Commentary based on Neijenhuis RML, MacDonald ST, Zemrak F, et al. Effect of sodium-glucose cotransporter 2 inhibitors in adults with congenital heart disease. J Am Coll Cardiol 2024;83:1403-14 and Fusco F, Scognamiglio G, Abbate M, et al. Dapagliflozin in patients with a failing systemic right ventricle: results from the DAPA-SERVE trial. JACC Heart Fail 2024;12:789-91.

Neijenhuis et al. and Fusco et al. addressed the safety, tolerability, and outcomes of patients with adult congenital heart disease (ACHD) treated with sodium-glucose cotransporter 2 inhibitors (SGLT2i).

Methods

The results of these two studies describing the use of SGLT2i in patients with ACHD were recently published (Table 1). The first study, by Neijenhuis et al., was a retrospective, multicenter, observational study that evaluated the safety and tolerability of SGLT2i in a variety of patients with ACHD from 2016 to 2023.¹ Heart failure (HF) hospitalizations (comparing 6 months before with 6 months after SGLT2i initiation) were reported.

The second study, by Fusco et al., was a prospective, single-center, randomized, open-label trial of the use of dapagliflozin in adult patients with systemic right ventricles (sRV), including congenitally corrected transposition of the great arteries and D-transposition of the great arteries after atrial switch (Senning or Mustard operations).² Patients were taking optimal medical therapy with angiotensin receptor–neprilysin inhibitors (ARNI) or angiotensin-converting enzyme inhibitors (ACEi) and had evidence of sRV systolic dysfunction with fractional area change (FAC) <35%. After 1 year of follow-up, notable outcomes assessed included medication tolerability, systolic blood pressure (SBP), 6-min walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, glomerular filtration rate (GFR), and measures of sRV function by echocardiography.

Table 1: The Results of Two Recent Studies Describing the Use of SGLT2i in Patients With ACHD

Results

Neijenhuis et al. identified 174 patients (mean age 48 years, 41% female) treated with SGLT2i in the study period (137 with dapagliflozin, 36 with empagliflozin, 1 with canagliflozin). ACHD complexity was variable (Table 1), with 12 patients (6.9%) having univentricular circulation and 59 (33%) having sRV. Most patients (45%) were in New York Heart Association (NYHA) functional class II HF, and 20% had been hospitalized because of HF in the previous year. Notably, at baseline, 82% of patients were taking background HF therapy with an ARNI/ACEi or angiotensin-receptor blocker, 75% with a beta-blocker, 69% with a mineralocorticoid-receptor antagonist, and 71% with a diuretic. SGLT2i adverse effects were reported in 18 patients (10.3%), which led to discontinuation of therapy in 12 patients (6.9%). There were fewer HF hospitalizations (n = 9) in the 6 months after starting SGLT2i than in the 6 months before (n = 36); the relative rate of HF hospitalization was 0.3 (95% confidence interval, 0.14-0.62; p = 0.001).

Fusco et al. randomized 25 patients with sRV (mean age 38 years) to dapagliflozin and 25 patients (mean age 34 years) to placebo, 92% of whom were taking background therapy with ARNI. The investigators found that dapagliflozin was well tolerated without any medication discontinuation. There were no differences between the groups in SBP, NT-proBNP levels, or 6MWD. The investigators reported a slight decrease in GFR in the treatment group (mean 111 vs. 93 mL/min/1.73 m²; p = 0.01), a statistically significant improvement in sRV FAC (mean increase 3.5% vs. 0.13%; p < 0.001), and a statistically significant improvement in sRV free wall global longitudinal strain (mean decrease -1.6% vs. -0.1%; p = 0.0005).

Conclusions

These two studies included 199 patients with ACHD who were treated with SGLT2i, with results showing that the medication is well tolerated, with adverse effect profiles similar to those of patients with acquired HF. Importantly, there is the potential for reduction in HF hospitalizations and improvement in sRV function.

Perspective

HF remains the leading cause of death in the ACHD patient population and is complex, with multiple phenotypes. Although the evidence for SGLT2i in patients with acquired HF is robust, these studies are the largest to date applying this therapy to patients with ACHD.

Although limited by its retrospective nature, the strengths of the study by Neijenhuis et al. included the large sample size (relative to many studies in ACHD) from multiple centers with a diverse cohort of ACHD anatomy and most patients (70%) having at least moderate systemic ventricular dysfunction already treated with background therapy of other HF medications.¹ Although the findings of HF hospitalization reduction must be put into the context of the study design and relatively low number of HF hospitalizations overall, they are a promising signal that, as the investigators noted, warrant further prospective study.

The prospective study by Fusco et al. was focused on a subtype of patients (those with sRV) who are at particularly high risk of HF.^2-4 Notably, the results of earlier studies in this population did not show a significant reduction in hard clinical endpoints with HF medical therapies,⁵ as have been seen in patients with acquired HF. As such, the ACHD guidelines do not endorse specific HF medical therapies.⁶ However, recent studies have had some promising results with ARNIs.^7,8 Although the main positive finding in the study by Fusco et al. was a small but significant improvement in sRV function by echocardiography, a strength of the study was that this improvement occurred in the context of most patients already taking ARNI therapy. In addition, as hypotension can limit HF medical therapy in this population of patients without concomitant hypertension, it is noteworthy that the addition of SGLT2i did not significantly lower SBP. Finally, the reduction in GFR in this study is important to note and should be studied further; even though the clinical significance of this change is unknown, in the context of the known renal benefits of SGLT2i therapy,⁹ this finding should not prevent further use.

Future studies with SGLT2i (and other HF medical therapy) in patients with ACHD should evaluate changes in exercise capacity and invasive hemodynamics and, if possible, use cardiac MRI for evaluation of ventricular function, especially in patients with sRV. However, the results of the study by Neijenhuis et al. confirm what is known in the ACHD community: these medications are being used in this population. Although further prospective, multicenter studies with SGLT2i are needed to show improvement in hard clinical outcomes in patients with ACHD and HF, the results of these two studies provide firm support for the safety of what is already occurring in clinical practice.

References

1. Neijenhuis RML, MacDonald ST, Zemrak F, et al. Effect of sodium-glucose cotransporter 2 inhibitors in adults with congenital heart disease. J Am Coll Cardiol 2024;83:1403-14.
2. Fusco F, Scognamiglio G, Abbate M, et al. Dapagliflozin in patients with a failing systemic right ventricle: results from the DAPA-SERVE trial. JACC Heart Fail 2024;12:789-91.
3. Broberg CS, van Dissel A, Minnier J, et al. Long-term outcomes after atrial switch operation for transposition of the great arteries. J Am Coll Cardiol 2022;80:951-63.
4. van Dissel AC, Opotowsky AR, Burchill LJ, et al. End-stage heart failure in congenitally corrected transposition of the great arteries: a multicentre study. Eur Heart J 2023;44:3278-91.
5. Zaragoza-Macias E, Zaidi AN, Dendukuri N, Marelli A. Medical therapy for systemic right ventricles: a systematic review (part 1) for the 2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:1564-78.
6. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e81-e192.
7. Fusco F, Scognamiglio G, Merola A, et al. Safety and efficacy of sacubitril/valsartan in patients with a failing systemic right ventricle: a prospective single-center study. Circ Heart Fail 2023;16:[ePub ahead of print].
8. Nederend M, Kiès P, Regeer MV, et al. Tolerability and beneficial effects of sacubitril/valsartan on systemic right ventricular failure. Heart 2023;109:1525-32.
9. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al.; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.