Das BB, Niu J.Am J Cardiovasc Drugs. 2025 Mar;25(2):231-240. doi: 10.1007/s40256-024-00697-7. Epub 2024 Dec 2.PMID: 39621203
Commentary By:
Dr. Yonatan Buber (Seattle, USA), chief section editor of ACHD Journal
Introduction
Given that SGLT2 inhibitors (SGLT2is) have become a first-line treatment for heart failure in the general adult population, this research aims to evaluate their safety and effectiveness when added to standard heart failure medications specifically in the limited-studied ACHD HF population. The study seeked to understand if SGLT2is can improve outcomes such as NYHA functional class and NT-proBNP levels in ACHD patients
Study Design:
This was a systematic review and meta-analysis study. The researchers conducted a comprehensive systematic search of databases including PubMed, Scopus, and Embase up to April 30, 2024, to identify publications on the role of SGLT2 inhibitors in chronic heart failure in ACHD . The inclusion criteria were patients aged ≥ 18 years with chronic heart failure with reduced ejection fraction due to congenital heart disease who received SGLT2 inhibitors in addition to standard heart failure therapy2 . Studies on decompensated heart failure and heart failure with preserved ejection fraction (HFpEF) were excluded.
The primary outcome was the change in the New York Heart Association (NYHA) functional class, and secondary outcomes included changes in ventricular function and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, as well as safety and tolerability.
Main findings and take-home Points:
- SGLT2 inhibitors (SGLT2is) appear to be well-tolerated in adult congenital heart disease (ACHD) patients with heart failure (HF). The adverse effect profile observed was comparable to that seen in routine HF patients, with urinary tract infections occurring in 5% of patients and medication withdrawal due to adverse effects in 7%1 . No instances of hypoglycemia or ketoacidosis were reported in this study.
- Adding SGLT2is to guideline-directed medical therapy (GDMT) significantly improved the New York Heart Association (NYHA) functional class (FC) in ACHD HF patients. This improvement was consistent across the included studies.
- SGLT2is significantly reduced N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in ACHD HF patients. This reduction is strongly linked to the observed clinical benefits and serves as an indicator of improvement in heart failure with reduced ejection fraction (HFrEF).
- A notable decrease in systolic blood pressure was observed with SGLT2i therapy in this patient population. While this reduction was statistically significant, the clinical significance of this change remains unclear
- The study found no significant overall effect of SGLT2is on serum creatinine (Cr) levels, although some individual studies reported an initial increase
- Despite these encouraging findings, the evidence is primarily based on retrospective studies with limited sample sizes, highlighting the need for further prospective, multicenter studies to confirm the safety and efficacy of SGLT2is in this unique patient population and to evaluate long-term outcomes such as reduced hospitalizations and mortality
- The heterogeneity of ACHD-related HF, including variations in ventricular morphology (systemic right ventricle, systemic left ventricle, single ventricle), poses challenges for conducting large clinical trials1
- The findings suggest that SGLT2is could be a beneficial addition to the treatment regimen for ACHD HF patients, potentially improving heart function and reducing hospitalizations.
- The study emphasizes that while GDMT strategies are often applied to treat HF in ACHD patients, there is a lack of definitive evidence supporting their efficacy compared to adult HF due to acquired heart diseases This meta-analysis provides initial support for the use of SGLT2is in this context
- The baseline use of angiotensin receptor–neprilysin inhibitors (ARNIs) was low among the studied ACHD HF patients
The main strengths of the study include:
- The researchers performed a meta-analysis of the included studies, which allowed them to quantitatively evaluate the effects of SGLT2is on key outcomes like NYHA functional class and NT-proBNP levels
- The study not only evaluated the efficacy of SGLT2is but also specifically assessed their safety and tolerability in ACHD HF patients by examining adverse effects, including changes in blood pressure, renal function markers, and the incidence of urinary tract infections, hypoglycemia, and ketoacidosis
- Focus on clinically relevant outcomes such as the New York Heart Association (NYHA) functional class and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, which are commonly used to assess heart failure severity and response to treatment
- Comparison to General HF Population: The study draws comparisons between the safety and tolerability profile of SGLT2is in ACHD HF patients and that reported in major clinical trials for the general adult HF population.
Some of the important limitations of the study include:
- The meta-analysis predominantly comprised retrospective studies with limited sample
- There was a considerable diversity in CHD types and HF severity. This heterogeneity makes it challenging to draw universal conclusions for all ACHD HF patients.
- Selection bias due to the absence of uniform echocardiographic parameters for determining ventricular dysfunction across the heterogeneous types of ACHD . This lack of standardization could affect the assessment of ventricular function improvement .
- There was no uniform reporting of whether changes in SBP and Cr/eGFR levels were clinically significant. This makes it difficult to interpret the practical implications of these observed changes.
- The ACHD patient data varied significantly, with gaps in information about the age at initial CHD repair, residual anatomical defects, surgical history, residual valvular issues, and other health conditions. This lack of detailed patient-level data could limit the ability to fully understand the factors influencing the response to SGLT2i treatment2 .
- The impact of comorbidities, in addition to diabetes, on the response to SGLT2i treatment remains uncertain. The study could not fully account for the influence of other coexisting conditions on the outcomes.
Summary and conclusion:
This systematic review and meta-analysis suggest that incorporating SGLT2 inhibitors into the existing combination therapy for ACHD patients with chronic heart failure significantly improves their New York Heart Association functional class. The study also found a notable reduction in NT-proBNP levels in these patients following SGLT2i therapy. Furthermore, the safety profile of SGLT2is in this unique population appeared to be comparable to that observed in the general adult HF population.
However, the authors emphasize that these encouraging preliminary results are primarily based on retrospective studies with limited sample sizes and significant heterogeneity in CHD types and HF severity. Methodological limitations in the included studies, such as the lack of uniform echocardiographic parameters and limited blinding, also warrant consideration. While a decrease in systolic blood pressure was a common side effect, its clinical significance remains unclear.Therefore, while the findings indicate that SGLT2is may be a beneficial addition to the treatment regimen for ACHD HF patients, potentially improving symptoms and surrogate markers of heart failure1 …, the authors strongly advocate for further large-scale prospective studies to definitively confirm the long-term safety and efficacy of SGLT2is in this growing patient population. Such research is needed to thoroughly evaluate the effects of SGLT2is on crucial clinical outcomes like hospitalization and mortality in ACHD-related HF
