Clinical outcomes and safety of SGLT2 inhibitor therapy in patients with a systemic right ventricle and heart failure: a pre-post analysis from the ACHIEVE-SGLT2i registry

Background Sodium-Glucose Cotransporter 2 Inhibitor (SGLT2i) therapy is an established pillar in the management of conventional heart failure (HF). Evidence on its effectiveness in adult congenital heart disease (ACHD) patients and more specifically those with a systemic right ventricle (sRV) is limited. Recent literature suggests a beneficial effect on systolic sRV function, 6MWD performance and self-perceived quality of life, but robust data on the clinical course, heart failure events and neurohumoral biomarkers under SGLT2i treatment are lacking (1-3). Material and methods Patients from 9 ACHD centers in Europe and North America with a sRV and HF who initiated SGLT2i therapy from April 2016 onwards and were enrolled in the ACHIEVE-SGLT2i registry were included. The primary outcome measure was clinical efficacy of SGLT2i, specified as difference in HF-related events within 12 months before and after SGLT2i initiation. A HF-related event was defined as any unscheduled visit with symptoms and/or signs of congestion and requiring escalation of diuretic therapy and/or intravenous diuretics. As secondary outcome measure, longitudinal changes in NT-proBNP levels within 12 months before and after SGLT2i initiation were evaluated. Lastly, safety and tolerability of SGLT2i therapy were investigated. Results A total of 104 sRV patients were included for analysis (mean age 47 ± 9.9 years, 38 (37%) female). The underlying condition was transposition of the great arteries after atrial switch operation (TGA-ASO) in 63 patients (61%; 75% Mustard and 25% Senning) and congenitally corrected TGA (ccTGA) in 41 patients (39%). The majority (62, 82%) of patients had moderately-severely reduced sRV function and 19 (27%) had tricuspid valve regurgitation grade ≥ 3. Median follow-up duration after SGLT2i initiation was 398 days [IQR 190-719], entailing 144 patient-years. Side effects were reported in 10 patients (10%), of whom 5 permanently discontinued therapy. A significant reduction in the HF-related event rate was observed in the 12 months after SGLT2i initiation compared to the 12 months prior (relative rate = 0.21, 95% CI 0.06-0.72, p = 0.01, Figure 1). Comparing the 12 months pre- and post-SGLT2i initiation period, the adjusted geometric mean NT-proBNP value decreased from 796 to 550 ng/L under SGLT2i, corresponding to a 31% reduction (exp(β) = 0.69, 95% CI 0.58-0.83, p < 0.001). Conclusion SGLT2i therapy seems to be well tolerated by sRV patients with comparable side-effects and discontinuation rates to conventional HF patients. SGLT2i therapy was associated with a 79% reduction in HF events in the year after SGLT2i therapy initiation compared to the year prior, accompanied by a mean 31% reduction in NT-proBNP levels. These results further support the uptake of SGLT2i therapy in the management of sRV patients.