Rationale and design of the Biventricular Evaluation of Gliflozins effects In chroNic Heart Failure: BEGIN‐HF study

Abstract

Aims

Sodium‐glucose cotransporter type 2 inhibitors (SGLT‐2i) represent a unique class of anti‐hyperglycaemic agents for type 2 diabetes mellitus that selectively inhibit renal glucose reabsorption, thereby increasing urinary excretion of glucose. Several studies have demonstrated the cardioprotective effects of SGLT‐2i in patients with heart failure (HF), unrelated to its glucosuric effect. It is unclear whether the benefits of SGLT‐2i therapy also rely on the improvement of left ventricular (LV) and/or right ventricular (RV) function in patients with HF. This study aimed to evaluate the effect of SGLT‐2i on LV and RV function through conventional and advanced echocardiographic parameters with a special focus on RV function in patients with HF.

Methods and results

The Biventricular Evaluation of Gliflozins effects In chroNic Heart Failure (BEGIN‐HF) study is an international multicentre, prospective study that will evaluate the effect of SGLT‐2i on echocardiographic parameters of myocardial function in patients with chronic stable HF across the left ventricular ejection fraction (LVEF) spectrum. Patients with New York Heart Association Class II/III symptoms, estimated glomerular filtration rate > 25 mL/min/1.73 m², age > 18 years, and those who were not previously treated with SGLT‐2i will be included. All patients will undergo conventional, tissue‐derived imaging (TDI), and strain echocardiography in an ambulatory setting, at time of enrolment and after 6 months of SGLT‐2i therapy. The primary endpoint is the change in LV function as assessed by conventional, TDI, and myocardial deformation speckle tracking parameters. Secondary outcomes include changes in RV and left atrial function as assessed by conventional and deformation speckle tracking echocardiography. Univariate and multivariate analyses will be performed to identify predictors associated with primary and secondary endpoints.

Conclusions

The BEGIN‐HF will determine whether SGLT‐2i therapy improves LV and/or RV function by conventional and advanced echocardiography in patients with HF irrespective of LVEF.

Introduction

Heart failure (HF) is becoming an increasingly important public health affecting ~26 million people globally and is associated with significant morbidity and mortality.¹ The prognosis of HF is poor with a mean 5 year survival rate of ~50–60% that is worse than some types of formidable cancers.² Drugs that act on the neurohumoral and haemodynamic modulation in HF reach an early therapeutic plateau, with limited additional advantage from incremental doses or addition of drugs to existing regimen that act on the same pathway. Hence, there has been a keen interest in the development of drugs for HF that focus on additional targets, such as cardiomyocyte structure and intracellular metabolism.³

Sodium-glucose cotransporter type 2 inhibitors (SGLT-2i, also known as ‘gliflozins’) represent an established class of anti-hyperglycaemic agents for type 2 diabetes mellitus (T2DM), which act independently of insulin to selectively inhibit renal glucose reabsorption, thereby enhancing excretion of glucose in urine.⁴ Interestingly, trials evaluating cardiovascular risk profile of SGLT-2i in T2DM management reported a significant reduction in adverse cardiovascular events. The EMPA-REG OUTCOME (The Empagliflozin. Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients Removing Excess Glucose) study was the first trial that demonstrated significant reduction in adverse cardiovascular outcomes with empagliflozin in patients with T2DM. Of note, HF hospitalizations were reduced by 35% by empagliflozin compared with placebo. The impressive reduction in HF hospitalizations drew the attention of the scientific community towards the possibility that pharmacological inhibition of SGLT2 receptor may have a role in HF therapy, irrespective of its effect on glycaemic control.⁵ Similar findings were reported in patients with T2DM in two other large, randomized placebo-controlled trials, the CANVAS⁶ Program (Canagliflozin Cardiovascular Assessment Study) and the DECLARE-TIMI 58 trial⁷ (Dapagliflozin Effect on Cardiovascular Events) with canagliflozin and dapagliflozin, respectively. These findings were subsequently reproduced in the DAPA-HF⁸ (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced⁹ (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) that reported a significant reduction in the primary composite outcome of HF hospitalizations and cardiovascular mortality with SGLT-2i in patients with HF with reduced ejection fraction (HFrEF) irrespective of patient's diabetes status. These findings were replicated in HF with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) trial that reported a significant reduction in the primary composite outcome of HF hospitalizations and cardiovascular mortality. Although several hypotheses have been proposed,^10,11 the biological mechanisms through which SGLT-2i reduce HF hospitalizations remain unclear.¹² Clinical studies have been conducted to evaluate the effect of SGLT-2i on left ventricular (LV) structure and function.^13,14 However, current available data and evidence are limited and even fewer data are available on the effects of gliflozins on right ventricular (RV) function.

We sought to evaluate the effect of SGLT-2i on LV and RV function and on left atrial (LA) function in HF, evaluating the modification of conventional and advanced echocardiographic parameters, focusing on speckle tracking echocardiography and the study of RV function.

Study design

Overall study design

The Biventricular Evaluation of Gliflozins effects In chroNic Heart Failure (BEGIN-HF) study is an international multicentre prospective observational study that will enrol outpatients diagnosed with HF and starting treatment with SGLT-2i in addition to guideline-directed medical therapy, as per clinical indication. The study will be conducted in the following HF centres: Spedali Civili Brescia, Italy; Foggia University Hospital, Italy; Bari University Hospital, Italy; Di Lorenzo Clinic, Avezzano, Italy; Santa Maria della Misericordia Hospital, Perugia, Italy; Pulse Heart Institute, Spokane, WA; Emergency Institute for Cardiovascular Diseases ‘C.C. Iliescu’, Bucharest, Romania; and Charité Universitäts Medizin, Berlin, Germany. A multidisciplinary team of researchers with expertise in cardiovascular diseases, endocrinology, and echocardiography has been assembled at all these centres. Each centre had at least one echocardiographic physician with expertise in strain analysis evaluation and echocardiographic scientific society certification.

The protocol has been approved by Brescia Spedali Civili Hospital Institutional Review Board. Signed informed consent will be obtained from all participants.

Participant inclusion and exclusion criteria

All patients aged >18 years with a diagnosis of HF (defined as clinical syndrome consisting of symptoms as breathlessness, ankle swelling, and fatigue, usually accompanied by signs as elevated jugular venous pressure, pulmonary crackles, and peripheral oedema due to a structural and/or functional abnormality of the heart that results in elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise) irrespective of left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (Modification of Diet in Renal Disease) > 25 mL/min/1.73 m², and New York Heart Association (NYHA) Class II, III, and IV symptoms will be included. Patients with a history of hypersensitivity/allergy or suspected contraindication to SGLT-2i, type 1 diabetes mellitus, restrictive cardiomyopathy, constrictive pericarditis, obstructive hypertrophic cardiomyopathy, active myocarditis, active urinary tract infection, recent (<12 weeks) valvular surgery, recent (<12 weeks) acute coronary syndrome, coronary revascularization, or cardiac resynchronization therapy (CRT), recent (<12 weeks) stroke or transient ischaemic attack, scheduled coronary revascularization, valvular surgery or CRT placement, and HF related to pulmonary hypertension, especially group I (pulmonary arterial hypertension) and group III PH (PH due to lung disease), and patients with a paced rhythm, anaemia (haemoglobin level below 10 g/dL), and poor acoustic windows on echocardiography will be excluded.

Heart valve disease of any degree of severity secondary to HF (such as mitral regurgitation and tricuspid regurgitation) will not represent an exclusion criterion due to the high prevalence in HF population.

Baseline patient characteristics

At enrolment (Figure 1), the following baseline characteristics of study participants will be collected from electronic/paper medical records: weight and height [with calculation of body mass index (kg/m²) and body surface area (m²)], previous implantation of cardiac devices, cardiovascular risk factors (i.e. arterial hypertension, T2DM, dyslipidaemia, and current or previous smoking habit), history of ischaemic heart disease or atrial fibrillation, NYHA class, current background medical therapy [angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitor, beta-blockers, mineralocorticoid receptor antagonists, diuretics, oral anticoagulants, etc.], comprehensive cardiovascular physical examination, systolic and diastolic blood pressure, heart rate, and laboratory tests [including brain natriuretic peptide (BNP) or N-terminal proBNP, serum creatinine, serum glucose, baseline haemoglobin A1c, C-reactive protein, and erythrocyte sedimentation rate]. A comprehensive echocardiogram will be performed at enrolment (see sections Echocardiography and Speckle tracking strain analysis for global longitudinal strain) and a repeat echocardiographic evaluation will be carried out at 6 months (Figure 1) (with an optional additional revaluation at 12 months). Any hospitalizations, all-cause mortality, or cardiovascular death will be recorded during follow-up. After enrolment, a direct clinical follow-up will be performed every 2 months. Clinical follow-up will be anticipated in the case of occurrence of acute HF. Therapeutic adherence will be documented by telephone follow-up at regular interval (every 3 weeks).

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Patients lost prior to follow-up echocardiographic evaluation, or those who underwent cardiac surgery, coronary, or mitral interventions before follow-up re-evaluation, will be excluded from final analysis. Patients with incomplete/missing follow-up data will also be excluded (Table 1).

Table 1 Patients' eligibility criteria

Key inclusion criteria	Key exclusion criteria
Heart failure irrespective of LVEF	History of hypersensitivity/allergy or suspected contraindication to SGLT-2i
NYHA Class II, III, IV	Type 1 diabetes mellitus
Estimated glomerular filtration rate (Modification of Diet in Renal Disease) > 25 mL/min/1.73 m2	History of cardiomyopathy: restrictive, hypertrophic
Age > 18 years, signing informed consent	Constrictive pericarditis
	Active myocarditis
	Active urinary tract infection
	Recent (in the previous 12 weeks) valvular surgery or acute coronary syndromes or coronary revascularization or cardiac resynchronization therapy (CRT) or TIA/stroke
	Scheduled coronary revascularization, valvular surgery, or CRT
	Poor acoustic windows

Endpoints

The primary endpoint of this study is the change in LV systolic and diastolic function from baseline at 6 months, evaluated by conventional and advanced echocardiographic parameters (speckle tracking echocardiography) (Table 2). Secondary endpoints include clinical and laboratory predictors of LV systolic or diastolic function and changes in LA and RV systolic function.

Table 2 Primary and secondary endpoints being investigated in the study

Endpoint
Primary endpoint
Improvement of Left ventricular systolic or diastolic function Evaluated by conventional and advanced echocardiographic parameters (speckle tracking echocardiography)
Secondary endpoint
Identifying clinical and laboratory predictors of Left ventricular systolic or diastolic function improvement Left atrial function improvement Right ventricular systolic function

Procedures involved in the study

Echocardiography

Conventional echocardiography will be used to assess LV dimensions and LVEF, trans-mitral early (E) and late diastolic (A) LV filling peak velocities, and the ratio of trans-mitral early to late (E/A ratio) LV filling velocity. LV dimensions and LVEF will be calculated according to recommendations from the joint ASE/ESC (American Society of Echocardiography/European Society of Cardiology) guidelines.¹⁵ LVEF will be calculated using Simpson's method¹⁵ and when available using three-dimensional (3D) echocardiography (3DE). Nevertheless, given the local availability and the nature of the study, mostly based on overall changes in cardiac structure and function (including strain imaging), 3DE was not considered mandatory.

LA volumes [maximal (V_max) and minimal (V_min)] will be measured using biplane method of discs from standard apical two- and four-chamber views at end systole (LAESVi) and end diastole (LAEDVi). LA ejection fraction (LAEF) will be calculated using the following formula: (V_max − V_min)/V_max × 100.^16,17

Pulsed Doppler mitral inflow velocities will be obtained by placing a 2–4 mm sample volume between the tips of the mitral leaflets in the apical four-chamber view. The Doppler beam will be aligned parallel to the flow direction. Tissue-derived imaging (TDI) measurements will be recorded at the septal and lateral mitral annulus in the apical four-chamber view and early (E′) diastolic velocities will be measured. The trans-mitral to mitral annular early diastolic velocity ratio (E/E′) will be also calculated. RV function will be assessed using tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (FAC) [calculated as (RV end-diastolic area − RV end-systolic area)/RV end-diastolic area], and tissue Doppler-based tricuspid annular peak systolic velocity. Pulmonary artery systolic pressures (PASP) will be estimated by calculating the systolic pressure gradient between RV and RA at the maximum velocity of the tricuspid regurgitant (TR) jet, using the modified Bernoulli equation, and then adding to this value the estimated RA pressures based on the size of the inferior vena cava and the change in its calibre with respiration. The peak tricuspid regurgitation velocity (TRV) will be assessed by placing a continuous Doppler across the tricuspid valve and the degree of TR will be evaluated using the colour mode. The TAPSE/PASP ratio, a variable reflecting the RV–pulmonary artery haemodynamic coupling, will be calculated. Mean pulmonary artery pressure (PAP) will be calculated based on the TRV–time integral as previously validated.¹⁸ Pulmonary vascular resistance (PVR) will be estimated using the following equation: 10 × TRV/velocity time integral (VTI) of the RV outflow tract.¹⁹ Pulmonary artery diastolic pressure will be calculated by the sum of diastolic velocity of the pulmonary valve assessed by the continuous Doppler and the estimated RA pressure. All echocardiographic studies will be interpreted by experienced physicians.

Speckle tracking strain analysis for global longitudinal strain

Speckle tracking strain analysis will be performed for each patient with the aid of a dedicated software (TOMTEC) that evaluates LV, RV, and LA function. Briefly, apical four-chamber, two-chamber, and long-axis views will be uploaded onto a personal computer for offline analysis using the Digital Imaging and Communications in Medicine (DICOM) software. From two-dimensional apical four-, two-, and three-chamber images, LV speckle tracking strain will be calculated applying an automated contouring detection algorithm on regions of interest with application manual adjustments where necessary. Global longitudinal strain (GLS) will be determined by calculating the average of 16 LV segments longitudinal strain peaks and will be expressed as an absolute value in accordance with current guidelines.¹⁵ From two-dimensional apical four-chamber images, longitudinal strain for the RV will be reported for the free RV wall (RVFW-LS) and the global four-chamber contour (RV-4Ch-LS) and will also be expressed as an absolute value in accordance with current guidelines. RV modified view will be obtained by angling the sound beam laterally, towards the patient's left shoulder. LA longitudinal strain will be calculated as the average LA strain in six segments. LASr or peak atrial longitudinal strain (PALS), LA conduit strain (LAScd), and LA contraction strain (LASct) or PACS will be used to represent the LA strain during the reservoir, conduit, and contraction phases, respectively.^20,21

Three-dimensional echocardiography

3DE datasets of the LV will be obtained from the apical approach using multi-beat full-volume acquisition during breath-holding and taking care to encompass the entire LV cavity in the dataset. 3D LV volumes and ejection fraction (EF) will be measured offline by a single experienced operator using a dedicated software package for the LV analysis. Measurement workflow will be started with the semi-automated detection of the LV endocardial borders. Manual editing will be used to optimize the endocardial contour identification. To trace the endocardial borders of both the two-dimensional echocardiography (2DE) and 3DE datasets, the end-diastolic frame will be selected as the frame before the mitral valve closure; instead, the end-systolic frame will be identified as the frame before mitral valve opening.

Each centre had at least one echocardiographic physician with expertise in strain analysis evaluation and echocardiographic scientific society certification.

Statistical analysis and sample size

Normality of distributions will be assessed using the Kolmogorov–Smirnov test. Categorical variables will be presented as frequencies or percentages and compared using χ² and Fisher's exact test, as appropriate. Associations of the crosstabs will be verified using standardized adjusted residuals. Continuous variables will be presented as mean ± standard deviation (in case of a normal distribution) or median with interquartile range and min/max (for skewed distributions). Means will be compared using Student's t-test or Wilcoxon's test for matched pairs, and correlations among variables will be examined using Pearson's or Spearman's rank correlation test. Cox multivariable regression analysis, including all variables with P < 0.05 in the Cox univariate analysis, will be used to determine the predictive factors of mortality. A two-sided α level of 0.05 will be used for all statistical tests. GPower® software Version 3.1 was used to calculate the sample size. The cut-off of a conserved LVEF is 40% and an improvement to 45% was approximated as a mean; the standard deviation of Group 1 (baseline) was assumed to be 25 and that of Group 2 (at T1) was 30. The correlation between groups is hypothesized to be 0.5. With a calculated effect size of 0.179, the total sample size results to be of 194 patients. The authors will have full access to and will take complete responsibility of the integrity of the data.

Discussion

There is a growing interest in the development of new drugs for HF therapy that are focused on additional biomolecular targets, which affirms the notion that pharmacological research does not have to stop at already proven haemodynamic effects of new drugs. This has also led to a greater emphasis on the effect of HF drug therapies on pre-specified cardiovascular endpoints.

The significant reduction in HF events with SGLT-2i in T2DM^5,6 and in HF regardless of the presence of T2DM when treated with gliflozins led to a designation of Class I recommendation for HFrEF and Class 2a recommendation for HFpEF by the AHA/ACC/HFSA (American Heart Association/American College of Cardiology/Heart Failure Society of America) Guideline Recommendations 2022.²² Dapagliflozin was the first SGLT-2i to receive US Food and Drug Administration (FDA) approval for treatment of HF, to reduce the risk of cardiovascular death and hospitalization for HF in adults with HFrEF in 2019 followed by empagliflozin in 2021. The evidence to explain these cardioprotective effects of SGLT-2i is progressively growing, but the exact biomolecular mechanism is still unknown. Several experimental and clinical studies have been conducted to better understand these mechanisms. Some studies have suggested that SGLT-2i may reduce oxidative stress²³ with resultant improvement in endothelial dysfunction,²⁴ which may partially explain its cardioprotective effects. Li et al. reported that empagliflozin ameliorates myocardial fibrosis through inhibition of collagen formation and deposition via the transforming growth factor-β/Smad pathway, and reduction in oxidative stress in mice with T2DM, which translated to improved LV structure and function within 8 weeks of therapy.²⁵ Connelly et al. reported that load-independent measures of cardiac contractility, preload recruitable stroke work, and the end-systolic pressure–volume relationship were higher in rats that received empagliflozin after myocardial infarction.²⁶ Furthermore, Shi et al. revealed that dapagliflozin exerted a cardioprotective effect by improving LV systolic function through inhibition of myocardial fibrosis and cardiomyocyte apoptosis in a TAC (transverse aortic constriction) mouse model.²⁷

There is also a considerable interest in structural and functional myocardial changes associated with SGLT-2i therapy. In the DAPA-LVH (Does Dapagliflozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes?) trial, dapagliflozin treatment significantly reduces LV mass compared with placebo in patients with T2DM.²⁸ In contrast, the REFORM (Dapagliflozin Versus Placebo on Left Ventricular Remodeling in Patients With Diabetes and Heart Failure) trial reported that 1 year of dapagliflozin therapy did not reverse LV remodelling based on serial cardiac magnetic resonance (CMR) assessment.²⁹ The SUGAR-DM-HF (Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure) trial reported that empagliflozin therapy for 36 weeks in patients with HFrEF conferred a significant reduction in LV volumes (LVESVi and LVEDVi) compared with placebo but did not find a significant improvement in LV GLS on CMR assessment.³⁰ The likely explanation of these conflicting results may be attributed to a better risk profile of patients enrolled in the REFORM study compared with those enrolled in SUGAR-DM-HF in terms of LVEF (45.5% in REFORM vs. 32.5% in SUGAR-DM-HF), NYHA class distribution (45% with NYHA Class 1 symptoms in REFORM vs. 0% in SUGAR-DM-HF), and baseline LV volumes (mean LVESVi, 52 mL/m² in REFORM vs. 77 mL/m² in SUGAR-DM-HF). Additionally, the small sample size in REFORM (n = 56) compared with SUGAR-DM-HF (n = 105) likely underpowered the trial to detect a statistically significant difference. The EMPA-HEART CardioLink-6 (Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease) trial reported a significant reduction in LV mass after 6 months based on CMR assessment.³¹ Verma et al. also reported a significant reduction in LV mass index and improvement in diastolic function in a systematic analysis of 10 subjects with T2DM and established cardiovascular disease after 3 months of empagliflozin therapy.³² Furthermore, a small randomized study reported that empagliflozin use was associated with modest reductions in LV and LA volumes with no significant changes in LVEF.³³ More recently, in the EMPA-TROPISM (ATRU-4) (Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction) trial of 84 participants, empagliflozin use in non-diabetic patients with HFrEF for 6 months significantly improved LV volumes, LV mass, and systolic function assessed by CMR compared with placebo.³⁴ Based on these results, we have designed a large international, multicentre, prospective study that aims to assess the effect of SGLT-2i on LV and RV function assessed by both conventional echocardiography and speckle tracking echocardiography. Several baseline characteristics of study participants will be collected from electronic/paper medical records and the study will allow to distinguish the effect of SGLT-2i in different subpopulations (such as ischaemic vs. non-ischaemic; diabetics vs. non-diabetics; or according to EF classification).

To our knowledge, this is the first international prospective study that will assess changes in biventricular function with empagliflozin use in patients with HF on SGLT-2i therapy in a routine healthcare setting.

The BEGIN-HF study will specifically investigate the effects of SGLT-2i in a real-world scenario on LV, LA, and RV function in patients with HF. The results of this study will comprehensively demonstrate biventricular structural changes induced by gliflozins on cardiac remodelling and ventricular function. This in turn will help develop a better understanding of underlying mechanistic effects of gliflozins responsible for improving cardiovascular outcomes in HF.

Conflict of interest

E.-L.A. received speaker fees from AstraZeneca and Boehringer Ingelheim. J.B. is a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor.

Funding

No funding.

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