure: Changes in LV stiffness constants (S+ and S-).
timeFrame: Baseline vs 12 months
measure: Changes in the slope, Emax, of the end-systolic pressure-volume relationship
timeFrame: Baseline vs 12 months
measure: Impact of iSGLT2 on myocardial remodeling.
timeFrame: Baseline vs 12 months
measure: Correlation of myocardial remodeling patterns with the intrinsic diastolic properties of chamber VI with systolic function.
timeFrame: Baseline vs 12 months
measure: Relative contribution of the intrinsic diastolic properties of the LV and the flow patterns on filling pressures and their modulation under treatment with iSGLT2.
timeFrame: Baseline vs 12 months
measure: Changes in serum levels of collagen type I C-terminal telopeptide to matrix metalloproteinase ratio (CITP:MMP-1)
timeFrame: Baseline vs 12 months
measure: Changes in N-terminal pro brain natriuretic peptide (pg/mL)
timeFrame: Baseline vs 12 months
measure: Changes in high sensitivity troponin T (pg/mL)
timeFrame: Baseline vs 12 months
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
Study officials:
affiliation: Hospital General Universitario Gregorio Marañón
name: Javier Bermejo Thomas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.